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Winston Crasto
Janet Jarvis
Melanie J. Davies
Handbook of
Insulin Therapies
Handbook of Insulin
Therapies
Winston Crasto Janet Jarvis
Melanie J. Davies
Handbook of Insulin
Therapies
Winston Crasto Melanie J. Davies
George Eliot Hospital NHS Leicester Diabetes Centre
Trust, Nuneaton Leicester General Hospital
United Kingdom Leicester
United Kingdom
Janet Jarvis
Leicester Diabetes Centre
Leicester General Hospital
Leicester
United Kingdom
ISBN 978-3-319-10938-1 ISBN 978-3-319-10939-8 (eBook)

DOI 10.1007/978-3-319-10939-8
Library of Congress Control Number: 2016946349
Springer International Publishing Switzerland 2016

This work is subject to copyright. All rights are reserved by the Publisher,
whether the whole or part of the material is concerned, specifically the rights of
translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduc-
tion on microfilms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or
dissimilar methodology now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service
marks, etc. in this publication does not imply, even in the absence of a specific
statement, that such names are exempt from the relevant protective laws and
regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and
information in this book are believed to be true and accurate at the date of pub-
lication. Neither the publisher nor the authors or the editors give a warranty,
express or implied, with respect to the material contained herein or for any errors
or omissions that may have been made.
Printed on acid-free paper
This Adis imprint is published by Springer Nature

The registered company is Springer International Publishing AG Switzerland
This book is dedicated to the people
living with diabetes, their families,
friends and carers and to those who
work tirelessly to support, deliver
and improve care for people with
diabetes.
Winston Crasto
Janet Jarvis
Melanie J. Davies
Contents
1 Introduction to Insulin Therapies . . . . . . . . . . . . . . . . . 1

1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.3 The Global Burden of Diabetes . . . . . . . . . . . . . . 4
1.4 The Human Insulin Molecule . . . . . . . . . . . . . . . . 5
1.4.1 Effect of Insulin on Metabolism . . . . . . . . . 6
1.5 History of Insulin Therapy . . . . . . . . . . . . . . . . . . . 8
1.5.1 The New Era of Insulin Therapies . . . . . . 10
1.5.2 Insulin Management: Combining
Art with Science . . . . . . . . . . . . . . . . . . . . . . 11
1.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2 Existing Insulin Therapies . . . . . . . . . . . . . . . . . . . . . . . 15
2.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.2 Animal Insulin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.3 Human Recombinant Insulin . . . . . . . . . . . . . . . . . 19
2.3.1 U-500 Insulin . . . . . . . . . . . . . . . . . . . . . . . . . 20
2.3.2 Animal Versus Human Insulin . . . . . . . . . . 20
2.4 Insulin Analogs . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.4.1 Rapid-Acting Analogs . . . . . . . . . . . . . . . . . 24
2.4.2 Long-Acting Insulin Analogs . . . . . . . . . . . 25
2.4.3 Premixed Insulin . . . . . . . . . . . . . . . . . . . . . . 44
2.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
3 Emerging Insulin Therapies . . . . . . . . . . . . . . . . . . . . . . 55
3.1 Injectable Insulin Products . . . . . . . . . . . . . . . . . . . 55
3.1.1 Ultra-Rapid-Acting Insulin . . . . . . . . . . . . . 55
vii
viii Contents
3.1.2 Long-Acting Basal Insulin Peglispro . . . . . 55

3.1.3 Glargine U300 Insulin . . . . . . . . . . . . . . . . . 59
3.1.4 Fixed Ratio Combinations . . . . . . . . . . . . . . 60
3.2 Non-injectable Insulin Products . . . . . . . . . . . . . . 64
3.2.1 Inhaled Insulin . . . . . . . . . . . . . . . . . . . . . . . 64
3.2.2 Oral Insulin . . . . . . . . . . . . . . . . . . . . . . . . . . 65
3.2.3 Buccal Insulin . . . . . . . . . . . . . . . . . . . . . . . . 70
3.3 Biosimilar Insulin. . . . . . . . . . . . . . . . . . . . . . . . . . . 71
3.4 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 76
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 82
4 Insulin Management in Type 2 Diabetes . . . . . . . . . . . 83
4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83
4.2 Insulin Therapy in Type 2 Diabetes . . . . . . . . . . . . 84
4.2.1 Factors Impacting on Insulin
Initiation and Clinical Inertia . . . . . . . . . . . 85
4.2.2 Patient Education . . . . . . . . . . . . . . . . . . . . . 86
4.2.3 Early Use of Insulin
in Type 2 Diabetes. . . . . . . . . . . . . . . . . . . . . 88
4.3 Insulin Regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
4.3.1 Basal Insulin Regimen . . . . . . . . . . . . . . . . . 93
4.3.2 Combination Therapy with
Conventional Oral
Glucose-Lowering Agents . . . . . . . . . . . . . . 93
4.3.3 Combination Therapy with Newer
Classes of Glucose-Lowering Agents . . . . 102
4.3.4 Basal-Plus Insulin Regimen . . . . . . . . . . . . . 107
4.3.5 Twice-Daily Premixed Insulin Regimen . . . 111
4.3.6 Prandial-Only Insulin Regimen . . . . . . . . . 113
4.3.7 BasalBolus Insulin Regimen . . . . . . . . . . . 118
4.4 Intensifying Insulin Therapy with
Inadequately Controlled Type 2 Diabetes . . . . . . 123
4.5 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .131
5 Insulin Management in Type 1 Diabetes . . . . . . . . . . . 133
5.1 Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
5.2 The Benefits of Tight Glycemic Control
in Type 1 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . 134
Contents ix
5.2.1 Adherence to Insulin Therapy

in Individuals with T1DM . . . . . . . . . . . . . . 136
5.2.2 Role of Continuous Glucose
Monitoring for Intensive
Insulin Therapy . . . . . . . . . . . . . . . . . . . . . . . 136
5.2.3 Sensor-Augmented Insulin
Pump Therapy . . . . . . . . . . . . . . . . . . . . . . . . 137
5.3 Insulin Regimens in Type 1 Diabetes . . . . . . . . . . 139
5.3.1 Conventional Insulin Regimen . . . . . . . . . . 140
5.3.2 Multiple-Daily Injections or
BasalBolus Insulin Regimen . . . . . . . . . . . 144
5.4 Continuous Subcutaneous Insulin
Infusion or Insulin Pump Therapy. . . . . . . . . . . . . 146
5.4.1 Determining Appropriateness
and Indications of CSII Therapy . . . . . . . . . 148
5.5 Technological Advances in Insulin
Pump Therapy: Moving Close
to the Artificial Pancreas . . . . . . . . . . . . . . . . . . . . 149
5.5.1 Non-closed-Loop Systems
(First Generation) . . . . . . . . . . . . . . . . . . . . . 154
5.5.2 Predictive Low-Glucose Management
System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
5.5.3 Closed-Loop Control Systems
(Second Generation) . . . . . . . . . . . . . . . . . . 158
5.5.4 Third-Generation APD Systems . . . . . . . . . 160
5.6 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167
6 Practical Aspects of Insulin Therapy . . . . . . . . . . . . . . 169
6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169
6.2 Insulin Injection Practices in Diabetes . . . . . . . . . 170
6.3 Insulin Initiation . . . . . . . . . . . . . . . . . . . . . . . . . . . 170
6.3.1 Verification . . . . . . . . . . . . . . . . . . . . . . . . . . 171
6.3.2 Storage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
6.3.3 Injection Technique and Administration . . . 172
6.3.4 Common Problems Encountered
with Insulin Injections . . . . . . . . . . . . . . . . . 177
6.4 Insulin Delivery Devices. . . . . . . . . . . . . . . . . . . . . 181
6.4.1 Insulin Syringes . . . . . . . . . . . . . . . . . . . . . . . 181
x Contents
6.4.2 Insulin Pens . . . . . . . . . . . . . . . . . . . . . . . . . . 181

6.4.3 Insulin Needles . . . . . . . . . . . . . . . . . . . . . . . 185
6.5 Common Problems with Insulin Therapy . . . . . . . 188
6.5.1 Weight Gain . . . . . . . . . . . . . . . . . . . . . . . . . . 188
6.5.2 Hypoglycemia with Insulin Therapy . . . . . . 188
6.6 Insulin Therapy in Special Groups . . . . . . . . . . . . 191
6.6.1 Insulin Therapy in Older Patients . . . . . . . . 191
6.6.2 Insulin Therapy and Pregnancy . . . . . . . . . . 194
6.6.3 Insulin Therapy in Gestational
Diabetes Mellitus . . . . . . . . . . . . . . . . . . . . . 195
6.6.4 Insulin Therapy in Chronic
Kidney Disease . . . . . . . . . . . . . . . . . . . . . . . 196
6.6.5 Insulin Therapy and Long-Distance
Travel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197
6.6.6 Driving and Insulin-Treated Diabetes . . . . 199
6.6.7 Insulin Therapy During Prolonged
Religious Fasting . . . . . . . . . . . . . . . . . . . . . . 200
6.6.8 Insulin Therapy at End of Life . . . . . . . . . . 202
6.7 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 202
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 203
Further Reading . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
Author Biographies
Winston Crasto, MBBS, MRCP, MD is a Consultant Physician

in Diabetes and Endocrinology at the George Eliot Hospital
NHS Trust, Nuneaton, UK and a Honorary Clinical lecturer
at the University of Leicester. His specialist research interests
are diabetic nephropathy, new therapies, and new types of
insulin. He has a wide list of publications and is a lecturer and
advisor to the MSc Diabetes program of study at the
University of Leicester. He is Co-Principal Investigator for
the GP Prompt study, an implementation strategy for reduc-
ing cardiac and renal complications in people with type 2
diabetes and microalbuminuria.
Janet Jarvis, RN, BSc (Hons), MSc is a Nurse Research Fellow

and Specialist Nurse at the Leicester Diabetes Centre at the
University Hospitals of Leicester NHS Trust. She has special-
ized in diabetes for 15 years and has been involved in major
trials in diabetes prevention and screening. Her specialist
research areas are patient education, microalbuminuria, and
disease prevention. She is an associate clinical teacher at the
University of Leicester and played a pivotal role in developing
the MSc degree program in diabetes.
Melanie J. Davies, CBE, MB, ChB, MD, FRCP is an honorary

Consultant Diabetologist at the University Hospitals of
Leicester NHS Trust, Leicester, UK, and is Professor of
Diabetes Medicine at the University of Leicester. She trained
in Sheffield and completed her training in Cambridge, Ipswich,
and Leicester. Her research is focused around the cause of
xi
xii Author Biographies
type 2 diabetes, screening and prevention of type 2 diabetes,

self-management, structured education, insulin management
(particularly in type 2 diabetes), and new antidiabetics, includ-
ing incretin-based therapies. Professor Davies has over 25
years of clinical experience and has published over 300 arti-
cles in high-impact journals, as well as over 350 published
abstracts and 10 book chapters. Professor Melanie Davies has
been responsible for major advances in diabetes and received
the Commander of the Most Excellent Order of the British
Empire (CBE) award for services to diabetes research in
2016.
Chapter 1
Introduction to Insulin
Therapies
1.1 Introduction
Diabetes mellitus is a chronic progressive metabolic disease
characterized by hyperglycemia due to absolute insulin defi-
ciency (type 1 diabetes mellitus, T1DM) or defects in insulin
action, secretion or both (type 2 diabetes mellitus, T2DM) [1].
The resulting abnormalities in carbohydrate, protein, and fat
metabolism, and the consequences of long-term poor meta-
bolic control, predispose these individuals to a higher risk of
microvascular (e.g., retinopathy, neuropathy, and nephropa-
thy) and macrovascular (e.g., cardiovascular disease, periph-
eral vascular disease and stroke) disease.
1.2 Classification
The World Health Organization (WHO) classifies diabetes
into T1DM, T2DM, and other specific types including gesta-
tional diabetes, monogenic diabetes, drug- or chemically
induced diabetes, and endocrinopathies [1]. The classification
of the different types of diabetes with their salient character-
istics and risk factors is summarized in Table 1.1.
W. Crasto et al., Handbook of Insulin Therapies, 1

DOI 10.1007/978-3-319-10939-8_1,
2 Chapter 1. Introduction to Insulin Therapies
Table 1.1 Classification of different types of diabetes with impor-

tant characteristics and risk factors
Classification of diabetes mellitus
Type Disease characteristics and risk factors
Type 1 diabetes Autoimmune destruction of pancreatic cells
mellitus (T1DM)
Absolute insulin deficiency
Individuals require insulin for survival
Usually develops in childhood and
adolescence
Individuals with variants in HLA-DQA1,
HLA-DQB1, and HLA-DRB1 genes
predisposed to greater risk of T1DM
Risk of T1DM increases with an affected
family member
Environmental factors such as exposure
to Coxsackie B4 virus, rotavirus, and
cytomegalovirus have been implicated as
risk factors
Type 2 diabetes Accounts for nearly 90 % of people with
mellitus (T2DM) diagnosed diabetes
Characterized by insulin resistance
(normally secreted insulin cannot enter
the liver and muscle cells for effective
metabolism) and/or a progressive decline
in insulin production
Initial management with diet and
glucose-lowering agents (e.g., non-insulin
therapies), though individuals eventually
need insulin to achieve optimal glycemic
control
Usually develops in adulthood and related
to aging, urbanization, obesity, unhealthy
lifestyle, unhealthy eating habits, and stress
1.2 Classification 3
Table 1.1 (continued)

Classification of diabetes mellitus
Type Disease characteristics and risk factors
Gestational Hyperglycemia developing during pregnancy
diabetes mellitus which commonly (not always) resolves within
(GDM) 6 weeks of delivery
Uncontrolled hyperglycemia affects
the mother and baby: increased risk of
premature labor, preeclampsia, congenital
malformations, macrosomia, and perinatal
mortality
Increased risk of gestational diabetes
(GDM) in future pregnancies and T2DM
later in life
Genetic defects Maturity-onset diabetes of the young
and syndromes (MODY)
Neonatal diabetes
Type A insulin resistance
Leprechaunism
RabsonMendenhall syndrome
Lipoatrophic diabetes
Endocrinopathies Acromegaly
Cushings syndrome
Glucagonoma
Exposure to Drugs: glucocorticoids, thiazides, adrenergic
certain drugs, agonists
viruses, or disease
Viruses: congenital rubella,
cytomegalovirus
Disease: pancreatitis, pancreatectomy,
hemochromatosis, cystic fibrosis
1.3 The Global Burden of Diabetes

Globally, diabetes is now the most common noncommuni-
cable disease, leading patients to have a reduced quality of
life, reduced life expectancy, and significant morbidity and
mortality from both acute and long-term complications [2].
Currently, an estimated 382 million people worldwide have
been diagnosed with diabetes, and these numbers are pro-
jected to rise to 572 million in the next 25 years (Fig. 1.1) [2,
3]. These grim figures are further compounded by the global
pandemic of obesity, an aging population, increasing seden-
tary lifestyles due to decreased physical activity, and a higher
prevalence of diabetes among socioeconomic disadvantaged
groups [2]. Recent estimates also indicate that the preva-
lence of T2DM is rising among young people. For example,
approximately 5 % of children and adolescents with diabetes
Europe
North America and

Caribbean Middle East and
North Africa
Western
South East Pacific
Asia
South and Central Africa

America
IDF 2013 2035 INCREASE

REGION MILLIONS MILLIONS %
Africa 19.8 41.4 109%
Middle East and North Africa 34.6 67.9 96%
South East Asia 72.1 123 71%
South and Central America 24.1 38.5 60%
Western Pacific 138.2 201.8 46%
North America and Caribbean 36.7 50.4 37%
Eestern Pacific 56.3 68.9 22%
World 381.8 591.9 55%
Figure 1.1 International Diabetes Federation (IDF) regions and

global projections of the number of people with diabetes (2079
years of age), 2013 and 2035 (Reproduced with permission from
International Diabetes Federation [3] IDF)
1.4 The Human Insulin Molecule 5
in Europe have been diagnosed with T2DM, a disease previ-

ously typically only seen in adults [4]. Further adding to the
disease burden is that insulin, which is vital for survival for
people with T1DM and some with long-standing T2DM, is
not readily accessible or affordable in many parts of the
world, leading to many otherwise avoidable deaths [1].
1.4 The Human Insulin Molecule

The term insulin was derived from the Latin word insula
or island to describe its origin from the pancreatic islets
of Langerhans. cells that lie exclusively within these islets
produce insulin, a peptide hormone, which facilitates the
entry of glucose into target organs such muscle, fat, and the
liver for further metabolism. The insulin molecule is com-
posed of two polypeptide chains linked by disulfide bridges:
chain A comprising 21 amino acids and chain B comprising
30 amino acids (Fig. 1.2). After it is released, insulin
attaches to a glycoprotein receptor on the surface of the
target cell. The subunit on the glycoprotein receptor
binds the insulin hormone, and the subunit (a tyrosinase-
specific protein kinase) mediates insulin action on metabo-
lism and growth [5].
Figure 1.2 Biochemical structure of insulin

1.4.1 Effect of Insulin on Metabolism
Insulin is directly released from the pancreatic cells in a

pulsatile fashion into the portal circulation. Two phases of
insulin secretion have been recognized in response to nutri-
ent (predominantly carbohydrate) ingestion. The first phase
is a sharp burst of insulin occurring within 510 min of carbo-
hydrate ingestion; the second phase is a sustained, slow
release of insulin which is directly related to the presence of
hyperglycemia [6, 7]. Loss of the insulin pulsatility factor or
loss of the first phase and an attenuated second phase of
insulin release contributes to the development of T2DM [8,
9]. Insulin secretion decreases in the presence of hypoglyce-
mia and increases in response to hyperglycemia, certain
amino acids (e.g., arginine, leucine, phenylalanine, tyrosine),
nonesterified fatty acids, and sympathetic and parasympa-
thetic stimulation [10]. The effects of insulin on glucose and
energy metabolism are particularly important in the fed
state and during fasting and exercise (Fig. 1.3).
Although insulin is the main regulator of glucose homeo-
stasis, it also has an effect on fat and protein metabolism. The
principal actions of insulin can be grouped under:
Excitatory (autacoid) action by stimulating glucose uptake
and lipid synthesis
Inhibitory (chalone) effects on lipolysis, proteolysis, glyco-
genolysis, gluconeogenesis, and ketogenesis
In brief, insulin facilitates glucose transport in liver and

muscle cells by modulation of GLUT4 glucose receptors,
stimulates storage of glucose in the form of glycogen (gly-
cogenesis), stimulates uptake of fatty acid and triacylglyc-
erol synthesis in adipose tissue and muscle, inhibits
lipolysis resulting in lowering of plasma fatty acids, stimu-
lates amino acid uptake and protein synthesis in liver,
muscle and adipose tissues, inhibits protein breakdown in
muscle.
1.4 The Human Insulin Molecule
7
Figure 1.3 The role of insulin hormone in human metabolism. GH growth hormone, FFA free fatty acid,
T2DM type 2 diabetes mellitus
1.5 History of Insulin Therapy

The landmark discovery and development of insulin as a
medical therapy can be traced back to the early nineteenth
century. Prior to the discovery of insulin, people with diabetes
were subjected to a starvation diet, with little hope for sur-
vival. In 1922, a series of experiments by Frederick Banting
and Charles Best saw the production of the first pancreatic
extract, which later was called insulin and transformed the
lives of people with diabetes (Fig. 1.4) [11]. In their landmark
experiment, Banting and Bests rigorous efforts to isolate a
purified form of pancreatic extracts from slaughtered animals
saved the life of a young boy, Leonard Thompson, from
impending coma and death due to diabetes [11].
Although pancreatic extracts remained the main source of
insulin for a long time, in 1936 Hans Christian Hagedorn dis-
covered that the action of insulin could be prolonged with the
addition of protamine, a basic protein widely available from
fish sperm. Following this discovery, protamine insulin, with
an approximate duration of 12 h, was increasingly used in
people with diabetes to good effect [12]. The subsequent dis-
covery of adding zinc to protamine insulin by Scott and
Fisher paved the way for the development of neutral
protamine Hagedorn (NPH). This longer-acting and more
stable insulin suspension was first marketed by Danish phar-
maceutical company Novo Nordisk in 1946 [13].
The sequencing of insulin by Frederick Sanger then led to
the synthesis of human insulin using DNA recombinant tech-
nology, which became widely available through the 1980s via
Eli Lilly pharmaceutical company [14]. Recognizing the need
to improve the physiological profile of insulin to mimic
endogenous insulin secretion and improved knowledge of
amino acid sequencing of the insulin molecule prompted the
emergence of synthetic (or analog) insulin. These are now
used extensively in people with diabetes [15]. A summary of
key events leading to the discovery and adoption of insulin
for use in diabetes is shown in Table 1.2.
1.5 History of Insulin Therapy 9
Figure 1.4 Banting (right) and Best (left) with one of the diabetic
dogs used in experiments with insulin (Reproduced courtesy of the
Thomas Fisher Rare Book Library, University of Toronto, Banting
and Best papers University of Toronto)
Table 1.2 Discovery of insulin timeline

Year Key figures Event
Circa Apollonius of Coined the term diabetes
230 Memphis
BC
1869 Paul Langerhans Identified the pancreatic islets of
Langerhans as insulin-producing
tissue
1889 Oskar Minkowski Confirmed the role of the pancreas
and Joseph von in the etiopathogenesis of diabetes
Mering
1921 Frederick Banting Discovered the insulin hormone
and Charles Best from canine pancreatic extracts
1922 James Collip Developed purified insulin extract
1922 Leonard First administration of insulin to a
Thompson person with diabetes
1923 Frederick Banting Awarded the Nobel Prize in
and John Macleod Medicine for the discovery of
insulin
1.5.1 The New Era of Insulin Therapies
Although human insulin has been used for many years, its use
does pose a few challenges. For example, basal (long-acting)
NPH insulin is associated with an increased risk of nocturnal
hypoglycemia, defensive snacking, and weight gain.Additionally,
the need to carefully time regular human insulin injections with
food intake is cumbersome and can restrict people with busy
lifestyles. The need to improve the physiological profile of insu-
lin to mimic endogenous insulin secretion and improved knowl-
edge of amino acid sequencing of the insulin molecule has
prompted the emergence of bioengineered analog insulin and
has heralded an exciting new era in insulin therapeutics.
Analog insulin is similar to human insulin with a slight
variation in amino acid composition and structure but with
improved pharmacokinetics [15]. In 1996, analog insulin
lispro was first marketed. Subsequently, a host of insulin
1.5 History of Insulin Therapy 11
analogs created by recombinant DNA technology, including

rapid-acting (e.g., aspart), premixed, and long-acting (e.g.,
glargine and detemir) analogs, have revolutionized diabetes
management. With the recent advent of second-generation
long-acting analogs (e.g., degludec, basal insulin, peglispro)
and oral formulations, the future of insulin therapeutics
looks promising. However, long-term data on their clinical
efficacy, safety, and economic impact are still needed.
Although efforts to make new insulin formulations more
reproducible and similar to human physiology are ongoing, in
recent years, there has also been avid interest in the role of
continuous subcutaneous insulin administration (or insulin
pumps), closed loop systems, and artificial pancreas combi-
nation devices. While these treatments are associated with
increased costs and may not be suitable for all patients, they
may improve quality of life.
1.5.2 Insulin Management: Combining Art

with Science
Exogenous insulin is a powerful therapeutic agent which is
lifesaving in T1DM and a valuable adjunct in individuals with
poorly controlled T2DM despite taking other glucose-lowering
therapies. Despite major strides in the field of insulin thera-
peutics, the clinical use of insulin is not exactly a perfect sci-
ence but more of an empirical art which requires an
individualized approach. Although adequate knowledge of
how insulin works is essential, education and training in
key skills such as insulin self-administration, insulin dose
adjustment, monitoring and interpretation of blood glucose,
and management of hypoglycemia are critical to self-care.
Transferring knowledge and skills to the insulin user is,
therefore, of vital importance.
Over the last few decades, insulin regimens in T1DM and
T2DM have been variable, ranging from simplistic, regular
insulin administration to more elaborate care plans.
Generally, health-care professionals tend to use regimens
which they have either used before and are comfortable with
or have been suggested to use in consensus guidelines,
although sometimes these choices can be arbitrary. The real-

ity is that for many individuals with diabetes, successful
treatment regimens are a process of trial and error, leading
to some undesirable outcomes along the way. What is vital in
this treatment journey is that patients are empowered to
work in partnership with clinicians to achieve their agreed
personal goals.
1.6 Summary
Nearly a century after its isolation, insulin remains a powerful
therapeutic agent and subject of continuing research and
development, with the common aim of improving the lives of
patients with both type 1 and type 2 diabetes. Certainly, one
of the biggest challenges with all insulin therapies is matching
insulin delivery to the constantly changing internal glucose
milieu and avoiding extremes of glucose excursions both in
the fasting and fed state. The impact of hyperglycemia on
long-term health needs to be balanced against the potential
risk of iatrogenic hypoglycemia from intensification of
glucose-lowering therapies.
Despite the imperfections of insulin therapy, it is antici-
pated that with the advent of newer insulin therapies and
technological advances including glucose sensors and insulin
pump technology (particularly in individuals with T1DM),
insulin replacement can be regulated with increasing accu-
racy as the scientific advances get closer to mimicking normal
human physiology. This will provide people with diabetes
requiring insulin the ability to lead lives with better glycemic
control and less fear of hypoglycemia. A systematic individu-
alized care approach focusing on patient education, empow-
erment and self-management will always be needed to
support advances in insulin technology. This needs to be
underpinned by a better understanding of the complex
underlying pathophysiological processes associated with dia-
betes. Thus, management of diabetes is so unique to each
patient that, although underpinned heavily by science, it will
always be an art:
References 13
After a certain level of technical skill is achieved, science and art

tend to coalesce in esthetics, plasticity, and form. The greatest
scientists are artists as well. Albert Einstein
Key Messages
Diabetes is now the most common noncommunicable dis-
ease in the world and causes reduced quality of life and life
expectancy.
Insulin was first discovered in 1922 and since its discovery
has transformed the lives of people with diabetes.
The 1990s saw the development of insulin analogs, which
revolutionized the management of diabetes once again.
Managing diabetes requires a systematic individualized
approach (an art not a science). All patients with diabe-
tes should have an individualized care plan.
Matching insulin delivery to the constantly changing inter-
nal glucose milieu is challenging; however, advances in
insulin technology mean that we are closer to finding
treatments that mimic normal human physiology.
References
1. World Health Organization (WHO). Definition, diagnosis and
classification of diabetes mellitus and its complications. Geneva:
WHO; 1999.
2. Sicree R, Shaw J, Zimmet P. The global burden: diabetes and
impaired glucose tolerance. Baker IDI Heart and Diabetes
Institute. IDF diabetes atlas, 4th ed. 2009. www.diabetesatlas.org.
Accessed July 18, 2016.
3. International Diabetes Federation (IDF). IDF diabetes atlas. 6th
ed; 2013. International Diabetes Brussels, Belgium: www.idf.org/
diabetesatlas. Accessed July 18, 2016.
4. Diabetes UK. State of the Nation 2012, England. Diabetes UK
website. www.diabetes.org.uk/documents/reports/state-of-the-
nation-2012.pdf. Accessed July 18, 2016.
5. Menting JG, Whittaker J, Margetts MB, Whittaker LJ, Kong
GWK, Smith BJ, et al. How insulin engages its primary binding
site on the insulin receptor. Nature. 2013;493:2415.
6. Curry DL, Bennett LL, Grodsky GM. Dynamics of insulin

secretion by the perfused rat pancreas. Endocrinology.
1968;83:57284.
7. Rorsman P, Renstrm E. Insulin granule dynamics in pancreatic
beta cells. Diabetologia. 2003;46:102945.
8. Wahren J, Kallas . Loss of pulsatile insulin secretion: a factor in
the pathogenesis of type 2 diabetes? Diabetes. 2012;61:22289.
9. Luzi L, DeFronzo RA. Effect of loss of first-phase insulin secre-
tion on hepatic glucose production and tissue glucose disposal in
humans. Am J Physiol. 1989;257:E2416.
10. van Loon LJ, Saris WH, Verhagen H, Wagenmakers AJ. Plasma
insulin responses after ingestion of different amino acid or pro-
tein mixtures with carbohydrate. Am J Clin Nutr.
2000;72:96105.
11. Banting FG, Best CH, Collip JB, Campbell WR, Flecher AA.
Pancreatic extracts in the treatment of diabetes mellitus. CMAJ.
1922;12:1416.
12. Lawrence RD, Archer N. Zinc protamine insulin. BMJ.
1937;1:48791.
13. Scott DA, Fisher AM. Studies in insulin with protamine.
J Pharmacol Exp Ther. 1936;58:7892.
14. Chance RE, Frank BH. Research, development, production, and
safety of biosynthetic human insulin. Diabetes Care. 1993;16
Suppl 3:13342.
15. Brange J. The new era of biotech insulin analogs. Diabetologia.
1997;40:S4853.
Further Reading
Amiel SA. Hypoglycemia: from the laboratory to the clinic. Diabetes
Care. 2009;32:136471.
Chapter 2
Existing Insulin Therapies
2.1 Introduction
The insulin hormone is normally synthesized and stored as

insulinzinc hexameric aggregates in pancreatic cells. After
release into the blood stream, the insulin complex dissoci-
ates into biologically active monomeric and dimeric forms
which interact at insulin receptors to affect metabolic action.
The aim of exogenously administered insulin therefore is to
simulate physiological insulin action based primarily on
modification of the human insulin molecule. Insulin has a
tendency for self-association into dimers or hexamers. Rapid
dissociation of hexamers to monomers accelerates the time
to onset of action, whereas retarding agents such as prot-
amine, zinc, amino acid substitutions and site-specific muta-
genesis are employed to delay absorption and hence prolong
action [1].
Depending on the source from which they are developed,
insulin therapies have evolved from three basic types natu-
ral animal insulin, recombinant human insulin, and insulin
analogs to a host of newer therapies, including oral, inhaled,
and biosimilar insulin, which have evoked considerable inter-
est and debate. Depending on their kinetics, insulin therapies
are available as:
Short acting (porcine or bovine insulin, regular human
insulin)

DOI 10.1007/978-3-319-10939-8_2,
16 Chapter 2. Existing Insulin Therapies
Rapid or quick acting (aspart, lispro, glulisine)

Ultra-rapid-acting recombinant human insulin (in
development)
Intermediate acting (porcine or bovine isophane, neutral
protamine Hagedorn [NPH])
First-generation long-acting analogs (glargine, detemir)
Second-generation long-acting analogs (degludec, basal
insulin peglispro [BIL - now discontinued], glargine U300)
2.2 Animal Insulin

Animal insulin is derived from the pancreatic extracts of pigs
(pork or porcine insulin) and cattle (bovine or beef insulin)
(Fig. 2.1) [2]. The story of their development and clinical use
spans from 1922 to 1970 when they were initially prepared by
mixing equal proportions of freshly minced animal pancreas
with 95 % ethyl alcohol, followed by commercial production
of bovine insulin by Eli Lilly (Fig. 2.2) and, later, porcine
insulin by Nordisk Insulin Laboratorium. Early animal insu-
lin varied considerably in purity and strength, resulting in
immunogenicity and local skin reactions such as lipoatrophy
and lipohypertrophy at injection sites. Technological advances
using protein chromatography in the 1970s led to more puri-
fied forms of single, peak monocomponent insulin with a
more consistent biological action and a less immunogenic
profile, which virtually eliminated problems encountered
with allergic skin reactions. With the advent of human insulin
in the 1980s, animal insulin was gradually phased out from
many commercial markets (e.g., discontinued in the United
States, primarily due to legislation around bovine spongiform
encephalopathy infection).
The amino acid sequence in the porcine insulin peptide
chain bears a close resemblance to human insulin but differs
at position B30. Similarly, three variations in the amino acid
sequence of bovine insulin differentiate it from human insu-
lin (Table 2.1). Neutral porcine/bovine insulins are clear,
colorless solutions. Isophane formulations are available in
2.2 Animal Insulin 17
Figure 2.1 Process of insulin extraction in the early ninetieth cen-

tury. (a) Pancreas glands are examined. (b) Pancreas glands are run
through grinders before insulin extraction (Reproduced with per-
mission from the Smithsonian Institute [2] Smithsonian Institute)
Figure 2.2 A bottle of insulin produced in 1923 (Reproduced with

permission from the Smithsonian Institute [2] Smithsonian Institute)
vials or cartridges as a white suspension of porcine/bovine

insulin with protamine sulfate, zinc chloride, and other
excipients. Lente formulations are sterile, white suspensions
of porcine/bovine insulin with zinc oxide and other excipi-
ents in water.
Table 2.1 Pharmacokinetics and pharmacodynamics of currently

available animal synthetic insulins
Animal Onset Peak of Duration
insulin Physicochemical of action of action
products properties action (hours) (hours)
Short-acting AA sequence 30 min 34 8
Porcine compared to
neutral human insulin
differs at one
site: AlaThreo
at B30
Short-acting AA sequence 30 min 34 8
Bovine compared to
neutral human insulin
differs at 3 sites:
Ala Threo at
A8; Val IL at
A10;
Ala Threo at
B30
Intermediate AA composition 46 h 814 1620
acting similar to
porcine neutral.
Suspension
of dissolved
crystalline
insulin with
protamine
Long acting AA composition 46 h 812 2430
similar to
bovine neutral.
Suspension of
bovine insulin +
protamine + Zn
chloride (PZI)
or with zinc
oxide (lente)
and other
excipients
Premixed 2h 412 Up to 24
AA amino acid, Ala alanine, IL isoleucine, PZI protamine zinc insu-
lin, Threo threonine, Val valine
2.3 Human Recombinant Insulin 19
2.3 Human Recombinant Insulin

Human (biosynthetic) insulin is developed using recombi-
nant DNA technology and is nearly identical to insulin pro-
duced by the human pancreas. The basic process involves:
1. Identifying a suitable vector such as bacteria or yeast (e.g.,
Escherichia coli, Saccharomyces cerevisiae) and plasmids
or extrachromosomal DNA with the potential to produce
insulin that is extracted from the vector.
2. Insert fragments coding for insulin gene in to the plasmid.
3. Plasmids reintroduced into the vector and get switched
on to code separate insulin chains.
4. Insulin chains harvested, purified, and combined to com-
plete the synthetic human insulin formation process.
Human insulin synthesized in E. coli bacteria was devel-
oped in 19801982 [3]. Thereafter, a short-acting recombinant
human insulin using cultures of S. cerevisiae was launched in
1987 [4].
The lag occurring between subcutaneous injection of regu-
lar human insulin and availability of biologically active
dimers and monomers in the blood stream requires injecting
30 min before a meal. NPH (basal) insulin has a peak effect
observed 48 h after injection, and bedtime administration
can result in nocturnal hypoglycemia without adequate con-
trol of fasting blood glucose (Table 2.2). Unpredictable
effects on blood glucose can occur due to between and
within-individual variability in absorption and pharmaco-
logical action [5].
Meta-analyses of human insulin trials have shown no
clinically relevant reductions in HbA1c with human insulins
when compared to analog insulin in T1DM and T2DM [6].
However, analog insulins are more effective for post-pran-
dial glucose lowering, improved effects on hypoglycemia,
and treatment satisfaction due to flexibility of injection tim-
ing, particularly in individuals with T1DM [7].
2.3.1 U-500 Insulin
U-500 is a five-time concentrated formulation of human insu-

lin U-100 (100 units/mL). It effectively reduces injection vol-
umes by 80 % and can improve local absorption and
compliance with treatment (larger injection volumes can
cause injection site discomfort). It is a viable alternative in
certain individuals with T2DM who are profoundly insulin
resistant and require large doses of insulin for optimal glyce-
mic control. Glycemic efficacy data from clinical case series
suggest improvements in HbA1c with modest weight gain
when compared to U-100 insulin [8, 9].
The pharmacokinetics of U-500 enables prandial insulin
cover though a prolonged duration of action (~24 h) can
occur in the presence of insulin receptor abnormalities
(Table 2.2). Glycemic efficacy of U-500 used in a multiple-
daily injections (MDI) and via continuous subcutaneous
insulin infusion (CSII) has shown HbA1c reductions ranging
from 1.0 to 3.3 % and comparable risk of hypoglycemia to
regular human insulin U-100 [9]. Practical considerations for
U-500 include the following:
U-500 is only available in a 20 mL vial containing 10,000
units.
Delivery with a syringe, not conventional insulin pens.
Designate 0.01 mL of U-500 insulin as 1 mark instead of
the conventional 1 unit (1 mark on a 0.5 mL tuberculin
syringe = 5 units of U-100).
Medication errors with dispensing and administration are
common and extra precautions are needed with its use.
The price per vial is higher than U-100 but the cost per
unit is considerably less [9].
2.3.2 Animal Versus Human Insulin
As the animal versus human insulin debate on clinical supe-

riority continues, the potential threat of shortage of animal
insulin, avoidance by certain groups due to religious beliefs,
Table 2.2 Pharmacokinetics and pharmacodynamics of currently available human synthetic insulin
Type of human Onset Peak of Duration
Generic name properties action (hours) (hours) Other comments
Short acting Recombinant 30 24 68 Available as a clear colorless
(regular) DNA with amino 60 min solution. For s/c or IM routes,
acid composition administer at least 30 min before
indistinguishable from meals
pancreatic insulin
2.3
Intermediate NPH suspensions 24 h 48 1416 Usually used for basal insulin

acting consist of crystalline requirements. Cloudy appearance;
(isophane or zinc insulin combined requires mechanical mixing to ensure
NPH) with protamine product uniformity. Free mixing with
regular insulin does not affect time
action profile. Tends to peak, intra-
subject variability can affect glucose
control
(continued)
Human Recombinant Insulin
21
22
Type of human Onset Peak of Duration

Generic name properties action (hours) (hours) Other comments
Premixed or Depending on the 30 24 1120 Cloudy in appearance; require
biphasic product, premixed 60 min mechanical mixing to ensure product
suspensions may have uniformity. Usually injected 30 min
varying combinations before meals. Intended to simplify
of dissolved crystalline dosing and may allow less frequent
insulin with protamine daily insulin injections
Concentrated Produced by 30 13 8 Useful in individuals with severe
human insulin recombinant DNA 60 min insulin resistance who may require
technology and >200 units insulin/day
identical to human
pancreatic insulin
Chapter 2. Existing Insulin Therapies
IM intramuscular, NPH neutral protamine Hagedorn, s/c subcutaneous

2.4 Insulin Analogs 23
and ceased production by major insulin manufacturers have

spurred preference for human and analog insulin over ani-
mal insulin products. However, when animal insulin efficacy
is compared to human insulin, there are no differences in
metabolic control, insulin dose requirements, and presence
of insulin antibodies [6, 10]. Additionally, there are no sig-
nificant differences in frequency, severity, or symptoms of
hypoglycemia [11]. Few reports suggest a loss of hypoglyce-
mic warning symptoms when switching from porcine to
human insulin in a clinical setting [12]. Direct comparisons
between animal insulin and analogs have not yet been car-
ried out. Thus, human insulin has not demonstrated signifi-
cant superiority over animal insulin for clinical outcomes
[7]. However, peak activity with short-acting animal insulin
is effective 34 h after injection, which impacts meal timings,
an issue which can be overcome with the faster absorption
and action profile of human and analog insulin. Nonetheless,
it is essential that animal insulin continues to be available
for those individuals who choose to use this treatment.
In recent years, higher costs and a lack of significant clini-
cal advantages with analogs (compared to human insulin)
have garnered global support for more widespread prescrib-
ing and use of human insulin formulations. In a real-world
setting, the action profile of regular human insulin requires
an inject and wait before you eat approach which may pose
a deterrent for individuals with a busy lifestyle. Also, the
higher risk of nocturnal hypoglycemia with NPH insulin may
favor analog use, although individualization of therapy and
patient preferences are important considerations.
U-500 insulin is an acceptable option for individuals
requiring insulin doses in excess of 200 units/day, particularly
those with severe insulin resistance and inadequately con-
trolled T2DM.
2.4 Insulin Analogs

Insulin analogs (also known as synthetic or designer insulin)
are produced by human recombinant DNA technology. Rapid-
acting analogs (lispro, aspart, glulisine) and long-acting analogs
(glargine, detemir) form the first-generation insulin analogs.

They have gained popularity with both patients and clinicians
due to their ability to simulate the pharmacodynamic and phar-
macokinetic profile of endogenous human insulin secretion. In
recent years, second-generation long-acting insulin analogs
(degludec, pegylated insulin lispro, and glargine U300) with
more favorable basal insulin profiles have been developed.
These offer greater flexibility in timing of dose while maintain-
ing glycemic control and can be advantageous to those with
unpredictable lifestyles such as shift workers and frequent trav-
elers and those who rely on a third party to inject them (i.e.,
may not be at the same time every day). The flexibility of this
type of insulin combined with the advantage of reduced hypo-
glycemia may lead to more adherence to insulin regimens,
offering a clinical advantage to individuals with diabetes.
2.4.1 Rapid-Acting Analogs
Rapid-acting analogs are prandial (or mealtime) types of insu-

lin. Spatial rearrangement of amino acid residues in the insulin
molecule induces charge repulsion which prevents self-associ-
ation into dimers, resulting in faster absorption and rapid onset
of insulin action. The rapid action profile allows injection
immediately before a meal, which is particularly convenient
for very young children and older people with variable food
intake. They can also be injected with or after a meal which can
be advantageous because it permits accurate estimation of
bolus dose and is more convenient for some individuals.
There are three available types of rapid-acting analog, and
they share similar pharmacodynamic and kinetic properties
(Fig. 2.3) [13]. They are absorbed within 1015 min of a sub-
cutaneous injection, peak within 3090 min, and have a dura-
tion of action of 46 h. Clinical outcomes are summarized in
Table 2.3 [1417].
Rapid-acting analogs share similar kinetics and similar gly-
cemic efficacy. Studies comparing rapid-acting analogs to regu-
lar human insulin in T1DM show no differences in HbA1c
outcomes [14, 15]. Favorable attributes include superior
Insulin activity
Insulin activity
Onset: 5-15 mins Onset: 30 mins
Peak: 0.5-1.55 hours Peak: 2-4 hours
Duration: 3-5 hours Duration 6-8 hours
0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 22 24
Hours Hours
Rapid-acting insulin action Short-acting insulin action
Insulin activity
Insulin activity
Onset: 2-4 hours Onset: 0-2 hours
Peak: 4-8 hours Peak: none
Duration: 14-16 hours Duration: 18-42 hours
0 2 4 6 8 10 12 14 16 18 20 22 24 0 2 4 6 8 10 12 14 16 18 20 22 24
Hours Hours
Intermediate-acting insulin action Long-acting insulin action
Figure 2.3 Insulin analogs: pharmacodynamics and pharmacokinet-

ics (Reproduced with permission from University Hospitals of
Leicester [13] University Hospitals of Leicester)
lowering of prandial glucose, reduced risk of nocturnal hypo-

glycemia, and improved treatment satisfaction and adherence
(which is linked to flexibility of treatment). In T2DM, rapid-
acting analogs show superior postprandial glucose lowering
with similar HbA1c benefits and no differences in rates of
hypoglycemia [14, 17].
2.4.2 Long-Acting Insulin Analogs
Long-acting insulin analogs are used to provide basal or back-

ground insulin cover alongside prandial insulin (basalbolus
therapy) in T1DM and as basal only or in combination ther-
apy with oral glucose-lowering agents, non-insulin injectable
therapies, and/or prandial insulin in individuals with T2DM.
Table 2.3 Rapid-acting insulin analogsa clinical outcomes in type 1

and type 2 diabetes mellitus
Type 1 diabetes Type 2 diabetes
Clinical effectiveness
Glycemic efficacy of rapid- Glycemic efficacy of rapid-
acting analogs compared to acting analogs compared to
regular human insulin [14] regular human insulin [14]
Minor improvements in No significant differences in
HbA1c, but not clinically HbA1c
relevant (WMD) = 0.12 %; Improved postprandial
95 % CI, 0.17 to 0.07 glucose lowering (WMD=
Improved postprandial 1.18 mmol/L; 95 % CI, 1.88
glucose lowering with to 0.47) [14]
significantly lower analog
insulin doses
No significant change in
fasting glucose
Comparative glycemic efficacy Comparative glycemic efficacy
between rapid-acting analogs between rapid-acting analogs
[15] [17]
Insulin aspart and lispro Direct comparisons of
as prandial insulin in an metabolic efficacy are lacking
intensified insulin regimen Compared to aspart and
or in CSII therapy are lispro, insulin glulisine lowers
both equally effective in blood glucose significantly in
controlling postprandial the immediate hour after a
glucose excursions meal with no differences in
rates of hypoglycemia
Safety
Significant reductions in No significant differences in
nocturnal hypoglycemia when rates of hypoglycemia compared
compared to regular human to regular human insulin [17]
insulin (risk reduction=0.67;
95 % CI, 0.540.83) [16]
Lower pump occlusion rates
are reported with insulin aspart
(9.2 %) compared to lispro
(15.7 %) and glulisine (40.9 %)

Patient-related outcomes
Higher treatment satisfaction Comparative studies between
scores reported due to greater analog and human insulin
flexibility with treatment examining treatment satisfaction
(WMD=0.31;95 % CI, 0.15 or quality of life have not been
0.47) [14] conducted
CI confidence interval, CSII continuous subcutaneous insulin infu-
sion, HbA1c glycated hemoglobin, WMD weighted mean difference
a
Lispro, aspart, and glulisine
2.4.2.1 Glargine
Glargine was launched in 2001 as a long-acting basal insulin

analog administered once daily, with a peakless action profile
and duration of action lasting up to 24 h. Glargine is pro-
duced using a genetically modified strain of E. coli. Reversal
of amino acid positions in the insulin B chain shifts the iso-
electric point to a slightly acidic pH, which makes it less
soluble. At the subcutaneous injection depot site, glargine
forms amorphous hexameric microprecipitates, which slowly
dissociate as monomers into the blood stream, resulting in
protracted action (Fig. 2.4) [18].
2.4.2.2 Detemir
Insulin detemir is a long-acting basal analog licensed for

once- or twice-daily administration; indications for use are
similar to insulin glargine. However, a salient feature distin-
guishing it from glargine is the propensity to induce less
weight gain. Potential mechanisms contributing to the weight-
sparing effect of detemir include a unique hepatoselective
action which suppresses hepatic glucose output without pro-
moting lipogenesis and restoring impaired satiety centers by
inducing changes in satiety factors, leptin, and ghrelin [19].
Subcutaneous (sc) layer skin

Amorphous precipitation sc injection of glargine
in sc tissue (pH 7.4) (acidic solution pH 4.0)
Slow dissolution of free
glargine hexamers
50m
Hexameric and dimeric disassociation Dimers Monomers

-3 -4 -5 -6
10 M 10 M 10 M 10 M
Capillary
2+
membrane Phenol Zinc Protracted absorption
Insulin in blood
Figure 2.4 Protracted absorption kinetics of insulin glargine. A

representation of insulin glargine amorphous precipitation and dis-
sociation, followed by absorption from subcutaneous tissue
(Reproduced with permission from Rosenstock and Owens [18]
Aesculapium Ltd and Edge Medical Communications)
Detemir is produced using a genetically modified strain of

S. cerevisiae. The amino acid alterations in the insulin B chain
increase self-association into hexamers and dihexamers and
promote reversible binding to albumin. From the subcutane-
ous depot site, detemir binds strongly to albumin and slowly
dissociates into monomers [20]. The net effect is slow differ-
ential distribution to peripheral target tissues which results in
protracted, predictable action profile with a unique hepatose-
lective action (Fig. 2.4). Clinical outcomes with long-acting
insulin analogs are summarized in Tables 2.4 and 2.5 [2128].
The evidence drawn from systematic reviews and com-
parative clinical trials of insulin glargine, detemir, and NPH
insulin suggest that long-acting analogs are not superior to
NPH insulin for HbA1c lowering (Tables 2.6 and 2.7) [2126].
However, they do significantly reduce the risk of nocturnal
hypoglycemia [23]. This may be relevant in determining the
choice of basal insulin therapy, particularly in individuals
with T1DM who are prone to frequent hypoglycemia.
However, there is evidence to suggest that basal analogs com-
pared to human insulin used in a basalbolus regimen in
T1DM offer a more physiological action profile, resulting in
Table 2.4 Pharmacokinetics and pharmacodynamics of insulin analogs
Peak Duration
Onset of of of action
Analog insulin Physicochemical properties action action (hours) Other comments
Rapid-acting (quick-acting) analogs
Lispro Formed by reversal of lysine 515 min 30 min 35 Clear appearance; usually
and proline amino acid to administered immediately
positions at B28 and B29 on the 1.5 h before a meal; safe for use
B chain in pregnancy
Aspart Formed by substituting aspartic Safe for use in pregnancy
acid for proline at B28
Glulisine A zinc-free preparation formed The use of glulisine
by substituting lysine for in pregnancy is not
2.4
asparagine at B3 and glutamic recommended due to lack

acid with lysine at B29 of safety studies
Long-acting (basal) analogs
Glargine Formed by adding two arginine 02 h No Up to 24 Clear in appearance; need
residues on the B chain and peak not be injected with a meal;
Insulin Analogs
replacing asparagine with longer duration of action

glycine at A21 and flat action profile
(compared to NPH)
29
(continued)
30
Peak Duration
Onset of of of action
Analog insulin Physicochemical properties action action (hours) Other comments
Detemir Formed by deletion of 02 h No Less than Duration of action lasts
threonine at B30 and adding a peak 24 up to 8 h at lower doses
myristic fatty acid residue to the (~0.1 IU/kg) and up to
-amino group of lysine at B29 2024 h at higher doses
(>0.4 IU/kg)
Degludec Threonine deleted at position 30 No Up to 42 Available as 100 U/mL
B30, a 16-carbon fatty acid 60 min peak and 200 U/mL; dose
residue is added to lysine at B29 conversion is not required
on the human insulin chain via when transferring between
a glutamic acid spacer the two strengths; allows
flexibility in injection
timing if same time daily

administration is not
possible (~8 h between
injections is required)
Premixed 25 % insulin lispro/75 % lispro 10 14 h Varies White and cloudy
(biphasic) protamine 20 min appearance; usually injected
analogs 30 % insulin aspart/70 % aspart immediately before a meal;
protamine intended to simplify dosing
50 % insulin lispro/50 % lispro and may allow less frequent
protamine daily insulin injections
2.4
Insulin Analogs
31
Table 2.5 Long-acting insulin analogs: clinical outcomes in type 1

and type 2 diabetes
Glycemic efficacy of long- Glycemic efficacy of long-acting
acting analogs compared to analogs compared to regular
regular human insulin [2124]: human insulin [25, 26]:
No clinically relevant No differences in glycemic
differences in HbA1c efficacy
(WMD = 0.14 %; 95 % CI,
0.21 to 0.08)
Superior HbA1c-lowering
effect was observed using
both rapid- and long-acting
analogs in a basalbolus
regimen compared to similar
regimen using regular and
basal human insulin
Comparative glycemic efficacy Comparative glycemic efficacy
studies between long-acting studies between long-acting
analogs [24]: analogs [27]:
No significant differences in No clinically relevant
glycemic efficacy of once- differences in HbA1c
daily glargine compared to Glycemic efficacies are
once- or twice-daily detemir comparable with once-daily
glargine and twice-daily
detemir, although higher total
doses of detemir are required to
achieve similar glycemic control
Safety
Reduced risk of all day, Reduced risk of nocturnal
nocturnal, and severe and symptomatic hypoglycemia
hypoglycemia observed with compared to NPH insulin
long-acting analogs (compared [25, 26]
to NPH) [2123]:
No differences in risk
of overall and nocturnal
hypoglycemia between
glargine and detemir [24]

Less weight gain with basal No significant difference in body
analogs compared to NPH weight in patients with type 2
insulin; significantly more diabetes treated with glargine as
pronounced with detemir compared with NPH
Detemir induced less gain in Detemir is associated with
weight compared to glargine less weight gain (0.30.8 kg)
(WMD, 0.5 kg [1.21 to 0.21]) compared to either glargine or
[28] NPH insulin [28]
Impact on quality of life, Patient satisfaction with
patient satisfaction, and long- treatment and health-related
term safety and efficacy have quality of life comparisons have
not been fully assessed not been fully assessed
CI confidence interval, HbA1c glycated hemoglobin, NPH neutral
protamine Hagedorn, WMD weighted mean difference
better metabolic control and reduced risk of hypoglycemia

without weight gain [24].
Both detemir and glargine show reduced risk of hypogly-
cemia and comparable glycemic efficacy, though detemir has
a propensity to induce less weight gain and may require
twice-daily administration and higher doses to provide simi-
lar glycemic efficacy to glargine [27]. Overall, the choice of
basal insulin should take into account individual preference,
accessibility, and cost.
2.4.2.3 Long-Acting Basal Analog: Insulin Degludec
Degludec is a long-acting basal analog with a prolonged

duration of action beyond 24 h (up to 42 h). Insulin degludec
has been investigated in the BEGIN clinical development
program, which has established its efficacy as a once-daily
basal insulin with the option of flexible dosing in individuals
with type 1 and type 2 diabetes [2932]. Degludec is approved
for use in Japan, Europe and received FDA approval for use
Table 2.6 Summary of meta-analyses comparing long-acting analogs with human basal insulin in patients with type 1
34
diabetes
Mean
change in
Mean Risk of body
Study difference hypoglycemia weight
Study details Subjects in HbA1ca odds ratioa (kg)a Other comments
Monami et al. 20 trials Age= 11.0 0.07 % Nocturnal: 0.69 0.26 Long-acting insulin
[21] with total 42.9 years; (0.13 to (0.550.86)b (0.06 analogs have a small
b
Detemir of 5981 DM 0.01) Severe: 0.73 0.47)b effect on HbA1c and
or glargine participants; duration (0.600.89)b reduced the risk of
(administered duration = 0.3 severe and nocturnal
once or ranged 18.5 years; hypoglycemia
twice daily) from 12 to Baseline compared with NPH
compared to 104 weeks HbA1c =
NPH human 6.88.8 %
basal insulin BMI =15.4

27.0 kg/m2
Sanches et al. 16 trials Age= Gla vs. Gla vs. NPH: Not Direct and indirect
[22] with total 39.2 years; NPH: Any reported comparisons show no
Insulin of 4771 BMI= 0.04 % hypoglycemia: significant differences
analogs participants; 24.9 kg/m2 (0.12 to 74.4 vs. between human
versus human duration 0.05)ns 74.1 %ns insulin and analogs in
insulin: direct ranged from glycemic efficacy or
Det BD vs. Det BD vs.
and indirect 4 weeks to safety
NPH: NPH:
meta-analyses 12 months
0.14 % Any
(0.21 hypoglycemia:
to0.01)b 79.2 vs.
81.5 %ns
(continued)
2.4
Insulin Analogs
35
Mean
36
change in
Mean Risk of body
Study difference hypoglycemia weight
Study details Subjects in HbA1ca odds ratioa (kg)a Other comments
Tricco et al. 39 trials Age = Gla OD vs. Det OD/BD vs. Det OD Cost-effectiveness
[23] included 2847 years; NPH OD: NPH OD/BD: vs. NPH varied across studies
Long-acting with total DM 0.39(0.59 0.62 (0.42 OD/BD: in this analysis but
versus of 7496 duration= to 0.19)b 0.91)b 4.04 glargine and detemir
intermediate- participants; 1127 years; (3.06 were more costly than
Det OD vs.
acting NPH duration Baseline 5.02)b NPH insulin in most
NPH OD:
insulin ranged from HbA1c = cases
0.26(0.48 Det OD/
4 to 104 6.99.5 %;
to 0.03)b BD vs.
weeks BMI =
NPH
23.1 Det OD/
OD:
28.0 kg/m2 BD vs.
5.51
NPH OD:
(6.56 to
0.36(0.59
4.46)b
to 0.19)b
Gla OD
vs. NPH
OD:
5.14
(6.07 to
4.21)b
Hermansen 18-week Mean age= 0.22 % Overall 1.01 Analog insulin in a
et al. [24] RCT of 595 39 years; (0.34 to hypoglycemia (1.37 to basalbolus therapy
Insulin participants DM disease 0.10)b risk lower with 0.66)b offers a more
analogs with T1DM duration= analogs: 0.79 physiological action
(detemir 15 years; (0.630.98)b profile, resulting in
+ aspart) Baseline better metabolic
Overall
compared HbA1c = control (i.e., reduced
nocturnal
to human 8.4 %; risk of hypoglycemia
hypoglycemia
insulins (NPH BMI = without increase in
risk lower with
+ regular 24.8 kg/m2 body weight)
analogs: 0.45
insulin) in a
(0.350.58)b
basalbolus
regimen in
T1DM
2.4
BD twice daily, BMI body mass index, Det insulin detemir, HbA1c glycated hemoglobin, Gla insulin glargine, NPH
neutral protamine Hagedorn, OD once daily
a
95 % confidence interval
b
Indicates significance at P < 0.05
Insulin Analogs
37
Table 2.7 Summary of meta-analyses comparing long-acting analogs with human basal insulin in patients with type 2
38
diabetes
Mean
change in
Mean Risk of body
Study difference in hypoglycemia weighta
Study details Subjects HbA1ca odds ratioa (kg) Other comments
Horvath 8 trials Mean age = GlarNPH Nocturnal Two No comparative
et al. [25] included 5262 years; insulin: hypoglycemia: studies evidence with
Insulin with total DM duration 0.00 % Glar vs. NPH in meta- NPH insulin
analog of 2293 = 814 years; (0.1 to 0.1)ns insulin analysis on mortality,
(glargine, participants; Baseline 0.66 (0.550.80)b found morbidity, quality
DetNPH
detemir) duration HbA1c = patients of life, or costs
insulin: Det vs. NPH
compared ranged 7.59.5 %;
insulin
on detemir Minor clinical
0.2 %
to NPH from 24 to BMI = gained
2
(0.02 to 0.3)ns 0.63 (0.520.76)b benefit with long-
insulin 52 weeks 2733 kg/m less weight acting analogs in
duration (0.8 to terms of lower

1.6 kg)b rates of nocturnal
compared hypoglycemia
to NPH
insulin.
Monami 14 trials Age = NPH insulin Nocturnal Detemir Long-acting
et al. [26] include for 58.4 years; showed a hypoglycemia: (not analogs show
Long- total of 4771 DM duration 0.1 % Glar vs. NPH glargine) no clinically
acting participants; = 10.5 years; improvement insulin associated relevant effect for
analogs duration Baseline over detemir, 0.69 (0.600.80)b with less HbA1c lowering
versus ranged from HbA1c=8.7 %; but not over weight but reduce risk
Det vs. NPH
NPH >12 months BMI = glargine gain than of symptomatic
insulin
insulin duration 28.9 kg/m2 NPH nocturnal
0.46 (0.380.55)b
insulin. hypoglycemia
compared with
NPH
BMI body mass index, CI confidence interval, Det detemir, Glar glargine, HbA1c glycated hemoglobin, hypo hypogly-
cemia, NPH neutral protamine Hagedorn, ns not significant
a
2.4
b
Indicates significance at P < 0.05
Insulin Analogs
39
in the USA in September 2015. Meanwhile, a dedicated car-

diovascular clinical outcomes trial (DEVOTE) initiated in
October 2013 is expected to report results in 2018/2019.
The degludec amino acid sequence and mechanism of
action are shown in Fig. 2.5 [33]. Degludec forms stable
dihexamers in the presence of phenol and zinc and reorga-
nizes to multi-hexamers after subcutaneous injection. Zinc
ions diffuse gradually to release monomeric insulin into the
bloodstream, resulting in protracted action.
Degludec has an onset of action of 3090 min, a flat and
stable profile, and a duration of action of 42 h. Despite vary-
ing injection times, glycemic efficacy or safety (risk of hypo-
glycemia) is not compromised compared to a once-daily
regimented (same time) administration. Degludec clinical
outcomes are summarized in Table 2.8 [2932].
2.4.2.4 Insulin Degludec 200
Insulin degludec 200 (200 units/mL; IDeg 200) is a double-

concentrated formulation with bioequivalence and similar
pharmacodynamic profile to 100 units/mL degludec. In specific
patient populations who use larger injection doses, IDeg 200
allows administration of higher doses in a single injection with
a convenient pen device, thereby minimizing pain and discom-
fort and sometimes avoiding the need for a second injection,
which may be required if larger injection volumes are needed.
When compared to basal analogs (glargine and degludec
100 U/mL), IDeg 200 had comparable glycemic efficacy to
glargine in insulin-nave individuals on oral glucose-lowering
agents with poorly controlled T2DM with a mean baseline
HbA1c of 8.3 % (treatment difference in HbA1c, 0.42 %;
95 % CI, 0.78 to 0.06) and had greater reductions in fasting
glucose (3.7 vs. 3.4 mmol/L; 67 vs. 61 mg/dL) [34].
Additionally with IDeg 200, mean daily insulin doses were
Figure 2.5 (a, b) Insulin degludec: structure of amino acid sequence

and mechanism of action (Reproduced with permission from
Johansen et al. [33] Springer)
Table 2.8 Insulin degludec: clinical outcomes in type 1 and type 2

diabetes mellitus
Comparable glycemic Comparable glycemic efficacy to
efficacy to basal analogs with glargine as a basal insulin added
prandial insulin aspart in a to OADs (treatment difference in
basalbolus regimen HbA1c: 0.09 %; 95 % CI, 0.04 to
Compared to glargine 0.22) [31]
(treatment difference in Comparable glycemic efficacy to
HbA1c, 0.01 %; 95 % CI, glargine in a basalbolus strategy
0.14 to 0.11) [29] added to prandial insulin aspart
with or without OADs (treatment
Compared to detemir
difference in HbA1c: 0.08 %; 95 %
(treatment difference in
CI, 0.05 to 0.21) [32]
HbA1c, 0.09 % (95 % CI,
0.23 to 0.05)) [30]
Mean fasting glucose
lower with degludec
compared to detemir
(treatment difference,
1.66 mmol/L [95 % CI,
2.37 to 0.95])
Safety
No differences in the rates Significantly lower rates of overall
of overall, daytime, or severe hypoglycemia (rate ratio, 0.83;
hypoglycemia compared to 95 % CI, 0.74 to 0.94; P < 0.05)
glargine or detemir and lower rates of nocturnal
Nocturnal hypoglycemia hypoglycemia (rate ratio, 0.68;
significantly lower by 25 % 95 % CI, 0.570.82; P < 0.05)
compared to glargine (rate compared to glargine [31, 32]
ratio, 0.75; 95 % CI, 0.59
0.96; P < 0.05) and lower by
34 % compared to detemir
(rate ratio, 0.66; 95 % CI,
0.490.88; P < 0.05) [29, 30]

No studies have reported on Mean weight gain similar to
patient-related outcomes glargine
Significant improvements in
overall physical and physical
functioning (estimated by the
health survey questionnaire in
clinical trials) were reported in
favor of degludec
Summary of the BEGIN clinical trials program [2932]
CI confidence interval, NPH neutral protamine Hagedorn, OAD
oral antidiabetic agent
11 % lower when compared to glargine. IDeg200 had compa-

rable glycemic efficacy to degludec (100 U/mL) with a
HbA1c treatment difference of 0.11 (95 % CI, 0.28 to 0.05)
[35]. There were comparable rates of overall hypoglycemia
with both glargine and degludec.
2.4.2.5 Summary
In clinical practice, inter- and intra-individual variation of

action with the basal analogs may not always confer a peak-
less pharmacodynamic effect over 24 h and consistent glyce-
mic efficacy with a single daily dose. Despite its attractive
pharmacokinetics, trial data suggest that glycemic-lowering
efficacy is comparable to the basal analogs both in T1DM and
T2DM. However, a lower risk of nocturnal hypoglycemia
compared to insulin glargine, flexibility of injection times in
individuals with busy lifestyles or assisted insulin injection
users, and a more physiological basal insulin cover may pro-
vide a comparative advantage to existing basal insulin.
2.4.3 Premixed Insulin
Premixed (or biphasic) human insulin and premix analogs

cover prandial and basal insulin requirements in a single insu-
lin injection and may be administered as once, twice, or thrice
daily. They are simple to initiate, and treatment can be intensi-
fied without the need for an increase in injection frequency
while ensuring adequate prandial and basal insulin cover. In
particular, they are best suited for individuals with a predict-
able lifestyle and who consume regular meals every day.
The various preparations and pharmacokinetics of the
premixed human insulin and premixed analogs are
described in Tables 2.2 and 2.4, respectively. Premixed ana-
logs exhibit a more physiological pharmacodynamic and
pharmacokinetic profile which is suitable for injecting
immediately before or following a meal, in contrast to pre-
mixed human insulin which should be administered 30 min
before meals. Clinical efficacy, safety, and patient-related
outcomes are summarized in Table 2.9 [36, 37].
2.4.3.1 IDegAsp
IDegAsp (also termed degludec plus) is a premixed formula-

tion which combines basal insulin degludec (70 %) and pran-
dial insulin aspart (30 %) in a prefilled pen device. IDegAsp
has been investigated in the BOOST clinical development
program and has shown comparable efficacy to analog insu-
lins (e.g., glargine, biphasic aspart) and a greater than 24 h
basal insulin effect [3840].
The dihexameric degludec molecule in the presence of
zinc and phenol is suited for combination with aspart. The
individual insulin components of IDegAsp do not interact,
and their distinct pharmacodynamics and kinetics are not
compromised by the coformulation. Clinical efficacy,
safety, and patient-related outcomes are summarized in
Table 2.10 [3840].
Table 2.9 Premixed analogs compared to premixed human insulins: clinical outcomes in T1DM and T2DM
Clinical effectiveness [36, 37]
BIAsp 30 tid showed comparable Comparative effectiveness of premixed analogs results of a systematic
efficacy for HbA1c lowering to review [37]:
human insulin used in a basalbolus Compared with premixed human insulin:
regimen (regular human insulin tid + Similar glycemic efficacy in reducing HbA1c and FPG
NPH insulin at bedtime) More effective in decreasing PPG (treatment difference = 1.1 mmol/L;
BIAsp 30 tid showed comparable 95 % CI, 1.4 to 0.7) (19.2 mg/dL; 95 % CI, 25.9 to 12.5)
efficacy for HbA1c lowering to a Compared with long-acting insulin analogs given once daily:
regimen of premixed human insulin Superior reductions in HbA1c [treatment difference= 0.39 % (95 % CI,
given at breakfast + regular human 0.50 to 0.28 %)]
insulin at lunch and dinner Superior reductions in PPG (treatment difference= 1.5 mmol/L; 95 %
CI, 1.9 to 1.2; 27.9 mg/dL; 95 % CI, 34.3 to 21.5)
2.4
BIAsp 30 bid showed comparable Inferior in reducing FPG (treatment difference= 0.7 mmol/L (95 % CI,
efficacy for HbA1c lowering to 0.31.0); [12.0 mg/dL; 95 % CI, 6.018.1])
premixed human insulin bid Compared with other (non-insulin) classes of glucose-lowering drugs:
Significant improvements in Superior reductions in HbA1c [treatment difference= 0.49 %; 95 % CI,
PPG levels observed with BIAsp 0.86 to 0.12 %]
compared to a basalbolus regimen Superior reductions in FPG (treatment difference= 1.1 mmol/L; 95 %
Insulin Analogs
using human regular and NPH CI, 1.7 to 0.6; 20.5 mg/dL; 95 % CI, 29.9 to 11.2)
insulin, as well as premixed human Superior reductions in PPG (treatment difference= 2.1 mmol/L; 95 %
insulin administered twice daily CI, 3.4 to 0.8; 37.4 mg/dL; 95 % CI, 61.0 to 13.7)
45
(continued)
46

Safety
No significant differences in the No significant differences in the risk of major and minor hypoglycemia
risk of hypoglycemia compared to (rate ratio=0.6; 95 % CI, 0.21.3) compared to premixed human insulin (rate
premixed human insulin [36] ratio=1.0; 95 % CI, 0.61.5)
Greater incidence of hypoglycemia (severity not specified) compared to
long-acting analogs (given once daily) [rate ratio= 2.0 (95 % CI, 1.33.0)]
[37]
No reported data on weight gain Similar weight gain compared to premixed human insulin
Greater weight gain compared to long-acting analogs (given once daily)
[treatment difference = 2.0 kg (95 % CI, 1.13.0)] [37]
Table 2.10 IDegAsp: clinical outcomes in type 1 and type 2 diabetes

mellitus
Comparable glycemic Comparable glycemic efficacy to
efficacy to basal analogs both basal analog used once daily
with prandial insulin aspart at dinner and premixed analog
in a basalbolus regimen used twice daily, in insulin-nave
individuals with poor glycemic
Compared to detemir
control on oral glucose-lowering
(treatment difference in
drugs
HbA1c, 0.05 %; 95 %
Compared to glargine (IDegAsp
CI, 0.18 to 0.08) [38]
IGlar treatment difference in
HbA1c, 0.11 %; 95 % CI, 0.41 to
0.19) [39]
Improved post-dinner
glucose lowering (IDegAsp
IGlar treatment difference,
1.34 mmol/L; 95 % CI, 2.45 to
0.23) [39]
Compared to biphasic aspart
(IDegAspBiAsp treatment
difference in HbA1c, 0.11 %;
95 % CI, 0.41 to 0.19) [40]
Improved fasting glucose levels
(IDegAspBiAsp treatment
difference, 0.99 mmol/L; 95 %
CI, 1.68 to 0.29) [40]
(continued)

Safety
No differences in the rates Similar lower rates of overall and
of overall hypoglycemia nocturnal hypoglycemia compared
compared to detemir + to glargine used once daily with oral
aspart in a basalbolus glucose-lowering drugs
regimen Lower rates of confirmed
Nocturnal hypoglycemia hypoglycemia compared to BIAsp
significantly lower by 37 % (RR, 0.42; 95 % CI, 0.230.75)* [40]
when compared to detemir
(RR, 0.63; 95 % CI, 0.49
0.81)* [38]
Mild increase in weight No significant increase in weight
gain (after 6 months) with (after 4 months) with IDegAsp
IDegAsp when compared compared to glargine [39]
to detemir (treatment
difference, 1.04; 95 % CI,
0.381.69)* [38]
Well tolerated with no
negative impact on quality
of life
Based on results from the BOOST clinical development program
[3840]
BiAsp biphasic insulin aspart, CI confidence interval, HbA1c
glycated hemoglobin, IDegAsp insulin degludec and insulin aspart,
IGlar insulin glargine, RR rate ratio
BIAsp 30 biphasic insulin aspart 30/70 (available as NovoMix 30),
bid twice daily, CI confidence interval, PPG postprandial glucose,
FPG fasting plasma glucose, tid three times daily
*P < 0.05
2.5 Summary 49
2.5 Summary
Amidst the armamentarium of insulin therapies, premixed

insulin provides a simple and convenient therapeutic option
by targeting both fasting and postprandial hyperglycemia and
is a valuable option in the glycemic management of T1DM
and T2DM. The premixed analogs show similar efficacy for
HbA1c reductions to their premixed human insulin
counterparts but offer convenience for flexibility of dosing
and are more effective for postprandial glucose lowering with
no significant increase in the risk of hypoglycemia. Degludec
plus is a newer premixed insulin analog which combines the
attractive long-acting profile of degludec with rapid-acting
insulin apart in a single injection and may offer the option of
once-daily dosing. It is noninferior to glargine and biphasic
insulin aspart for glycemic control with lower rates of hypo-
glycemia and is a novel treatment option in individuals with
T1DM and T2DM. Whichever insulin is chosen, it is impor-
tant that individualization of therapy and patient preferences
are considered.
Key Messages
There are three basic categories of insulin therapy avail-
able: natural animal, recombinant human, and analog.
The choice of insulin should take into account individual
preference, accessibility, and cost.
Rapid-acting insulin analog offers greater flexibility of
administration, treatment satisfaction, and effective lower-
ing of postprandial hyperglycemia.
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35. Bode BW, Chaykin LB, Sussman AM, Warren ML, Niemeyer M,
Rabl R, et al. Efficacy and safety of insulin degludec 200 U/mL
and insulin degludec 100 U/mL in patients with type 2 diabetes
(Begin: Compare). Endocr Pract. 2014;20:78591.
36. Valensi P. Biphasic insulin aspart 30/70 (BIAsp 30) in the treat-
ment of type 1 and type 2 diabetes. Diabetes Metab Syndr Obes.
2009;2:6171.
37. Qayyum R, Bolen S, Maruthur N, Feldman L, Wilson LM,
Marianopoulos SS, et al. Systematic review: comparative effec-
tiveness and safety of premixed insulin analogs in type 2 diabe-
tes. Ann Intern Med. 2008;149:54959.
38. Hirsch IB, Bode B, Courreges JP, Dykiel P, Franek E, Hermansen
K, et al. Insulin degludec/insulin aspart administered once daily
at any meal, with insulin aspart at other meals versus a standard
basal-bolus regimen in patients with type 1 diabetes: a 26-week,
phase 3, randomized, open-label, treat-to-target trial. Diabetes
Care. 2012;35:217481.
39. Heise T, Tack CJ, Cuddihy R, Davidson J, Gouet D, Liebl A, et al.
A new-generation ultra-long-acting basal insulin with a bolus
boost compared with insulin glargine in insulin-naive people
with type 2 diabetes: a randomized, controlled trial. Diabetes
Care. 2011;34:66974.
40. Niskanen L, Leiter LA, Franek E, Weng J, Damci T, Muoz-
Torres M, et al. Comparison of a soluble co-formulation of insu-
lin degludec/insulin aspart vs biphasic insulin aspart 30 in type 2
diabetes: a randomised trial. Eur J Endocrinol. 2012;167:28794.
Chapter 3
Emerging Insulin Therapies
3.1 Injectable Insulin Products
3.1.1 Ultra-Rapid-Acting Insulin
Ultra-rapid-acting insulin formulations are currently in early

development. Early studies suggest a more physiological
prandial insulin action compared to currently available rapid-
acting analogs (Table 3.1) [16]. They have the potential to
benefit continuous subcutaneous insulin infusion (CSII)
therapy and artificial closed-loop systems due to faster reac-
tion times, allowing pump algorithms to dose insulin in real
time. Earlier recombinant human insulin-based formulations
have not yet received approval by the US Food and Drug
Administration (FDA) or European Medicines Agency
(EMA) and are currently undergoing development.
3.1.2 Long-Acting Basal Insulin Peglispro
Basal insulin peglispro (BIL) is a pegylated insulin lispro

with the attributes of a long-acting basal insulin and is cur-
rently in development for the treatment of type 1 (T1DM)
and type 2 diabetes mellitus (T2DM). Phase II study results
have shown superior improvements in HbA1c, lower rates of

DOI 10.1007/978-3-319-10939-8_3,
56
Table 3.1 Novel ultra-rapid-acting insulin products in the pipeline

Type of ultra-
rapid-acting
insulin Brief description Clinical studies and development
Recombinant BIOD-123: an ultra-rapid- BIOD-123 compared to insulin lispro, 18 week, Phase II RCT in
human acting mealtime insulin subjects with type 1 diabetes mellitus (T1DM)a [1]:
insulin containing disodium
Mean HbA1c difference with BIOD-123, 0.17 % (95 % CI,
(RHI)-based ethylenediaminetetraacetic
2 0.01 to 0.35), and confirms noninferiority
formulations acid (Na EDTA), citrate,
and magnesium sulfate. Postprandial glucose lowering was within 30 min (BIOD-123) vs.
Na2EDTA chelates zinc within 120 min (lispro)
to destabilize the insulin
hexamer; citrate ions mask Injection site with pain: 15 % vs. 1.5 %
Chapter 3. Emerging Insulin Therapies
surface charges impeding

reaggregation and facilitating
monomer absorption
Type of ultra-
rapid-acting
Analog- BIOD-238 and BIOD- BIOD-238 and BIOD-250 compared to lispro in a double-blind,
based 250: analog formulations three-way, crossover RCT [2]:
formulations manufactured using insulin
Pharmacokinetics suggest superior time to peak insulin
lispro
concentration compared to lispro- and RHI-based
formulations
BioChaperone Lispro Ultra-rapid BioChaperone insulin lispro vs. insulin lisproa [3]:
U-100: a mealtime
Significantly more rapid onset of action compared to lispro
insulin analog that uses
(23.1 7.0 vs. 34.4 15.3 min; P < 0.0001)
BioChaperone technology
69 % stronger metabolic effect in the first 2 h in subjects with
T1DM
FIAsp: an insulin aspart with Phase I results show 1- and 2 h greater postprandial glucose
excipients, nicotinamide reductions when compared to insulin aspart; reductions confirmed
(speeds absorption), and in Phase III trial (ONSET) [4]
arginine (stabilizes insulin)
BioChaperone Combo: a BioChaperone Combo compared to insulin lispro mix 25a [5]:
combination of glargine with
Faster onset of action (25 11 vs. 40 13 min; P = 0.002)
lispro using Biochaperone
technology with the potential Early metabolic effect, as well as pronounced late metabolic
for once-daily dosing effect, compared to biphasic analog
57
(continued)
58
Type of ultra-
rapid-acting
Concentrated BIOD-531: a concentrated BIOD-531 (at 1.0 U/kg and 0.5 U/kg) compared to HumulinR
insulin U-400 RHI-based U-500 and Humalog Mix75/25 double-blind, four-way, crossover,
formulation RCTa [6]:
BIOD-531 demonstrates faster absorption rates than U-500
and Humalog Mix 75/25
Onset of action: BIOD-531 (7.2 4.1) vs. U-500 (21.4 6.7)
minutes; BIOD-531 (14.6 6.0) vs. Humalog Mix75/25
(35.9 7.9) minutes
BIOD-531 has ~18 h duration of action; consistent with basal
insulin
Significantly lower injection volumes required

CI confidence interval, RCT randomized controlled trial, RHI recombinant human insulin
a
Data presented in abstract form at the American Diabetes Association 74th Scientific Sessions, San Francisco, CA;
June 1314, 2014 and 50th European Association for the Study of Diabetes, Vienna, Austria, Sept 1519th, 2014
3.1 Injectable Insulin Products 59
nocturnal hypoglycemia, and significant weight loss when

compared to existing types of basal insulin [7, 8].
BIL is produced by covalent coupling of lispro to a polyeth-
ylene glycol (PEG) moiety via urethane bound to lysine at
position B28. This creates a large hydrodynamic diameter
which slows diffusion and renal filtration, delaying subcutane-
ous absorption. BIL has a duration of action of at least 36 h
and a low intra-subject variability. The large molecular size also
affects tissue distribution. BIL demonstrates a unique hepa-
toselective action which can mediate suppression of hepatic
glucose output, and the preferential entry into the liver than to
peripheral sites can increase lipid oxidation and lipolysis and
reduced lipogenesis. These factors may be responsible for the
weight loss effect with BIL seen in clinical trials [7].
IMAGINE was a Phase III clinical trial program to evalu-
ate BIL in nearly 6000 individuals with T1DM and T2DM
[915]. In individuals with T1DM (IMAGINE-1, IMAGINE-3,
and IMAGINE-7 studies), there were superior reductions in
HbA1c with BIL compared to insulin glargine, significantly
more total and daytime hypoglycemia, lower risk of nocturnal
hypoglycemia, and less weight gain [911]. In individuals with
T2DM (IMAGINE-2, IMAGINE-4, IMAGINE-5, and
IMAGINE-6 studies), there were similar superior HbA1c
reductions with BIL compared to insulin glargine [1215]. In
clinical trials with BIL, increase in liver enzyme alanine amino-
transferase (ALT), serum triglycerides and liver fat content
were observed. There was no evidence of BIL-induced hepato-
cellular damage up to 78 weeks of follow-up [9]. However,
development of BIL has now been halted due to disappointing
trial results.
3.1.3 Glargine U300 Insulin
Glargine U300 is a concentrated formulation of glargine (300

units/mL) with a long duration of action (beyond 24 h), com-
parable glycemic efficacy, and a lower risk of daytime and
confirmed or severe nocturnal hypoglycemia when compared
60 Chapter 3. Emerging Insulin Therapies
to glargine U-100. Glargine U-300 shares a similar molecular

structure and mode of action to glargine U-100. It has a flat-
ter duration of action, requires a smaller injection volume
load, and forms a compact subcutaneous depot after injec-
tion, which causes a gradual and prolonged release of insulin.
These attributes may be desirable for some people requiring
large injection volumes and for certain individuals in whom
glargine (100 U/mL) does not provide adequate 24 h basal
cover and thus require two injections a day to optimize glyce-
mic control.
Glargine U-300 was evaluated as part of the EDITION
clinical development program in individuals with T1DM and
T2DM (Table 3.2) [1622]. Preliminary data suggest glycemic
noninferiority when compared with glargine U-100, with
lower rates of nocturnal hypoglycemia [16]. Full publication of
study results from the EDITION program is awaited and will
further inform its role in special patient groups (e.g., obese,
insulin resistant), as well as the clinical management of T1DM
and T2DM. Glargine U-300 has now been approved for use in
the United States.
3.1.4 Fixed Ratio Combinations
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are

injectable therapies which improve glycemic control by mim-
icking the effects of GLP-1, a gut hormone secreted during
meals. They are a valuable adjunct in the treatment pathway
for individuals with T2DM not adequately controlled on oral
glucose-lowering drugs. The principal mode of action includes
enhanced glucose-dependent insulin secretion, suppression
of glucagon, and inhibition of endogenous glucose produc-
tion. Fixed combinations of GLP-1RAs with basal insulin in
a single injection offer convenience and clinical benefit from
the complementary effects of both drugs and are a novel
approach in the management of T2DM. Prospective trials
indicate superior glycemic efficacy, less weight gain, and
lower risk of hypoglycemia with combination therapy com-
pared to the use of a GLP-RA or basal insulin alone.
Table 3.2 Glargine U-300: summary of results from the EDITION clinical development program
Clinical effectiveness of U-300
Comparative glycemic efficacy compared Comparable glycemic efficacy to Gla-100, used once daily and added
to Gla-100 in a basalbolus regimen to mealtime insulin metformin (EDITION 1 studya [16])
(EDITION 4 studyb [17]): HbA1c difference at 6 months: 0.00 % (0.11 to 0.11)a
HbA1c difference at 6 months from Comparable glycemic efficacy to Gla-100 used once daily and
baseline 8.1 %: 0.04 % (0.100.19)a added to OADs in individuals previously treated with basal insulin
Comparative glycemic efficacy compared (EDITION 2 studya [19])
to Gla-100 in a basalbolus regimen in HbA1c difference in at 1 year: 0.06 % (0.22 to 0.12)a
Japanese people with T1DM (EDITION JP1 Comparable glycemic efficacy to Gla-100, used once daily and added
studyb [18]): to OADs in insulin-nave individuals (EDITION 3 studyb [20])
HbA1c difference at 6 months: 0.04 % HbA1c difference at 6 months: 0.04 % (0.09 to 0.17)a
(0.100.19)a Comparable glycemic efficacy to Gla-100 used once daily and added
to OADs in Japanese individuals previously treated with basal
insulin (EDITION JP2 studyb [21])
HbA1c difference at 6 months: 0.10 % (0.08 to 0.27)a
(continued)
61
62

Safety
Confirmed or severe hypoglycemia Meta-analysis of EDITION 1, 2, and 3 studies 6-month results [22]:
comparable to Gla-100 Rates of daytime (RR, 0.85 [0.760.96]) and nocturnal
Nocturnal hypoglycemia significantly 31 % hypoglycemia (RR, 0.68 [0.570.82]a) were significantly lower with
lower compared to Gla-100 (RR, 0.69 [0.53 Gla-300 compared with Gla-100
0.91])a 31 % reduction in confirmed or severe nocturnal hypoglycemia
(3.9 mmol/L [70 mg/dL]); RR: 0.69 [0.570.84]a
37 % reduction in confirmed or severe nocturnal hypoglycemia at
1 year in the EDITION 2 studyb; RR: 0.79 (0.420.96)a
Treatment was well tolerated with no Weight gain was lower with Gla-300 than Gla-100 (P < 0.05)
significant treatment-emergent side effects Treatment was well tolerated with slightly better scores for
treatment convenience and flexibility with Gla-300 compared to
Gla-100
Gla-300 glargine 300 units/mL, Gla-100 glargine 100 units/mL, OAD oral antidiabetic drugs, RR rate ratio
a
b
Data presented in abstract/poster form at the ADA 74th scientific sessions, San Francisco, California, June 1317, 2014
3.1 Injectable Insulin Products 63
3.1.4.1 IDegLira
One such combination is IDegLira, a novel, fixed-dose com-

bination of insulin degludec and liraglutide, administered
once daily (independent of meals) in a single injection for
individuals with inadequately controlled T2DM. Degludec
(an ultra-long-acting basal insulin analog) targets fasting
hyperglycemia; liraglutide (a once-daily GLP-1 analog)
reduces fasting glucose with a modest effect on postprandial
glucose, mitigates weight gain, and can potentially offset
hypoglycemia.
IDegLira has been investigated in the DUAL I trial, which
found that IDegLira had superior glycemic efficacy to liraglu-
tide monotherapy (0.64 %; 95 % CI, 0.75 to 0.53) and
noninferiority to degludec monotherapy (HbA1c: 0.47 %;
95 % CI, 0.58 to 0.36) [23]. These findings were echoed in
DUAL II, which compared IDegLira and degludec mono-
therapy [24], showing a greater reduction in fasting glucose
with IDegLira (0.73 mmol) and reduction in body weight
(2.5 kg), with comparable rates of overall hypoglycemia [24].
IDegLira combines the complementary effects of basal insu-
lin and GLP-1 analogs with the potential to improve glycemic
control in individuals inadequately controlled with oral
glucose-lowering agents and/or basal insulin.
3.1.4.2 LixiLan
LixiLan is a coformulation of lixisenatide, a GLP-1 receptor

agonist, with insulin glargine in a single-pen device for the
management of T2DM. Phase II study suggest robust reduc-
tions in HbA1c with weight loss (1.4 kg) and no increased
hypoglycemia when compared to glargine in individuals with
T2DM inadequately controlled on metformin [25]. Results
of a Phase III study met the primary endpoint of statistically
superior reduction in HbA1c in comparison with insulin
glargine, leading to FDA approval in the US. As with all of
the aforementioned combination therapies, utilizing comple-
mentary actions might benefit certain individuals in whom
meeting glycemic targets must be balanced against the risk

of hypoglycemia and weight gain.
3.2 Non-injectable Insulin Products
3.2.1 Inhaled Insulin
Technosphere insulin (TI), delivered in a compact hand-

held inhaler device, is an alternative to subcutaneous pran-
dial insulin and has been approved in the United States by
the FDA as a prandial insulin for the treatment of individu-
als with T1DM and T2DM. TI is a freeze-dried powder
formulation of recombinant human insulin adsorbed onto
fumaryl diketopiperazine to form microparticles for inhala-
tion. It is rapidly absorbed within 1215 min of inhalation
with a peak action of approximately 53 min and a duration
of action of approximately 23 h. The action profile is,
therefore, quite similar to rapid-acting insulin. TI is deliv-
ered by a breath-powered device (Fig. 3.1), which than
deagglomerates and aerosolizes the powder formulation.
After absorption into the systemic circulation, the drug is
completely cleared from the lungs within 12 h of dosing.
Clinical efficacy, safety, patient-related outcomes, and practical
a b
Figure 3.1 Technosphere insulin (Reproduced with permission

from MannKind MannKind)
3.2 Non-injectable Insulin Products 65
advice are summarized in Tables 3.3 and 3.4 [2628].

Published clinical evidence in individuals with T2DM, car-
diovascular safety outcomes, and long-term surveillance
are needed.
3.2.2 Oral Insulin
The history of oral insulin development has been one of con-

tinuous enterprise and varied success. Recent advances in
nanotechnology and efficient gastrointestinal delivery of
protein and peptides hold promise for the development of
insulin delivery by the per oral route. Apart from the distinct
advantage of being a non-injectable route of administration,
oral insulin delivery mimics physiological insulin extraction
by directly entering the portal circulation which promotes
increased uptake of net hepatic glucose production.
Various oral insulin delivery systems have employed
enzyme inhibitors which prevent premature breakdown of the
insulin protein, absorption enhancers which directly transport
insulin across the intestinal epithelium without affecting its
solubility, and mucoadhesive polymers which increase drug
concentration gradient at the target sites [29]. Table 3.5 pro-
vides a summary of proprietary oral insulin products in clini-
cal development. Going forward, challenges in developing
proprietary oral insulin formulations include:
Reproducibility of action profile (intraindividual
variability).
Interference of insulin absorption from the gut due to
meals, gastric motility, and impact of coadministered drugs.
Risk of deleterious long-term side effects due to the insu-
lin formulation or presence of its excipients will require
further evaluation.
Although the insulin market is largely reliant on subcuta-
neous insulin administration, several pharmaceutical compa-
nies are currently poised to offer the option of oral insulin to
a growing population affected with diabetes. As patent appli-
cations grow, there is an urgency to circumvent the potential
Table 3.3 Technosphere insulin: clinical outcomes in type 1 and type

2 diabetes
Type 1 diabetes mellitus Type 2 diabetes mellitus
Clinical effectiveness of TI
Prandial inhaled TI with Prandial inhaled TI + glargine
glargine showed comparable compared with twice-daily
glycemic efficacy when biaspart insulin showed
compared with lispro + glargine comparable glycemic efficacy [28]
in a basalbolus regimen
Significantly greater Phase II study showed that TI
reductions observed in has a dose-dependent, glucose-
fasting and postprandial lowering effect [27]
glucose excursions compared
to the lispro group [26]
Safety
Significant reductions in Significantly lower risk of mild-to-
total hypoglycemia events moderate hypoglycemia [rate ratio,
(6.2 vs. 8.2; P < 0.05) and 0.41 (95 % CI, 0.300.57)] with
mild/moderate hypoglycemia inhaled insulin + insulin glargine
events (6.0 vs. 8.0; P < 0.05) compared with twice-daily biaspart
insulin [28]
Safety has not been Significantly lower risk of severe
established in individuals hypoglycemia [rate ratio, 0.41
<18 years of age (95 % CI, 0.22 0.78)] with inhaled
insulin + insulin glargine, compared
with twice-daily biaspart insulin [28]
Mean weight gain was Mean weight gain was significantly
significantly lower with lower with inhaled insulin + insulin
TI + glargine when compared glargine than with twice-daily
with a lispro + glargine biaspart insulin (treatment
regimen (mean change, 0.6 difference, 1.6 kg; 95 % CI, 2.4 to
vs. +1.4 kg; P < 0.05) 0.7) [28]
Inhaled insulin users report TI was well tolerated, apart from
increased convenience, an increased frequency of cough
comfort, and ease of regimen and increased risk of upper
adherence [26] respiratory tract infections
CI confidence interval, TI Technosphere insulin
3.2 Non-injectable Insulin Products 67
Table 3.4 Practical aspects for use with Technosphere insulin

Technosphere Ultra-rapid-acting TI inhalation powder is
insulin (TI) premetered into single-use dose cartridges
which can be slotted into a compact inhaler
device
Indicated for use as a mealtime insulin in
individuals with type 1 diabetes and those
with type 2 requiring insulin
Cartridge Two types available:
Blue cartridge = 4 units of insulin
Green cartridge = 8 units of insulin
Available in sealed foil package
Refrigerate at 28 C
Used at room temperature
Storage Keep in a cool, dry environment at
temperature between 2 and 25 C
Side effects Hypoglycemia
Cough
Acute bronchospasm (particularly in
patients with asthma and COPD)
Cautions Perform spirometry prior to initiation
Assess pulmonary function (e.g.,
spirometry) after 6 and 12 months
of treatment, even with no manifest
respiratory symptoms
Not for use in patients with chronic lung
disease or active lung cancer
COPD chronic obstructive pulmonary disease
Table 3.5 Summary of proprietary oral insulin products in clinical development
68
Oral insulin Formulation Delivery system Clinical development

ORMD-0801 Capsule Salts of EDTA (enteric RCT in patients with T2DM treated with two doses of
coated + PE) ORMD-0801
Bedtime administration lowers fasting glucose
with no risk of hypoglycemia
Duration of action of ~5 or 6 h, onset of action
[30]
Phase IIa study in patients with T1DM showed
that oral insulin three times daily before meals was
safe, well tolerated, and stabilized blood glucose
concentrations [31]
IN-105 Tablet Pegylated alkylated insulin, Pharmacokinetic studies in T1DM and T2DM showed
where human insulin is peak action 30 min to 2 h after administration, no
conjugated at position B29 episodes of symptomatic hypoglycemia, and linear

with PEG linked to an acetyl dose response reduction in postprandial glucose with
chain considerable intra-patient variability [32]
Phase III results indicate no significant reductions in
HbA1c
Capsulin Enteric- Axcess delivery system Safe and well tolerated in Phase II studies in T1DM and
coated made up of a simple mixture T2DM [33, 34]
capsule of registered pharmacopoeial
Blood glucose reductions were dose dependent,
or generally recognized as safe
lasting up to 6 h with peak plasma insulin within
excipients
2 h of dosing
Oral HDV-I Capsule Hepatic-directed vesicle Three-test-meal per day model in patients with T2DM
insulin (HDV-I) showed effective lowering of postprandial glucose and
that therapy was safe and well tolerated [35]
BioOral Tablet Calcium phosphatePEG Animal experiments indicate a prolonged hypoglycemic
insulincasein (CAPIC)-based effect after oral administration [36]
insulin microparticle protects
from acidic degradation
Oraldel Tablet Vitamin B12-coated Phase I study successfully completed. No clinical data
carbohydrate-based nanopar- available
ticle protects from enzymatic
digestion
NN1954 Tablet GIPET technology Phase I study successfully completed. No clinical data
available
3.2 Non-injectable Insulin Products
EDTA ethylenediaminetetraacetic acid, HbA1c glycated hemoglobin, PE penetration enhancers, PEG polyethylene
glycol, RTC randomized controlled trial, T1DM type 1 diabetes mellitus, T2DM type 2 diabetes mellitus
69
challenges and develop oral insulin formulations which are

clinically effective, safe, and available at an affordable cost.
3.2.3 Buccal Insulin
The buccal mucosa (lining of the mouth) provides a

non-injectable route of insulin administration. Oral-lyn
(Generex Biotechnology Corporation, Toronto, Canada) is
currently the only buccal insulin available for prandial admin-
istration and is licensed for use in many countries in Southeast
Asia, Africa, and South America. It is also currently enrolled in
an FDA-approved Investigational New Drug Treatment pro-
gram with a Phase III trial planned.
Oral-lyn is a tasteless liquid formulation of human recom-
binant insulin encapsulated into nanopellets to facilitate buc-
cal delivery. The aerosol is delivered by a spray device at high
velocity (~100 mph) and absorbed via the mucosal lining of
the oral cavity (Fig. 3.2). Each puff delivered equals 1 unit of
insulin absorbed into the systemic circulation. Because insulin
is quickly absorbed from the vascular oral mucosa, glucose-
lowering activity is observed within 5 min, with peak insulin
action at approximately 30 min, and a duration of action of 2 h
(shorter than subcutaneous human insulin).
Oral-lyn as a prandial insulin has shown to have a com-
parable glycemic efficacy to regular human insulin in indi-
viduals with T1DM receiving twice-daily basal insulin
analog [37]. Additionally, when added to oral glucose-lower-
ing agents in individuals with T2DM with inadequate glyce-
mic control, it showed superior reductions in 2 h postprandial
glucose levels compared to oral glucose-lowering agents
[38]. Comparative studies with insulin analogs in T2DM
have not yet been carried out. In terms of safety, no signifi-
cant side effects have been observed in clinical studies,
although occasional mild, self-limiting dizziness can occur
during administration. Insulin spray formulation may sig-
nificantly impact treatment compliance. However, more
3.3 Biosimilar Insulin 71
Figure 3.2 Buccal insulin spray (Reproduced with permission from

Generex Generex)
clinical studies are needed to inform glycemic durability,

safety, and tolerability.
3.3 Biosimilar Insulin

By definition, a biosimilar is a therapeutic protein molecule
which has an identical amino acid sequence (notwithstanding
minor variations in clinically active components) to a previ-
ously marketed reference product with no significant differ-
ences in efficacy and safety [39]. Simply put, biosimilar
products are similar but not identical to reference products.
To comply with regulatory guidelines, biosimilar medicines
must demonstrate both in vitro and in vivo nonclinical char-
acteristics similar to the reference product, similar pharmaco-
dynamics and pharmacokinetics within predefined regulatory
acceptance limit, and no clinically meaningful differences in
clinical efficacy, drug-related adverse events, or immunoge-

nicity (Table 3.6) [4042].
As patent expiry for a number of insulin products has been
realized or is fast approaching (e.g., the patent for insulin
glargine expired in February 2015 in the United States and
May 2015 in Europe), there has been intense global interest
in the development of biosimilar insulin. A recent survey
conducted by the Alliance for Safe Biologic Medicines
among the European physician community identified a
strong need for additional education and information on bio-
similars [43]. Recent examples of biosimilar insulin develop-
ment are summarized in Table 3.7 [4447].
Table 3.6 Rationale and key challenges of biosimilars

Rationale for introduction of
biosimilars Challenges with biosimilars
May increase the number of Less rigorously regulated in
treatment options available countries other than in Europe
to patients, prescribers, and and the United States
payors
Typically associated with Lower than anticipated cost
cost savings which may affect savings relative to those with
patient acceptance directly generics
(out of pocket expense)
and indirectly (placed on
a preferred prescription
formulary)
May increase accessibility to All biologics (including
treatments biosimilars) should have a
clear naming scheme with
distinguishable names to
facilitate clear prescribing and
monitoring
Table 3.7 Biosimilar insulin clinical development
Test insulin Comparator Study details HbA1c outcomes Other comments
Biosimilar insulin product: clinical efficacy and safety data
Biosimilar Glargine ELEMENT 1 study [44]: Hba1c (LY LY IGlar compared with
insulin glargine (Glar) T1DM subjects; 52 IGlarGlar) analog glargine used in
(Abasalglar/ weeks, Phase III, open- after 52 weeks = combination with lispro
Basalglar label, parallel group 0.020 % (95 % CI, provided equivalent
RCT 0.099 to 0.140) efficacy and a similar safety
LY IGlar + IL tid profile (including risk of
with meals (n = 267) hypoglycemia) in patients with
vs. Glar + IL tid with T1DM
meals (n = 268).
ELEMENT 2 study [45]: Hba1c (LY LY IGlar compared with analog
T2DM subjects, insulin IGlar Glar) glargine in combination with
3.3
nave in combination after 24 weeks OADs provided equivalent

with OADs; 24 weeks, =0.052 % (95 % efficacy and similar safety profile
Phase III, double-blind, CI, 0.070 to (including risk of hypoglycemia)
parallel group RCT 0.175) in T2DM. LY IGlar is
LY IGlar OADs recommended for marketing
(n = 376) vs. authorization in the EU and for
Glar OADs (n = 380) use in individuals with T1DM
and T2DM. The US FDA has
Biosimilar Insulin
approved its use in December

2015 but not as a biosimilar
73
product.
(continued)
74

Biosimilars without internationally accepted regulatory approval [46]
Basalog Glar Open-label, multicenter Hba1c from Similar incidence of insulin
RCT, 12 weeks of baseline to 12 antibodies and rates of
duration. T1DM weeks hypoglycemia between Basalog
subjects, randomized to Basalog: and Glar (40.2 vs. 41.6 %)
Basalog (n = 107) or Glar 7.86 % 1.11 to
(n = 108) 7.80 % 1.24
Glar:
7.76 % 1.17 to
7.58 % 1.27b
c
Recombinant insulin products [47]
(a) Soluble (a) Humulin ac: double blind, CHMP review for marketing
rapid-acting S parallel group, 24 week authorization report:
insulin (Insulin RCT. 526 participants Quality data do not support
Human Rapid (T1DM, n = 243); T2DM, biosimilarity
Marvel) n = 283. Subjects aged Clinical efficacy studies not
1875 years, both blinded
(b) Long-acting (b) Humulin
genders No available data on PK
isophane insulin I
studies, limited data on
(Insulin Human
immunogenicity
Long Marvel)
(c) 30:70 mixture (c) Humulin
(Insulin M3
3.3
Human Mix
30/70 Marvel)
Pipeline Glar NCT02059161 is an ongoing
MK-1293 Phase III trial of MK-1293 vs.
Glar in subjects with T1DM
and T2DM [48]
OADs oral antidiabetic drugs, CHMP Committee for Medicinal Products for Human Use, Glar insulin glargine, HbA1c
Biosimilar Insulin
glycated hemoglobin, IL insulin lispro, PK pharmacokinetics, T1DM type 1 diabetes mellitus, RCT randomized controlled
trial, T2DM type 2 diabetes mellitus, tid three times daily
a
75
= adjusted mean difference between groups with confidence intervals

b
P = nonsignificant between groups
c
Rejected for approval in Europe
3.4 Summary
Scientific advances in redesigning the insulin molecule have
opened up new and exciting possibilities for more physiologi-
cal insulin replacement therapy. The expanding portfolio of
ultra-fast-acting insulin formulations, more highly concen-
trated insulin, and combination formulations (e.g., with
GLP-1 agonists) in clinical development aims to improve the
metabolic profile and address the complex and variable
needs of people living with diabetes. Newer strategies have
explored inhalation, oral, and buccal routes of delivery, and
the future holds much promise. Consequently, it is incumbent
upon both insulin manufacturers and the global medical com-
munity to continue to aim for an insulin product which is
effective, convenient, bereft of significant side effects, and
affordable.
In using insulin, it would of course be ideal if it could be supplied
so as to imitate the natural process. JJ Macleod and WR Campbell,
1925
Key Messages
There are many new and versatile injectable types of insu-
lin in the pipeline representing exciting possibilities for
more physiological insulin replacements.
Scientific advances have brought new routes of insulin
delivery such as oral, inhaled, and buccal, which may expand
treatment opportunities for some people with diabetes.
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lin formulation BIOD-123 in patients with type 1 diabetes.
Webcast presented at 74th ADA Scientific Sessions, San
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2. Kaye J, Krasner A, Canney L, Pichotta P, Simms P, Krishnarajah
J, et al. Novel formulations BIOD-238 and BIOD-250 result in
more rapid absorption and declines from peak than Humalog.
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June 13-14, 2014. Abstract 1028.
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6. Morrow L, Canney L, Pichotta P, Hompesch M, Krasner A, De
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13-17, 2014. Abstract 82-LB.
7. Bergenstal RM, Rosenstock RM, Arakaki RF, Prince MJ, Qu Y,
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LY2605541, a novel long-acting basal insulin, versus insulin
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8. Rosenstock J, Bergenstal RM, Blevins TC, Morrow LA, Prince
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11. Garg S, Selam J, Bhargava A, et al. HbA1c reduction and hypo-
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Presented at 75th American Diabetes Association (ADA)
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15. Grunberger G, Chen L, Rodriguez , et al. Basal insulin peglispro
(BIL) provides clinically and significantly better HbA1c control
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Scientific Sessions; June 5-9, 2015; Boston. Abstract 1004-P.
16. Riddle MC, Bolli GB, Zieman M, Muehlen-Bartmer I, Bizet F,
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17. Home PD, Bergenstal RM, Bolli GB, Zieman M, Rojeski M,
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19. Yki-Jrvinen H, Bergenstal R, Ziemen M, et al. New insulin
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control and hypoglycemia in a 6-month randomized controlled
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20. Bolli GB, Riddle MC, Bergenstal RM, Ziemen M, Sestakauskas
K, Goyeau H, et al. New insulin glargine 300 U/ml compared
with glargine 100 U/ml in insulin-nave people with type 2 diabe-
tes on oral glucose-lowering drugs: a randomized controlled trial
(EDITION 3). Diabetes Obes Metab. 2015;17:38694.
21. Terauchi Y, Koyama M, Cheng X, Shimizu S, Takahisa H;
EDITION JP 2 Study Group. Glycaemic control and hypogly-
caemia in Japanese people with T2DM receiving new insulin
glargine 300 U/ml in combination with OADs (EDITION JP 2).
Diabetologia. 2014;57(suppl 1):S401. Abstract 95-LB.
22. Ritzel R, Roussel R, Bolli GB, Vinet L, Yki-Jarvinen H. New
insulin glargine 300 U/mL: glycemic control and hypoglycemia in
a meta-analysis of Phase 3a EDITION clinical trials in people
with T2DM. Can J Diabetes. 2014;38:S224.
23. Gough SCL, Bode B, Woo V, Rodbard HW, Linjawi S, Poulsen P,
et al. Efficacy and safety of a fixed-ratio combination of insulin
degludec and liraglutide (IDegLira) compared with its compo-
nents given alone: results of a phase 3, open-label, randomised,
26-week, treat-to-target trial in insulin-naive patients with type 2
diabetes. Lancet Diabetes Endocrinol. 2014;2:88593.
24. Buse JB, Vilsbll T, Thurman J, Blevins TC, Langbakke IH,
Bttcher SG, et al. Contribution of liraglutide in the fixed-ratio
combination of insulin degludec and liraglutide (IDegLira).
25. Rosenstock J, Diamant M, Silvestre L, Souhami E, Zhou T,
Fonseca V, et al. Benefits of a fixed-ratio formulation of once-
daily insulin glargine/lixisenatide (LixiLan) vs. glargine in type 2
diabetes inadequately controlled on metformin. Poster resented
at the European Association for the Study of Diabetes annual
meeting, Vienna, September 15-19th, 2014. Abstract 241.
26. Bode BW, Lorber DL, Gross J, et al. Reduced hypoglycemia
risk with an inhaled insulin compared to injected prandial insu-
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Francisco.
27. Tack CJ, Christov V, de Galan BE, Derwahl KM, Klausmann G,
Peliknov T, et al. Randomized forced titration to different
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28. Rosenstock J, Lorber DL, Gnudi L, Howard CP, Bilheimer DW,
Chang PC, et al. Prandial inhaled insulin plus basal glargine ver-
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29. Satake S, Moore MC, Igawa K, Converse M, Farmer B, Neal DW,
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30. Neutel J, Kidron M, Arbit E, Homer K. Bedtime oral insulin low-
ers fasting blood glucose levels in T2DM patients. American
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31. Eldor R, Corcos A, Arbit E, Kidron M. Concomitant oral and
subcutaneous insulin therapy toward stabilization of uncon-
trolled Type 1 Diabetes Mellitus (T1DM). Presented at Diabetes
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32. Khedkar A, Iyer H, Anand A, et al. A dose range finding study of
novel oral insulin (IN-105) under fed conditions in type 2 diabe-
tes mellitus subjects. Diabetes Obes Metab. 2010;12:65964.
33. Luzio SD, Dunseath G, Lockett A, Broke-Smith TP, New RR,
Owens DR. The glucose lowering effect of an oral insulin
(Capsulin) during an isoglycemic clamp study in persons with
type 2 diabetes. Diabetes Obes Metab. 2010;12:827.
34. Broke-Smith TP, Luzio SD, Lockett A, New RCC, Owens
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35. Geho WB, Rosenberg LN, Schwartz SL, Lau JR, Gana TJ. A
single-blind, placebo-controlled, dose-ranging trial of oral
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36. Morl T, Nagappan P, Nerenbaum L, Mitchell A, Bell SJ. Calcium
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Fioriti E, et al. Biokinetics of buccal spray insulin in patients with
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38. Guevara-Aguirre J, Guevara M, Saavedra J, Mihic M, Modi
P. Beneficial effects of addition of oral spray insulin on insulin
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PHYSICIANS-SURVEY-ON-BIOSIMILARS-Ex-summary.
pdf. Accessed July 18, 2016.
44. Blevins T, Dahl D, Rosenstock J, et al. Similar Efficacy and Safety
with LY2963016 Insulin Glargine Compared with Lantus
Insulin Glargine in Patients with T1DM: The ELEMENT 1 Study.
Scientific Sessions; June 13-17, 2014; San Francisco. Abstract
69-OR.
45. Rosenstock J, Hollander P, Bhargava L, et al. Similar efficacy and
safety with LY2963016 insulin glargine compared with Lantus
insulin glargine in patients with T2DM: The ELEMENT 2 Study.
Scientific Sessions; June 13-17, 2014; San Francisco.
46. Verma M, Hazra P, Iyer H, et al. Basalog is similar to Lantus
in producing glycemic control in patients with type 1 diabetes
mellitus on multiple daily insulin regimens. Int J Diabetes Dev

Countries. 2011;31:2631.
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Medicines for Human Use. Withdrawal Assessment Report for
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MK-1293 compared to Lantus in subjects with type 1 diabetes.
https://clinicaltrials.goc/ct2/NCT02059161. Accessed July 18, 2016.
Further Reading
Berger M. Oral insulin 19221992: the history of continuous ambi-
tion and failure. In: Berger M, Gries FA, editors. Frontiers in
insulin pharmacology. Stuttgart: Thieme Publishing Group;
1993:1448.
Crasto W, Jarvis J, Khunti K, Davies MJ. New insulins and new insu-
lin regimens: a review of their role in improving glycemic control
in patients with diabetes. Postgrad Med J. 2009;85:25767.
Heller S, Kozlovski P, Kurtzhals P. Insulins 85th anniversaryan
enduring medical miracle. Diabetes Res Clin Pract. 2007;78:
14958.
Chapter 4
Insulin Management in Type 2
Diabetes
4.1 Introduction
Type 2 diabetes mellitus (T2DM) is a progressive disease
typically characterized by insulin resistance and diminishing
-cell reserve, eventually leading to insulin deficiency. In
addition to insulin resistance within the muscle, liver, brain,
and cells, other pathogenic abnormalities include acceler-
ated lipolysis within adipose tissue, gastrointestinal incretin
deficiency/resistance, hyperglucagonemia, and abnormalities
in renal glucose reabsorption and require a multifaceted
approach to management [1]. From a clinical standpoint, this
is reflected by initial management with lifestyle modification
and treatment with metformin and addition of other classes
of glucose-lowering therapies, including conventional agents,
such as sulfonylureas (SUs), thiazolidinediones (TZDs), meg-
litinides, and newer therapies including glucagon-like pep-
tide-1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase-4
(DPP-4) inhibitors, and sodiumglucose co-transporter 2
(SGLT2) inhibitors to achieve satisfactory glycemic targets.
Despite optimization of these therapies, many individuals
still require some form of insulin therapy over time to
achieve satisfactory glycemic targets. Findings from the UK
Prospective Diabetes Study (UKPDS), the largest and lon-
gest randomized trial in T2DM to date, showed that 6 years
after diagnosis, nearly 44 % individuals suffered secondary

DOI 10.1007/978-3-319-10939-8_4,
84 Chapter 4. Insulin Management in Type 2 Diabetes
failure with conventional glucose-lowering agents and required

initiation of insulin therapy to optimize glycemic control [2].
Although the UKPDS findings were published before the
advent of newer therapies, non-insulin therapies may not
always address multiple underlying pathophysiological abnor-
malities or exert a potent glucose-lowering effect. Drug side
effects and compliance are other important limitations. In
recent years, combination therapy with newer glucose-lowering
therapies (e.g., GLP-1RAs + basal insulin) are being increas-
ingly used in the treatment paradigm of T2DM and may offer
certain advantages such as an insulin-sparing effect, weight
loss, and a lower risk of hypoglycemia [3].
Insulin therapy can be initiated by health-care profession-
als both in community (primary care) and hospital (second-
ary care) settings. While initiation of certain insulin regimens
may be straightforward, optimization and intensification of
insulin therapy with disease progression and/or suboptimal
glycemic control is required. This chapter will address three
main clinical questions in the management of T2DM:
1. What are the indications for insulin therapy in T2DM?
2. Which are the different types of insulin regimen, indica-
tions, and evidence for use in a clinical setting?
3. How can insulin therapy be optimized to achieve adequate
glycemic targets?
4.2 Insulin Therapy in Type 2 Diabetes

Insulin is an effective treatment for people with T2DM and
can be combined with other glucose-lowering agents and
used at any stage of the disease. Although the vast majority
of people who take insulin do not experience any significant
adverse effects, drug-induced hypoglycemia and weight gain
are major concerns both for patients and health-care profes-
sionals. The key indications for insulin therapy in T2DM are:
Failure to achieve glycemic targets (e.g., HbA1c 7.5 %;
59 mmol/mol) with diet and other glucose-lowering agents
or an appropriate target agreed with the individual
4.2 Insulin Therapy in Type 2 Diabetes 85
Symptomatic individuals (e.g., rapid weight loss, polyuria,

nocturia, recurrent bacterial or fungal infections, painful
and acute neuropathies)
Intolerance/contraindication to non-insulin therapies
Gestational diabetes if further optimization of glycemic
control is required
Steroid-induced diabetes
Postmyocardial infarction
Diabetic amyotrophy or hyperglycemic neuropathy (char-
acterized by widespread paresthesias of extremities that
rapidly improve with control of hyperglycemia)
Young patients with overlapping phenotype typical of both
type 1 (T1DM) and T2DM (i.e., obese and/or with signs of
insulin resistance) and positive for markers of -cell auto-
immunity (also known as double or hybrid diabetes)
Young patients with T2DM-related complications
4.2.1 Factors Impacting on Insulin Initiation

and Clinical Inertia
Insulin therapy is an important treatment decision for the con-
cerned individual and/or their carers. Barriers to insulin therapy
and suggestions to overcome them are discussed in more detail
in Chapter 6. Key factors which impact on consideration or
initiation of insulin therapy in individuals with T2DM include:
Hypoglycemia
Weight gain
Restrictions placed on lifestyle due to complex insulin
regimen
Practical problems with insulin dose titration to address
hyper- and hypoglycemia
Clinical inertia
Needle phobia (rare)
Coexisting obesity, where starting insulin may lead to
more weight gain
Elderly or people with significant physical or mental health
problems where the benefits of strict glycemic control out-
weigh the potential risks of hypoglycemia
Driving entitlement
Employment in high-intensity occupations such as armed
forces and emergency services
Despite well-documented benefits of timely glycemic con-
trol, clinical inertia (or failure to intensify treatment) exists
and mandates more effort from both health-care profession-
als and people with poorly controlled T2DM in order to
optimize management (Fig. 4.1) [4]. A suggested roadmap to
improve diabetes care highlights the need for a patient-
centered team approach with greater ownership by the per-
son with diabetes for their own care, a multifactorial approach
to diabetes, and incentivizing good management. Although
outcome-based financial incentives for health-care providers
have been a much debated option, what is most needed are
open communication and more time spent in collaboration
with patients to determine appropriate targets for the best
possible health-related quality of life [5].
4.2.2 Patient Education

When commencing insulin, it is important to provide the
patients with relevant information including type of insulin
used, mechanisms and duration of insulin action, insulin regi-
men, potential side effects of insulin therapy, mode of deliv-
ery, and importance of blood glucose monitoring. If individuals
understand that T2DM is a progressive disease and that over
a lifetime most people with T2DM will ultimately need insu-
lin to achieve adequate glycemic control, then feelings of
failure can be prevented.
A detailed consultation prior to insulin initiation should
address any anxieties or fears. Practical issues such as the
stages of insulin therapy initiation, optimization, and
intensification of regimen should be discussed and gly-
cemic targets agreed with the patient. If relevant, advice
on safe driving should also be emphasized. Driving enti-
tlement and legislation for patients with diabetes varies
between countries and needs to be clearly communicated.
4.2
Figure 4.1 Clinical inertia in people with type 2 diabetes requiring insulin therapy. OAD (oral antidiabetic) (Adapted
Insulin Therapy in Type 2 Diabetes
with permission from Khunti et al [4] American Diabetes Association)

87
Hypoglycemia management is of paramount importance and

should be discussed in the context of recognition, treatment,
and avoidance of hypoglycemia triggers. Referral to a dieti-
cian may be appropriate at an early stage because insulin
therapy can be associated with mild-to-moderate weight
gain, depending on the insulin formulation. Emphasis on the
importance of a low-calorie diet and regular exercise should
also be part of the consultation.
4.2.3 Early Use of Insulin in Type 2 Diabetes
Insulin therapy in a symptomatic, newly diagnosed patient

can improve well-being and allow for rapid control of hyper-
glycemia. Whether insulin therapy should be introduced as
early as possible in the disease process remains contentious,
although salutary effects on preservation of -cell mass and
function, and anti-inflammatory effects which protect against
endothelial damage, may justify early use. A brief summary of
clinical studies which address early insulin therapy initiation
have been summarized in Table 4.1 [612].
4.3 Insulin Regimens

An ideal insulin regimen in T2DM should address the needs
of the individual by taking into account their lifestyle and
physical and mental capabilities, to provide satisfactory glyce-
mic control with the least possible number of adverse effects.
A myriad of factors may need consideration such as age, life
expectancy, disease duration, associated medical conditions,
working schedules, willingness or ability to cope with com-
plex therapies (e.g., insulin regimen requiring multiple injec-
tions and active titration), properties of the insulin formulation
used, propensity for hypoglycemia, weight gain, and treat-
ment cost. While insulin regimens that are less restrictive with
a lower risk of hypoglycemia are often favored, there is no
one size fits all, and individualization of therapy is required.
Table 4.1 Summary of clinical studies which have initiated insulin therapy early in the management of T2DM
Description of clinical study Study results
Effects of very early intensive control of T2DM with insulin therapy
Effects of IIT over 48 weeks in 34 individuals 68 % individuals had FPG <7 mmol/L after any glucose-
(mean duration of T2DM approximately 6 years) lowering agent at one day post-IIT (responders) and showed
[6] greater improvements in -cell function
Effects of IIT (detemir + aspart) over 4 weeks in 61 Greater improvements in glycemic variability resulted in
individuals greater improvements in -cell function
(mean duration of T2DM approximately 3 years) [7]
Effects of IIT on -cell function and glycemic Individuals on insulin achieved target glycemic control in
control in 382 individuals with newly diagnosed less time (4 days) than those treated with oral hypoglycemic
T2DM: a multicenter randomized trial [8] agents (9.3 days) greater remission rates at 1 year with
improvements in -cell function
Short-term IIT in adults with newly diagnosed Glycemic remission was achieved in 66 % after 3 months,
T2DM: a systematic review [9] 59 % after 6 months, 46 % after 12 months, and 42 % after 24
months of follow-up
Individuals achieving remission had higher BMI and lower
FPG at baseline compared to those who did not
(continued)
89
Table 4.1 (continued) 90
Description of clinical study Study results

Effects of intensive control of T2DM with insulin therapy
UKPDS: effects of intensive glycemic control with After 10 years, HbA1c was 7.0 % in the intensive control
SU or insulin compared to conventional treatment group vs. 7.9 % in the conventional treatment group (mean
Chapter 4.
in 3867 individuals with newly diagnosed T2DM HbA1c in both groups at start of study was 7.0 %)
over 10 years [10] 25 % risk reduction in microvascular end points
16 % trend to a reduced risk of myocardial infarction
Higher rates of hypoglycemia in intensive (1.8 % with
insulin therapy)
Weight gain was significantly higher in intensive (mean
2.9 kg) vs. conventional group
UKPDS: effects of 10-year post-interventional 24 % risk reduction in microvascular end points
follow-up of intensive glucose control in newly
9 % risk reduction in diabetes-related end points
diagnosed individuals with T2DM [11]
15 % risk reduction in myocardial infarction
13 % risk reduction in death from any cause
Long-term insulin treatment in adults with newly Neutral impact on cardiovascular outcomes
Insulin Management in Type 2 Diabetes
diagnosed T2DM: (ORIGIN) trial [12]

No evidence of increased cancer risk with insulin glargine
BMI body mass index, HbA1c glycated hemoglobin, IIT intensive insulin therapy, FPG fasting plasma glucose,
SU sulfonylurea, T2DM type 2 diabetes mellitus, UKPDS United Kingdom Prospective Diabetes Study
4.3 Insulin Regimens 91
Figure 4.2 Relative contributions of fasting and postprandial

hyperglycemia to HbA1c (Adapted with permission from Monnier
et al. [13])
Although, HbA1c is a function of both fasting and post-

prandial hyperglycemia, their relative contributions vary.
Postprandial glucose excursions are predominantly greater in
individuals with fairly controlled diabetes, whereas fasting
hyperglycemia has a greater contribution at higher HbA1c
(Fig. 4.2) [13, 14]. These observations may, therefore, also influ-
ence the choice of insulin regimen.
A systematic review which examined the efficacy of insu-
lin monotherapy compared to combinations therapies with
insulin and oral glucose-lowering agents in T2DM concluded
that twice-daily insulin monotherapy (neutral protamine
Hagedorn [NPH] or mixed insulin) provided superior
glycemic control to combination therapy regimens with insu-
lin added to oral agents, where insulin was administered as a
single morning injection [14].
Whatever the insulin regimen chosen (Table 4.2), it is
important that health-care professionals adopt a collabora-
tive approach that includes patient empowerment with a
view to self-management and is complemented by structured
education programs and support.
Table 4.2 Types of insulin regimen in type 2 diabetes mellitus

Insulin
regimen Glycemic target Comments
Basal only Targets FPG Basal insulin is recommended
initial starting regimen
Basal plus Targets FPG and
Overtime, escalation to more
PPG at the meal
complex insulin regimen
with the greatest
may be required to sustain
PPG excursion
glycemic targets
Prandial Targets PPG Biphasic regimen
insulin demonstrates superior efficacy
at higher HbA1c levels and
Premixed Targets FPG and may offer convenience in
(biphasic) PPG certain individual groups
Basal Targets FPG and Individual merits of human
bolus PPG and basal analog insulin need
to be considered
Insulin therapy in combination with conventional oral glucose-
lowering agents in T2DM
Metformin Targets FPG Continuation of prior
oral glucose-lowering
SUs Targets PPG
agents is recommended
TZD Targets FPG and unless contraindicated/not
PPG tolerated/increased risk of
hypoglycemia or weight gain
Insulin therapy in combination with newer classes of glucose-
lowering agents in T2DM
GLP-RA Short- and long- Continuation of prior therapy
acting formulations is recommended as above
have differential As add-on therapy, these
effects on FPG and drugs may offer improved
PPG. clinical benefits keeping in
mind their salutary effects
DPP-4 Targets PPG on weight, hypoglycemia,
inhibitors insulin dose sparing and blood
SGLT2 Targets FPG and PPG pressure
DPP-4 dipeptidyl peptidase-4, FPG fasting plasma glucose, GLP-1
glucagon-like peptide-1 receptor agonist, HbA1c glycated hemoglo-
bin, PPG postprandial glucose, SGLT2 sodiumglucose transport
proteins, SU sulfonylurea
4.3.1 Basal Insulin Regimen
A long-acting or intermediate-acting basal insulin added to

other glucose-lowering agents is commonly recommended
when initiating insulin regimen in individuals with inade-
quately controlled T2DM (Table 4.3 and Fig. 4.3) [12, 1520].
Broad principles of a basal-only regimen include once- or
twice-daily injection administration starting at a relatively
modest dose and patient-directed insulin titration toward
agreed fasting blood glucose targets. Compared to other com-
plex insulin regimens, less weight gain and lower risk of hypo-
glycemia are important clinical benefits [11].
Health-care providers may consider changing or intensify-
ing insulin therapy from a basal-only regimen if the patient has:
Higher HbA1c or HbA1c not at target due to relative
greater contributions from postprandial hyperglycemia,
despite fasting glucose levels at target
Suboptimal control despite maximal titration of basal
insulin
Recurrent and/or unresolved hypoglycemia
A treatment preference
4.3.2 Combination Therapy with Conventional

Oral Glucose-Lowering Agents
Continuation of oral agents such as metformin, SUs, and
TZDs alongside, rather than in place of, insulin has potential
advantages (Table 4.4) [1925]. Apart from a glucose-lowering
effect, metformin therapy results in improvements in insulin
resistance, oxidative stress, endothelial dysfunction, lipid pro-
file, and fat redistribution, which may contribute to greater
reduction in cardiovascular risk [21]. Less glycemic variability
and hypoglycemia may result from improved effectiveness of
endogenous insulin secretion with a SU/TZD, although weight
gain and increased risk of long bone fractures is a trouble-
some complication with TZDs, whereas individuals on SUs
are particularly prone to a greater risk of hypoglycemia [22].
Table 4.3 Basal-only insulin regimen
94
When to consider basal-only insulin Suboptimal HbA1c targets (most guidelines suggest HbA1c target of
7.5 %) despite maximal titration of other glucose-lowering agents
or due to intolerance/contraindication to these agents [15]
How to initiate and self-manage basal-only A single injection of basal insulin ~1012 units in the evening or at
Chapter 4.
insulin bedtime (note: in the case of NPH insulin, twice daily may be also be
required to provide adequate basal insulin cover)
Aim for FPG target between 5.56.6 mmol/L
Analog insulin titration is usually based on three consecutive
fasting self-monitored blood glucose (SMBG) levels:
If SMBG above FPG target, increase by 2 units with 34
interval days between adjustments. Consider nocturnal
hypoglycemia if FPG readings remain consistently high
If SMBG below FPG target or unexplained hypoglycemia,
reduce by 24 units or 20 % of total daily insulin dose.
Remember: daytime hypoglycemia may be due to coexisting
oral drugs (e.g., sulfonylureas) which may need dose reduction
or cessation of therapy
Starting insulin in groups takes half the time as individual

initiation and is recommended [16]
Clinical evidence Treat-to-Target Trial [17]:
(key studies)
Efficacy and safety of basal insulin added to oral glucose-lowering
agents to achieve glycemic targets
Systematic titration of bedtime basal insulin to FPG target of
5.6 mmol (100 mg/dL) can achieve HbA1c target of <7 %
Glargine compared to NPH insulin is associated with less
nocturnal hypoglycemia
Treating to Target in Type 2 Diabetes (4-T) [18, 19]:
Safety and efficacy of starting basal-only, twice-daily biphasic,
and prandial insulin regimen in individuals with inadequately
controlled T2DM on oral glucose-lowering agents:
Similar HbA1c lowering at 3 years
Lower rates of hypoglycemia and less weight gain were observed
with a basal insulin regimen
Clinical outcomes with different glucose-lowering regimen and
taking at least one oral agent in individuals with T2DM a
systematic review [19]:
(continued)
95
96
Superior HbA1c reductions seen with premixed and basal

bolus compared to basal-only regimen, although the latter is
more advantageous due to less weight gain and lower risk of
hypoglycemia
Chapter 4.
ORIGIN trial [12]:

Efficacy of once-daily self-titrated basal insulin glargine oral
agent in high-risk individuals with T2DM
Near-normal FPG (94 mg/dL [5.2 mmol/L] and HbA1c [6.2 %])
was achieved and maintained for 6 years (mean HbA1c at
baseline = 6.2 %)
Advantages Disadvantages
The regimen is safe and effective, has Once FPG levels are normalized, increasing the basal insulin dose
potential for decreasing weight gain and will not adequately address postprandial hyperglycemia, which has a
lower risk of hypoglycemia, is easy to initiate greater contribution to HbA1c levels and will require intensification
and titrate, and is a relatively easy insulin of insulin therapy
regimen for HCPs to facilitate and support
Patient-directed titration confers greater Basal insulin must be preferably administered at the same time of
improvements in glycemic control and lower day though second-generation basal analogs (e.g., insulin degludec
risk of severe hypoglycemia without a need may allow flexibility around injection times)
for physician-managed titration [20]
Useful regimen in certain individuals or
circumstances where symptom relief and not
tight control is desired
FPG fasting plasma glucose, HbA1c glycated hemoglobin, NPH neutral protamine Hagedorn
97
98
Algorithm Titration Other considerations
2-4-6-8 Start with 10 IU/day bedtime basal insulin and adjust weekly No increase if blood glucose <72 mg/dL (<4.0
Treat to Target Mean of self-monitored fasting glucose Insulin dose titration mmol/l) documented at any time in the
values from preceding 2 days (IU/day) preceding week.
180 mg/dL (10 mmol/l) 8
Small decreases (2-4 IU/day per adjustment) in
Chapter 4.
140160 mg/dL (7.810.0 mmol/L) 6 insulin dose if severe hypoglycemia (requiring

120140 mg/dL (6.77.8 mmol/L) 4 assistance) or blood glucose <56 mg/dL (<3.1
100120 mg/dL (5.66.7 mmol/L) 2 mmol/L) documented an y time in the preced-
ing week.
3-2-1 ATLANTUS Starting basal insulin dose differed between physician-led and The starting basal insulin dose for
patient-led algorithms insuline-nave subjects was 10 IU/day in the
physician-led titration algorithm.
Mean of self-monitored fasting Titration done Titration every 3
glucose from preceding 3 days weekly managed days managed The starting basal insulin dose for insulin-nave
by physician by patient subjects was numerically equivalent to the
highest fasting blood glucose (FBG) value in
100 mg/dL and <120 mg/dL millimoles per liter over the previous 7 days (for
02 02
(5.5 mmol/L and <6.7 mmol/L) example, if the FBG measure was 12 mmol/L,
120 mg/dL and <140 mg/dL the initial dose would be 12 IU).
2 2
(6.7 mmol/L and <7.8 mmol/L)
A simple patient-led titration algorithm confers
140 mg/dL and <180 mg/dL 4 2 improved glycemic control with low incidend-
(7.8 mmol/L and <10 mmol/L) de of severe hypoglycemia compared with a
180 mg/dL (10 mmol/l) 68 2 physician-managed titration.
Figure 4.3 Basal insulin titration algorithms in the Treat-to-Target and AT. LANTUS studies (Reproduced with
permission from Riddle et al and Davies et al [17, 20] American Diabetes Association)
Table 4.4 Selected trials illustrating glycemic efficacy and safety of Insulin added to conventional oral glucose-lowering drugs
Insulin added to oral
glucose-lowering
drugs Selected trials illustrating glycemic efficacy and safety Comments
Metformin Systematic review comparing metformin + insulin vs. insulin alone [19]: Met + insulin is associated
Met + insulin results in further reductions in HbA1c (0.5 %), with glycemic improvement,
lower weight gain (1 kg), and lower insulin dose (5 units) when weight loss, an insulin-sparing
compared with insulin alone effect, and beneficial effects on
Combination therapy does not affect all-cause mortality or CV cardiovascular disease
mortality Met-associated lactic acidosis
is a serious consequence of
Metabolic and cardiovascular effects of metformin (Met + insulin
Met therapy in individuals with
vs. insulin + PBO; mean HbA1c at baseline = 6.2 %.) in the
impaired renal function. UK
Hyperinsulinemia: the Outcome of its Metabolic Effects (HOME)
NICE guidance recommend
randomized controlled trial [23]:
review of Met dose if eGFR
Met + insulin improved glycemic control (mean difference in
<45 and stopping therapy when
HbA1c = 0.40 %; 0.250.55)
eGFR <30 mL/min/1.73 m2; FDA
Prevented weight gain (mean difference = 3.07 kg; 95 % CI, 2.28 guidance suggest stopping Met if
3.85) eGFR <45
Reduced insulin requirements (mean difference = 19.63 IU/day;
95 % CI, 14.3624.91; or 0.18 IU/kg; 95 % CI, 0.120.23)
39 % reduced risk of macrovascular disease (hazard ratio 0.61; 95 %
CI, 0.400.94)
(continued)
99
100
Insulin added to oral

glucose-lowering
drugs Selected trials illustrating glycemic efficacy and safety Comments
Sulfonylureas or Systematic review of glycemic efficacy of sulfonylurea in T2DM [24]: Stimulate insulin secretion
secretagogues SU + insulin compared to insulin alone lowered HbA1c by 0.46 % independent of blood glucose
Chapter 4.
Glyburide (6 mmol/mol; 95 % CI, 0.240.69) SU-induced hypoglycemia is

(glibenclamide in Lower insulin doses are required with SUinsulin combination a significant complication and
Europe), glipizide, therapy caution is required, particularly
and glimepiride Mean increase in weight of 2.31 kg (95 % CI, 1.313.32) in the in elderly individuals and those
SU-treated groups when compared with comparator groups with renal impairment
Regular dose review is
recommended; consider
halving dose or discontinue if
hypoglycemia ensues
Glyburide is associated
with higher risk of severe
hypoglycemia compared to
glipizide or glimepiride
SUinsulin combination therapy
can induce further weight gain
Thiazolidinediones Systematic review comparing efficacy of PIO + insulin vs. similar PIO is the only available TZD
(TZD) or glitazones insulin regimen without oral glucose-lowering agents [25]: which reduces insulin resistance
PIO + insulin combination therapy showed greater reductions in without stimulating insulin
HbA1c (mean difference = 0.58 %; 95 % CI, 0.70 to 0.46)a release
Greater risk of hypoglycemia (relative risk = 1.27; 95 % CI, 0.99 PIO exerts an insulin-sparing
1.63)a effect
Greater weight gain (mean difference = 2.91 kg; range: 3.85 Increased levels of HLD
3.50 kg)a cholesterol with PIO therapy
Peripheral edema is commonly
reported with PIO therapy
1020 % individuals on PIO
therapy may experience drug-
related congestive heart failure
Contraindicated in individuals
with history of heart failure,
bladder cancer, bone fractures,
or macroscopic hematuria
CI confidence interval, CV cardiovascular, FDA US Food and Drug Administration, Met metformin, NICE National Institute
for Health and Care Excellence, PBO placebo, PIO pioglitazone, SU sulfonylurea, WMD weighted mean difference
a
Denotes significance value at P < 0.05
101
However, combination therapy also requires maximal titra-

tion of insulin dose to achieve optimal therapeutic effect.
4.3.3 Combination Therapy with Newer Classes

of Glucose-Lowering Agents
4.3.3.1 Insulin in Combination with GLP-1RAs
GLP-1RA injectable therapies are synthetic modified gut

peptides used as second- or third-line adjuncts to oral glucose-
lowering agents for inadequately controlled T2DM. Among
individuals on a basal-only insulin regimen who are unable to
achieve satisfactory HbA1c despite optimizing fasting glucose
targets, one strategy is intensification of therapy with a pran-
dial insulin. However, combination therapy with GLP-1RA
and basal insulin presents a more appealing option by utilizing
the complementary effects of basal insulin on glucose excur-
sions in the fasting and postabsorptive state (i.e., glucose
excursions approximately six hours after a meal) and GLP-
1RAs, which reduce postprandial hyperglycemia via insulin-
mediated glucose disposal, suppression of hyperglucagonemia,
and reduced gastric emptying.
Notable differences in the pharmacotherapeutic attributes
of the two main subclasses of GLP-1RA therapies are short
acting (e.g., exenatide, lixisenatide) and have more robust
effects on postprandial hyperglycemia and gastric emptying
with less pronounced effects on fasting glucose, while long-
acting (e.g., liraglutide, once-weekly exenatide, albiglutide,
and dulaglutide) have more potent fasting glucose-lowering
effects and less nausea with less pronounced effects on post-
prandial glucose excursions [26]. Clinical advantages with
combination therapy include superior glucose lowering com-
pared to either agent alone, lower risk of hypoglycemia, less
weight gain, and lower insulin dose requirement [26].
Therefore, combination therapy can effectively address the
underlying defective pathophysiological pathways of T2DM
and offer important clinical benefits.
The sequence of basal insulin and GLP-1 prescribing may

vary in clinical practice. While short-acting GLP-1RAs exert
a more potent glucose-lowering effect on postprandial glu-
cose and may be more suited as add-on therapy to basal
insulin, preferential benefits of short- vs. long-acting GLP-
1RAs in combination therapy with basal insulin have not yet
been established. Combination fixed formulations of GLP-
1RA and basal insulin have been evaluated in clinical trials
(Table 4.5) and may allow more convenient administration of
both drugs in a single injection [2732].
4.3.3.2 Insulin in Combination with DPP-4 Inhibitors
DPP-4 inhibitors (or gliptins) are novel oral glucose-lowering

agents for the management of individuals with inadequately
controlled T2DM. They inhibit the DPP-4 enzyme, thereby
retarding the breakdown of endogenous GLP-1. The net
effect is augmented glucose-dependent insulin release and
inhibition of glucagon with little effect on gastric emptying.
Sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin
are examples of available drugs in this class.
DPP-4 inhibitors used either as monotherapy or combina-
tion therapy with other oral glucose-lowering agents share
similar glycemic efficacy and safety profile [33]. However,
linagliptin may offer a particular advantage because it does
not require dose adjustment with impaired renal function
(estimated glomerular filtration rate [eGFR] <30 mL/min)
due to its nonrenal route of drug excretion. As a second- or
third-line agent after metformin in the treatment pathway,
DPP-4 inhibitors have similar glycemic efficacy as SUs with
no increase in weight and lower risk of hypoglycemia but are
inferior to injectable GLP-1RA therapies [34, 35].
Key findings from clinical trials with DPP-4 inhibitors and
insulin in combination therapy have shown that DPP-4
inhibitor add-on therapy is well tolerated and results in an
additional glucose-lowering effect of approximately 6.6
8.7 mmol/mol (0.60.8 %) from a baseline HbA1c of
6778 mmol/mol (8.39.3 %), with no increase in the risk of
Table 4.5 Combination therapy of GLP-1 with insulin in individuals with inadequate glycemic control in type 2 diabetes mellitus
104
Insulin added to
novel glucose-
lowering drugs Selected trials illustrating glycemic efficacy and safety Comments
GLP-1 RA or Efficacy of GLP-1RA added to existing treatment with Improve glycemic control by their insulinotropic
incretin mimetic basal insulin with or without conventional oral glucose- and glucagonostatic effect
Chapter 4.
Available as lowering agents in a systematic review [27]: Combination therapy attenuates the risk of insulin-
short acting Superior glycemic efficacy with combination GLP-1 induced hypoglycemia with considerable reductions
(exenatide, RA + basal insulin therapy vs. basal insulin alone (mean in weight and confers an insulin dose-sparing effect
lixisenatide) or HbA1c difference = 0.44 %; 95 % CI, 0.60 to 0.29) Beneficial effects on blood glucose and weight are
long acting Lower relative risk of hypoglycemia (relative influenced by optimal titration of basal insulin
(exenatide long- risk = 0.99; 95 % CI, 0.761.29) All GLP-1RAs show modest reductions in BP
acting release, Greater reduction in weight (mean (systolic BP by ~2 mmHg) with a small increase
liraglutide, difference = 3.22 kg; 95 % CI, 4.90 to 1.54) in HR; HR effect is more pronounced with long-
albiglutide, Efficacy and safety of lixisenatide as add-on to basal insulin acting GLP-1RAs but clinical CV significance has
dulaglutide) vs. once-daily rapid-acting insulin + basal insulin [28]: not yet been established [29]
Greater likelihood of achieving HbA1c target of Long-term durability and safety of combination
7.0 % (relative risk = 1.92; 95 % CI, 1.432.56) therapies have not been established
Efficacy of GLP-1RA added to basal Contraindications: history of acute pancreatitis,
insulin vs. basalbolus insulin regimen [27]: severe gastrointestinal disease, type 1 diabetes, and
Superior glycemic efficacy with combination GLP-1 pregnancy
RA + basal insulin therapy (mean difference in Use in CKD/eGFR threshold vary according to
HbA1c = 0.10 %; 95 % CI, 0.17 to 0.02) specific GLP-1 RA drug (e.g., lixisenatide used
Lower risk of hypoglycemia (relative risk = 0.67; 95 % with eGFR >30)

CI, 0.560.80)
Greater reduction in weight (mean
difference = 5.66 kg; 95 % CI, 9.80 to 1.51)
GLP-1 Efficacy and safety IDegLira compared to basal insulin Fixed-dose combinations have a satisfactory safety
RA + basal degludec in phase III trials (DUAL-I and DUAL-II) profile and offers greater reduction in HbA1c than
insulin in individuals with inadequately controlled T2DM either therapy alone
fixed-dose (HbA1c at baseline across groups = 8.3 %) [30, 31]: Nausea (commonly seen with GLP-1 RAs) is
combination in a In both trials, IDegLira was titrated in dose steps less pronounced with fixed combination therapy
single injection (IDeg 1 unit/lira 0.0036 mg = 1 dose step) with an because of the gradual dose titration
Two initial 16-dose step (16 units IDeg + 0.6 mg Lira for Dual therapy in a single fixed-dose combination is
formulations IDegLira and 16 units for IDeg) and titrated to convenient and may improve adherence
IDegLira and maximum 50 dose steps in both arms to achieve FPG
LixiLan have target of 45 mmol/L.
been evaluated DUAL-I: Greater HbA1c reductions of 1.9 %
in phase III trials (from baseline of 8.3 %) with IDegLira, achieving
the primary end point of superiority vs. liraglutide;
noninferiority vs. insulin degludec (1.3 % and
1.4 %; P < 0.0001, respectively)
DUAL-II: Greater HbA1c reductions (1.9 % with
IDegLira and by 0.9 % with IDeg) from baseline
HbA1c of 8.8 % with estimated treatment difference
of 1.1 % (95 % CI, 1.3 to 0.8)
Greater weight reduction (~2.7 kg) and comparable
rates of hypoglycemia
(continued)
105
106
Insulin added to
novel glucose-
Efficacy of LixiLan (lixisenatide 1 g/glargine 2 units)
vs. glargine alone [32]:
Chapter 4.
HbA1c at baseline in both groups = 8.0 %

Superior glycemic efficacy with LixiLan (mean
HbA1c difference = 0.17 %; 95 % CI, 0.31 to 0.04)
Significant weight loss 1.4 kg (95 % CI, 2.1 to 0.8)
No increase in hypoglycemia
BP blood pressure, CI confidence interval, CKD chronic kidney disease, CV cardiovascular, eGFR estimated glomerular filtration
rate, FPG fasting plasma glucose, GLP-1 RA glucagon-like protein-1 receptor agonist, IDegLira insulin degludec + liraglutide, HR
heart rate, IDeg insulin degludec, Lira liraglutide, LixiLan lixisenatide + insulin glargine
hypoglycemia and no effect on body weight [35]. Thus, adding

a DPP-4 inhibitor to basal insulin therapy can be advanta-
geous when compared to an intensified regimen with pran-
dial insulin aimed at lowering postprandial hyperglycemia,
which may result in more weight gain and hypoglycemia.
4.3.3.3 Insulin in Combination with SGLT2 Inhibitors
SGLT2 inhibitors are novel oral glucose-lowering agents used

in the management of individuals with T2DM. They reduce
tubular reabsorption of glucose by selective, reversible inhibi-
tion of SGLT2 proteins which are expressed in the renal
tubule, resulting in urinary loss of glucose. The clinical effects
of SGLT2 inhibition, which is independent of insulin stimula-
tion, result in improvements in glycemic control, lower risk of
hypoglycemia, and weight loss. Modest reductions in blood
pressure are also observed due to a natriuretic effect.
SGLT2 inhibitors in combination with insulin may provide
additional glycemic benefits, may mitigate weight gain, and
have been shown to be a useful adjunct to insulin therapy.
Trials with SLGT2 inhibitors such as dapagliflozin, cana-
gliflozin, and empagliflozin as an add-on to basal insulin have
shown glycemic improvement without increased risk of hypo-
glycemia (Table 4.6) [3639]. For example, in the EMPA-
REG multiple daily injections (MDI) of insulin study, add-on
empagliflozin therapy in obese individuals with inadequate
glycemic control despite using high-dose MDI insulin showed
greater improvements in glycemic control without an
increased risk of hypoglycemia [39]. The results demonstrate
that SGLT2 inhibitors are a safe and attractive option in
individuals who fail to achieve HbA1c targets despite using
more physiological insulin regimen.
4.3.4 Basal-Plus Insulin Regimen
Intensifying insulin therapy by adding prandial insulin to

basal insulin is a practical and effective strategy when post-
prandial glycemic excursions cannot be adequately controlled
Table 4.6 Selected trials illustrating glycemic efficacy and safety of insulin added to novel glucose-lowering drugs:
108
SGLT2 inhibitors
Insulin added to
novel glucose-
SGLT2 inhibitor Efficacy and safety of dapagliflozin as an add-on therapy to Act by selective
Chapter 4.
(gliflozins) high-dose insulin (30 IU/day) oral agents in individuals with inhibition of renal
Dapagliflozin, inadequately controlled T2DM over 2 years [36]: tubular SGLT2 proteins
canagliflozin, Mean baseline HbA1c 8.5 %; mean BMI 33.2 kg/m2 which reduces tubular
and Superior glycemic efficacy with dapagliflozin 10 mg/day (mean glucose reabsorption and
empagliflozin treatment difference = 0.35 %; 95 % CI, 0.55 to 0.15) promotes a glucuretic
are the currently No reported major hypoglycemia and weight reduction of ~3 kg effect
approved drugs over 2 years with dapagliflozin The mode of action of
in this class SGLT2 inhibitors is
independent of -cell
function and therefore
does not confer a high
risk of hypoglycemia
Treatment with the
gliflozins is well tolerated
Genitourinary bacterial
and fungal infections are

more common in women
Efficacy and safety of canagliflozin as add-on therapy to basal
insulin over 18 weeks in individuals with inadequately controlled
T2DM [37]:
Mean baseline HbA1c 8.3 %; mean BMI 33.8 kg/m2
Superior glycemic efficacy with canagliflozin 100 mg and 300 mg,
respectively (mean HbA1c treatment difference vs. PBO = 0.65
to 0.73 %, respectively)* at 18 weeks
More patients attained HbA1c <7 % with canagliflozin (20
25 %)* vs. PBO (8 %) at 18 weeks
Higher incidence of hypoglycemia with canagliflozin 100 and
300 mg (both 49 %) vs. PBO (37 %)
Efficacy and safety of empagliflozin as add-on therapy to basal
insulin after 78 weeks in individuals with inadequately controlled
T2DM the EMPA-REG BASAL study [38]:
Mean baseline HbA1c 8.2 %; mean BMI 32.2 kg/m2
Superior glycemic efficacy with empagliflozin 10 mg and 25 mg,
Greater reductions in insulin doses (~ 6 IU/day), weight (~
2 kg)* and blood pressure (~ 4 to 2.4 mmHg) vs. PBO at 78
weeks
No differences in hypoglycemic events between treatment groups
109
(continued)
110
Insulin added to
novel glucose-
Efficacy and safety of empagliflozin as add-on therapy to MDI
Chapter 4.
insulin metformin after 1 year of treatment in obese individuals

with inadequately controlled T2DM (mean baseline HbA1c 8.3 %,
mean BMI 34.8 kg/m2, mean insulin dose 92 IU/day) : the EMPA-
REG MDI
study [39]:
Superior glycemic efficacy with empagliflozin 10 mg and 25 mg,
Greater reductions in insulin doses (9 to 11 IU/day) and weight
(2.39 to 2.48 kg)* vs. PBO at 52 weeks
More patients attained HbA1c <7 % with empagliflozin (31
42 %)* vs. PBO (21 %) at 52 weeks
No differences in hypoglycemic events between treatment groups
BMI body mass index, HbA1C glycated hemoglobin, PBO placebo, MDI multidose injection, T2DM type 2 diabetes
mellitus
*
P < 0.01
with a basal-only insulin regimen (Table 4.7 and Fig. 4.4)

[4044]. However, there are no consensus recommendations
on whether the breakfast meal, the largest meal of the day
(typically dinner), or the meal which impacts most on post-
prandial glucose levels should be the initiating target for pran-
dial insulin therapy. In the Treating to Target in Type 2
Diabetes (4 T) study, 67.7 %, 73.6 %, and 81.6 % individuals on
biphasic, prandial, and basal insulin regimen, respectively,
required a second type of insulin to achieve satisfactory glyce-
mic targets [18]. Furthermore, sequential addition of prandial
insulin to other meals of the day may be required before
intensification to a basalbolus regimen.
4.3.5 Twice-Daily Premixed Insulin Regimen
Twice-daily premixed (biphasic) mixture insulin regimens are

commonly employed as a treatment intensification measure
in individuals failing to achieve HbA1c targets with a basal-
only insulin regimen (Table 4.8) [4547]. It provides cover for
both prandial and basal insulin requirements, while reducing
the frequency of injections required with a basalbolus regi-
men. Although it has comparable glycemic efficacy to a basal-
plus (one prandial injection) insulin strategy, potential
drawbacks include lack of flexibility in fine adjustment of
fasting (postprandial glucose targets because the specific
titration of individual components of the insulin mixture is
not possible), weight gain, and higher rates of hypoglycemia,
which may also preclude its use in frail and elderly people.
Nonetheless, they are recommended and commonly pre-
ferred regimen in insulin-naive individuals with T2DM pre-
senting with a high baseline HbA1c (>9.5 %) due to their
glycemic superiority over a basal-only insulin regimen [48].
Premixed insulin analogs may have a distinct advantage over
biphasic human insulin in terms of improved glycemic con-
trol, lower risk of hypoglycemia, lower treatment discontinu-
ation rates, and cost-effectiveness.
Health-care professionals may consider switching or inten-
sifying insulin therapy from a twice-daily premixed regimen
Table 4.7 Basal-plus insulin regimen in individuals with poorly

controlled type 2 diabetes (T2DM)
When to consider Suboptimal HbA1c targets despite
basal-plus regimen maximal titration of a basal-only insulin
regimen
How to initiate and A single injection of prandial insulin at
self-manage ~46 units (~10 % of the total daily basal
insulin dose) is added to the largest meal
or to the meal which impacts most on
postprandial glucose levels
Clinical evidence Efficacy of single prandial insulin injection
(key studies) in individuals with HbA1c (7.59.5 %) on
maximally titrated basal insulin : proof of
concept study [41]:
Greater HbA1c reductions
(treatment difference: basal plus vs.
basal [0.37 vs. 0.11 %; P < 0.05])
Rates of hypoglycemia and mean
weight change were similar between
groups
Efficacy of adding prandial insulin
glulisine injection either at breakfast
or with main meals, in individuals with
suboptimal HbA1c (>6.59.0 %) on
glargine + oral glucose-lowering drugs
the OPAL study [42]:
At 24 weeks, greater and significant
improvements in HbA1c (baseline
vs. end point) in the breakfast (7.4
vs. 7.0 %) and main mealtime groups
(7.3 vs. 6.9 %)
Efficacy of basal glargine + 1 injection
glulisine vs. basal glargine + up to 3
injections prandial glulisine vs. twice-
daily premixed insulin aspart in
T2DM the All to Target study [43].
Noninferiority of basal-plus (one

injection) regimen to premixed
regimen
Glycemic efficacy of self-titration
algorithms adjusting prandial insulin
lispro every day or every 3 days for 24
weeks the AUTONOMY trial [44]:
Similar reductions in HbA1c with no
differences in rates of hypoglycemia
Greater HbA1c May eventually need a second or third
reductions compared prandial injection to achieve adequate
to basal-only insulin glycemic control
regimen
Low risk of
hypoglycemia
compared to a
basalbolus regimen
if glucose control remains suboptimal despite maximum titra-

tion of regimen. Factors such as nocturnal hypoglycemia and
excessive weight gain are other considerations. In some cases,
the individuals may prefer a more flexible regimen to address
issues around quality of life.
4.3.6 Prandial-Only Insulin Regimen
A prandial-only insulin regimen involves adding a prandial

insulin at mealtimes, starting with the largest meal of the day
(Table 4.9). It is not commonly employed, although clinical
trials using such a regimen have shown greater improve-
ments in HbA1c (mean reduction = 0.40; 95 % CI, 0.29 to
0.51) compared to basal-only insulin regimen with oral
agents [45]. Importantly, most of these studies used three
prandial injections and provoked more hypoglycemia and
weight gain [45].
114
Chapter 4.
Figure 4.4 Insulin dose titration in the basal-plus insulin regimen in individuals with poorly controlled type 2 diabetes
mellitus. FPG fasting plasma glucose, PPG postprandial glucose (Adapted from Bergenstal et al [40] American
Diabetes Association)
Table 4.8 Twice-daily premixed insulin regimen in individuals with

poorly controlled type 2 diabetes (T2DM)
When to consider Suboptimal HbA1c targets with a basal-
twice-daily premixed only insulin regimen other glucose-
insulin lowering agents
Higher baseline HbA1c >9.5 %
and/or dominance of postprandial
hyperglycemia with majority of
fasting glucose readings closer to
target, particularly in insulin-nave
individuals with poor glycemic
control
As an alternative to basal-plus insulin
regimen
May suit certain individuals with
a regimented lifestyle and eating
patterns
How to initiate and Begin with 10 units or 0.2 units/kg before
self-manage breakfast and before evening meal; a
lower dose may suit certain individuals
(e.g., elderly or slim patients)
Titrate insulin based on three
consecutive self-monitored blood
glucose (SMBG) levels:
Morning dose is titrated against
pre-lunch and pre-evening meal
blood glucose readings: 2 unit
increments or 10 % increase aiming
for target glucose of <6 mmol/L
before lunch and before evening
meal
Evening dose is titrated against
pre-bedtime and pre-breakfast
blood glucose readings. 2 unit
increments or 10 % increments
aiming for target blood glucose of
5.56 mmol/L pre-breakfast and
<6 mmol/L pre-bedtime
(continued)
Pre-bedtime blood glucose should

ideally remain between 6 and
8 mmol/L. If <6 mmol/L, beware of
the risk of nocturnal hypoglycemia
and defer insulin dose titration
Clinical evidence (key Efficacy of a twice-daily premixed
studies) regimen compared to a basal-only
regimen with both regimen using similar
oral glucose-lowering agents in insulin-
nave individuals a systematic review
[45]:
Superior glycemic efficacy with
twice-daily premixed insulin
regimen (mean treatment
difference in HbA1c = 0.28 %; 95 %
CI, 0.200.36)
Higher insulin doses used with
premixed insulin (42 IU/day) vs.
basal insulin (37 IU/day) regimen
Greater increase in weight gain
with premixed (3.7 kg) vs. basal
(2.2 kg) insulin regimen
Lower risk of hypoglycemia with
basal compared to premixed insulin
regimen
Efficacy of a twice-daily premixed
regimen compared to basal-only
regimen with both regimen using oral
glucose-lowering agents in previously
insulin-treated individuals a
regimen

Greater increase in weight gain
with premixed compared to basal
insulin regimen
Greater risk of hypoglycemia with
premixed compared to basal insulin
regimen
Efficacy of biphasic versus basal
insulin regimen a systematic review
[46]:
regimen (mean treatment
difference in HbA1c = 0.45 %; 95 %
CI, 0.190.70)
Efficacy of insulin analogs in
achieving HbA1c target of <7 % in
T2DM: meta-analysis [47]
Greater proportion of individuals
achieved HbA1c <7 % with
biphasic compared with basal
insulin regimen (odds ratio
1.88 [95 % CI, 1.382.55]) but
was associated with greater
risk of hypoglycemia (mean
difference = 0.34 events/
patient/30 days [range 00.69] and
weight gain = 1.0 kg [0.281.73])
It has the potential Less flexibility (short/rapid or basal
to control basal components cannot be individually
(postabsorptive) and titrated)
prandial excursions in
a simplistic regimen
requiring two
injections a day
(continued)
Convenient, can be Increased risk of hypoglycemia and

initiated with ease, and weight gain compared to basal-only
does not significantly regimen
impact on health-
related quality of life
Demonstrates Titration may become complicated and
superior glycemic difficult (particularly for the patient), if
efficacy to basal-only wide variability in blood glucose occur
insulin regimen and either due to erratic meals or exercise
is a step forward in
intensification of
insulin therapy
CI confidence interval, HbA1c glycated hemoglobin
Prandial-only regimens may not suit all individuals and

some may find difficulty coping with multiple injections.
Another consideration may be inability to achieve satisfac-
tory glycemic targets despite adequate control of prandial
hyperglycemia and/or presence of higher fasting blood glu-
cose indicating the need for basal insulin.
4.3.7 BasalBolus Insulin Regimen
A basalbolus strategy involves at least three or four injec-

tions a day, comprising of basal insulin with prandial insulin
added at mealtimes. It mimics the physiological profile of
endogenous insulin production and, hence, offers the best
opportunity to achieve optimal glycemic control (Table 4.10).
Although such a regimen offers the flexibility of independent
titration to achieve fasting (postabsorptive) and postprandial
glucose targets, it also requires frequent glucose monitoring
and active insulin dose titration. Therefore, it works well in
highly motivated individuals and is a good choice for those
with an erratic lifestyle, unpredictable eating habits, shift
workers, those engaged in competitive sports, and for those
who may benefit from intensified glycemic control.
Table 4.9 Prandial-only insulin regimen in individuals with poorly

controlled type 2 diabetes
When to Suboptimal HbA1c targets with a basal-only
consider insulin regimen other glucose-lowering agents
prandial-only
Dominance of postprandial hyperglycemia
insulin
with majority of fasting glucose readings
closer to target, particularly in insulin-nave
individuals with poor glycemic control
May suit certain individuals with active
lifestyle and variable eating patterns
How to initiate Titrate insulin based on three consecutive self-
and self-manage monitored blood glucose levels
Use 2 unit increments or 10 % increase
aiming for target glucose of <6 mmol/L
before lunch and before evening meal
Pre-bedtime blood glucose should ideally
remain between 68 mmol/L
If <6 mmol/L, beware of the risk of
nocturnal hypoglycemia and defer insulin
dose titration
Clinical Efficacy of a prandial regimen compared to a
evidence (key basal-only regimen with both regimen using
studies) similar oral glucose-lowering agents, in insulin-
nave individuals: systematic review [45]:
Superior glycemic efficacy with prandial
insulin regimen (mean treatment
difference in HbA1c = 0.40 %; 95 % CI,
0.29 to 0.51)
Greater increase in weight gain with
prandial (3.7 kg) vs. basal (2.2 kg) insulin
regimen
Greater risk of hypoglycemia with
prandial insulin regimen compared to
basal-only insulin regimen
(continued)
Efficacy of prandial versus basal-only

insulin regimen: findings of a systematic
review [45]:
Superior glycemic efficacy with prandial
insulin regimen (mean treatment
difference in HbA1c = 0.45 %; 95 % CI,
0.160.73)
Potential Increased risk of hypoglycemia and weight
to control gain compared to basal-only regimen
postprandial
glucose
excursions
The regimen May require more than one prandial insulin
is flexible and injection to achieve glycemic targets. Titration
convenient may become complicated and difficult
and does not (particularly for the patient), if wide variability
significantly in blood glucose results from erratic meals and
impact on exercise
quality of life
In insulin-nave individuals with inadequately controlled

T2DM on other glucose-lowering agents, both basalbolus
and premixed insulin regimen show comparable glycemic
efficacy, and the choice of starting insulin regimen requires
individual consideration. However, weight gain and risk of
hypoglycemia are more common when compared to other
less intensive insulin regimens [18]. With the advent of newer
second-generation basal analogs (e.g., insulin degludec, insu-
lin glargine U300) which have a more robust physiological
basal insulin profile and lower risk of overall and nocturnal
hypoglycemia, further improvements in the safety profile of
intensive basalbolus regimen can be anticipated.
Some individuals may find basalbolus regimens very
demanding, especially when coping with multiple injections
making a basal-plus regimen a preferred choice. If a patient
Table 4.10 Basalbolus insulin regimen in individuals with poorly

controlled type 2 diabetes
When to consider Suboptimal HbA1c targets with a basal-
basalbolus insulin plus or twice-daily premixed insulin
regimen other glucose-lowering agents
May suit certain individuals with an
erratic lifestyle and eating patterns
How to initiate In insulin nave or those on a basal-only
and self-manage regimen:
Calculate total daily insulin dose 0.3
0.5 units/kg and divide into 50 % basal
insulin (preferably at bedtime) and
50 % prandial insulin to cover three
meals
For example, for an individual weighing
70 kg: TDI = 0.5 70 = 35 units; basal
insulin = 50 % of TDI = ~18 units; bolus
insulin =50 % of TDI divided between
three meals = 6 units at each main meal
Approach when transferring from a
twice-daily premixed insulin regimen to a
basalbolus regimen:
Add up total daily dose of the existing
premixed regimen and reduce this
dose by 20 % (may not apply if
blood glucose readings/HbA1c are
significantly elevated)
Give 50 % of the total daily dose as a
basal insulin and 50 % to cover main
meals
For example, Humalog Mix 25 or
Humulin M3: 50 units am, 50 units pm.
Total daily dose =100 units (20 % = 80
units). Give 40 units as basal insulin
and 1214 units as prandial insulin
taking into consideration meal quality,
portions, and eating habits
(continued)
Clinical evidence Efficacy of a basalbolus regimen compared

(key studies) to a twice-daily premixed regimen, in
previously insulin-treated individuals a
Greater HbA1c reductions with
basalbolus compared with premixed
(biphasic) insulin regimen (mean
HbA1c treatment difference = 0.2 %;
95 % CI, 0.36 to 0.03)
Greater increase in weight with basal
bolus (3.2 kg) compared to premixed
(2.3 kg)
Risk of hypoglycemia was comparable
Efficacy of a basalbolus regimen
compared to a twice-daily premixed
regimen in insulin-naive individuals [49]:
Similar HbA1c reductions were
obtained with both insulin regimens in
a systematic review
The regimen has Requires frequent blood glucose monitoring
the potential to and active insulin dose titration to optimize
target both basal therapeutic effect
(postabsorptive)
and prandial
glucose excursions
and offers
flexibility of
individual dose
titration
Most suited for Increased risk of weight gain compared to
those with erratic basal-only and premixed insulin regimen
lifestyles and
eating habits
4.4 Intensifying Insulin Therapy 123

Works well in Titration may become complicated and
highly motivated difficult (particularly for the patient) if wide
individuals variability in blood glucose occurs either due
to erratic meals or exercise
Demonstrates
superior glycemic
efficacy to basal-
only, basal-plus,
and premixed
insulin regimen
and is a step
forward in
intensification of
insulin therapy
has a regimented lifestyle where injection frequency can be

reduced without significantly compromising glycemic con-
trol, then a regimen change (e.g., twice-daily premixed insulin
regimen) may be an option. Suboptimal control despite maxi-
mal titration of regimen and excessive weight gain are other
considerations.
4.4 Intensifying Insulin Therapy

with Inadequately Controlled Type 2
Diabetes
Broad strategies of intensification of insulin therapy in
T2DM include initiation with a basal-only insulin regimen
(adding basal insulin to other glucose-lowering agents),
subsequent intensification with prandial insulin, and progres-
sion to a basalbolus regimen when satisfactory glycemic
targets are not achieved. However, as previously discussed,
twice-daily premixed regimen and complementary newer
therapies with insulin merit consideration and may add a new
dimension to intensification of insulin therapy in the manage-
ment of T2DM. Figure 4.5 illustrates a stepwise approach to

intensify insulin therapy in individuals with inadequately
controlled T2DM.
4.5 Summary
The conventional approach to treating T2DM is a stepwise
introduction of lifestyle modifications, oral glucose-lowering
drugs, and non-insulin injectable therapies (depending on
their indication) before recommending insulin. The main
concern for both health-care providers and patients is
insulin-induced hypoglycemia and weight gain. In recent
years, newer therapies such as GLP-1RAs, DPP-4 inhibitors,
and SGLT2 inhibitors have gained greater appeal. In combi-
nation with other classes of glucose-lowering therapies, these
newer agents may allow delay in insulin initiation or, in com-
bination with basal insulin, may offer an insulin dose-sparing
effect, augment weight loss, and lower the risk of hypoglyce-
mia. Accordingly, they are increasingly being used in the
T2DM treatment paradigm.
The evidence base for the optimal starting insulin regimen
suggests a once-daily basal-only insulin regimen added to
other glucose-lowering agents in individuals with inade-
quately controlled T2DM. Most individuals will eventually
need intensification of treatment with sequential addition of
prandial insulin to basal insulin, progressing to a basalbolus
regimen to attain glycemic targets. In recent years, the man-
agement of T2DM has moved away from being exclusively
glucocentric to targeted control of multiple risk factors to
reduce cardiovascular risk and mortality. While clinicians
continue in their attempts to use better and more effective
insulin therapies, the focus has shifted to using newer glucose-
lowering therapies which have a salutary effect on weight,
blood pressure, and lipid levels to improve the metabolic
profile of some individuals with T2DM. Acknowledging that
the thrust of patient care in most countries is centered on the
primary care setting, more efforts are required to tackle the
problem of clinical inertia and improve knowledge of insulin
4.5 Summary 125
Sub-optimal HbA1c targets (e.g., 7.5% ~ 59 mmol/mol) despite lifestyle change,

continued and maximal titration of glucose lowering agents (including Metformin, SU,
TZD or newer agents such as GLP-1RA, DPP-4 inhibitors or SGLT-2 inhibitors) used
singly or in combination or if intolerance/contra-indication to these therapies precludes
their use.
A. BASAL ONLY INSULIN REGIMEN
Titrate to fasting glucose targets ( other glucose lowering agents continued)
Sub-optimal HbA1c targets (e.g., 7.5%/~ 59 mmol/mol) despite maximal titration of a

basal-only insulin regimen other glucose lowering agents, lifestyle change continued.
Twice-daily GLP-1 RA (if not B. BASAL + 1 PRANDIAL INSULIN

premixed previously treated) to REGIMEN
insulin basal insulin.
regimen Add a single prandial insulin to the largest
- May benefit obese
meal or to the meal with greatest
individuals and/or if
postprandial blood glucose excursions.
- Higher basal insulin at high
baseline dose (~1.5u/kg) and/or if
HbA1c > 9.5%. increase in insulin doses
results in weight gain
without improvement in
blood sugars. Sub-optimal HbA1c targets with a basal-plus
- As an
Fixed ratio formulations insulin regimen
alternative to
basal-plus of Basal insulin with
insulin GLP-1
regimen. C. BASAL + 2 PRANDIAL INSULIN
(Insulin Degludec with
Liraglutide (IDegLira) REGIMEN
and Insulin Glargine with
Lixisenatide (LixiLan) Add a second prandial insulin as necessary.
Sub-optimal HbA1c targets (e.g., 7.5% ~ 59 mmol/mol) despite maximal titration of a

basal-plus insulin regimen other glucose lowering agents, lifestyle change continued.
D. Basal-bolus insulin regimen
Basal insulin with 3 to 4 prandial insulin added to mealtimes
Fig. 4.5 Stepwise intensification of insulin therapy in the manage-

ment of type 2 diabetes. DPP4i dipeptidyl peptidase-4 inhibitor,
GLP-1 RA glucagon-like peptide-1 receptor agonist, HbA1c gly-
cated hemoglobin, SGLT2 sodiumglucose transport protein 2, SU
sulfonylurea, TZD thiazolidinedione
regimens among health-care professionals caring for people

with T2DM.
I am convinced that the key to stopping the deadly, costly, and
life-disrupting complications of diabetes is to ensure that every
person with diabetes is part of a patient-centered diabetes care
team. Richard M. Bergenstal
Key Messages
Type 2 diabetes is initially managed with lifestyle modifi-
cation and treatment with metformin.
Despite optimization of oral therapies, many individuals
require some form of insulin therapy over time to achieve
satisfactory glycemic targets.
In recent years, combination therapy with newer glucose-
lowering therapies such as GLP1 receptor agonists and
basal insulin are being used.
Clinical inertia among health-care professionals exists and
may prevent timely initiation and optimization of insulin
treatment.
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atic review and meta-analyses. Diabetologia. 2009;52:19902000.
Further Reading 131
47. Giugliano D, Maiorino MI, Bellastella G, Chiodini P, Ceriello A,

Esposito K. Efficacy of insulin analogs in achieving the hemoglo-
bin A1c target of <7% in type 2 diabetes: meta-analysis of ran-
domized controlled trials. Diabetes Care. 2011;34:5107.
48. American Diabetes Association (ADA). 6. Glycemic targets.
Assessment of glycemic control. Diabetes Care. 2015;38 (Suppl 1):
S340.
49. Wang C, Mamza J, Idris I. Biphasic vs basal bolus insulin regimen
in Type 2 diabetes: a systematic review and meta-analysis of ran-
domized controlled trials. Diabet Med. 2015;32:58594.
Further Reading
Crasto W, Jarvis J, Khunti K, Davies MJ. New insulins and new insu-
lin regimens: a review of their role in improving glycaemic con-
trol in patients with diabetes. Postgrad Med J. 2009;85:25767.
Davies MJ, Gargliardino JJ, Gray LJ, Khunti K, Mohan V, Hughes
R. Real-world factors affecting adherence to insulin therapy in
patients with type 1 or type 2 diabetes mellitus: a systematic
review. Diabet Med. 2013;30:51224.
Chapter 5
Insulin Management in Type 1
Diabetes
5.1 Overview
Type 1 diabetes mellitus (T1DM) is characterized by absolute
insulin deficiency, primarily due to autoimmune-related
destruction of pancreatic islet cells. It is usually diagnosed in
children and young adults but can occur at any age. The rate
of -cell death is variable and individuals are usually clini-
cally symptomatic when nearly 7080 % of pancreatic cell
mass is depleted. Treatment with exogenous insulin is lifesav-
ing and ensures survival [1]. Globally, the prevalence of
T1DM is growing at approximately 3 % per year (Fig. 5.1).
Incidence rates show a wide geographic variation and of the
estimated 497,100 children worldwide with T1DM, 26 % live
in Northern Europe, followed by 22 % in North America and
the Caribbean. In the last decade, rising incidence has been
observed in parts of India, Middle East, and sub-Saharan
Africa. The global increase in the numbers of individuals
diagnosed with T1DM therefore has implications both for
health-care resources and cost of management and places a
greater demand on diabetologists, diabetes specialist nurses,
dieticians, and primary care health-care professionals.
This chapter will address two main clinical questions in the
management of T1DM:
1. What are the different types of insulin regimen in T1DM,
indications, and evidence for use in a clinical setting?

DOI 10.1007/978-3-319-10939-8_5,
Figure 5.1 New cases of type 1 diabetes (014 years per 100,000
children per year), 2013 (Reproduced with permission from the
International Diabetes Federation (IDF) [1] IDF)
2. What are the technological advances in continuous subcu-

taneous insulin delivery (insulin pump), and how have they
helped individuals with T1DM?
5.2 The Benefits of Tight Glycemic Control

in Type 1 Diabetes
Glycemic targets for children with T1DM proposed by the
American Diabetes Association (ADA) and the International
Society for Pediatric and Adolescent Diabetes (ISPAD)
recommend a tight HbA1c target of <7.5 % (58 mmol/mol).
The largest and longest prospective study in adolescents
and young adults, the Diabetes Control and Complications
Trial (DCCT), and its follow-up Epidemiology of Diabetes
Interventions and Complications (EDIC) study demon-
strated that early and tight glycemic control with intensive
insulin therapy (multiple-daily injections or insulin pump
therapy) when compared to conventional therapy with one
or two daily insulin injections reduces the risk of long-term
5.2 The Benefits of Tight Glycemic Control 135
microvascular complications and cardiovascular disease [2,

3]. However, findings from recent systematic reviews (which
also included trial data from the DCCT/EDIC studies) sug-
gest that tight glycemic control versus a conventional
approach reduces the risk of macrovascular disease out-
comes but without significant effects on all-cause mortality
or cardiovascular mortality [4, 5]. Beneficial reductions in
microvascular complications with intensive glycemic control
were most evident in younger individuals with shorter dura-
tion of T1DM. Furthermore, the effects of tight blood glucose
control seem to weaken once complications are manifest and
must be weighed against the risks of severe hypoglycemia in
older adults with T1DM.
The post-DCCT era has seen a surge of technological
advances in diabetes management aimed at helping people
with T1DM achieve near-normal glycemia with a reduced
risk of hypoglycemia. A few examples include the advent of
newer and more physiological insulin analogs, sophisticated
continuous glucose monitoring (CGM) devices, and closed-
loop or artificial pancreas device systems, which is now an
area of active research [6]. Although successful pancreas and
islet implantation therapy has proven efficacy in improving
the quality of life of people with diabetes, these therapies are
restricted by the availability of human donor pancreas, come
with attendant risks of immunosuppressive therapy, and, thus,
have been met with limited success.
Glycemic management in individuals with T1DM requires
an individualized approach that considers physical and psy-
chological maturity and the diverse age group with this con-
dition. Health-care professionals and carers must be aware of
a multitude of factors which can affect management of young
people with T1DM, such as unpredictable eating habits and
activities, nonadherence to medication, risk-taking behaviors,
pregnancy and sexual health, eating disorders and body
image, insulin resistance, and microvascular complications.
Although an intensive insulin regimen is unequivocally the
gold standard of care, it is not without an undue risk of
hypoglycemia and can be mitigated by frequent blood glucose
monitoring and efficient insulin self-management. However,

while increasing the frequency of injections and improved
modes of insulin delivery are important facets of manage-
ment, all individuals with T1DM should have access to a dedi-
cated multidisciplinary team who can support and equip them
with the knowledge, skills, and education to achieve autonomy
in insulin self-management and to live a life with dietary free-
dom and without constraints.
5.2.1 Adherence to Insulin Therapy in Individuals

with T1DM
Adherence to insulin therapy is associated with satisfactory
glycemic control. However, adherence to an insulin regimen
can be daunting, particularly in adolescents with T1DM who
are expected to independently self-manage their own condi-
tion. A constellation of factors can impact treatment adher-
ence including lack of motivation, lack of diabetes-specific
knowledge and skills, attitudes and stigma regarding diabetes,
difficulties with time management, adolescent relations with
parents and peers, and the stress or burnout of caring for a
chronic condition [7].
5.2.2 Role of Continuous Glucose Monitoring

for Intensive Insulin Therapy
While self-monitoring of capillary blood glucose (SMBG)
using finger prick testing is a reliable way to manage diabetes,
some individuals may not meet satisfactory glycemic targets
using this method. Furthermore, SMBG testing may not suf-
ficiently inform on daily and day to day oscillations in glucose
concentrations (glucose variability) which is an independent
predictor of severe hypoglycemia particularly in individuals
with frequent low blood glucose levels [8]. CGM offers less
discomfort compared to conventional blood glucose testing
and is a useful adjunct to SMBG. It has the potential to
5.2 The Benefits of Tight Glycemic Control 137
improve glycemic control, assess within- and between-day

glucose variability, assess changes in response to therapy, and
reduces the risk of hypoglycemia [9].
The basic components of a CGM device are a sensor,
transmitter, and a wireless receiver. The sensor is a very fine
needle, approximately half an inch long, and is inserted under
the skin for several days. It estimates interstitial glucose and
can provide over 250 glucose readings in 24 h. The transmitter
hooks into the sensor and streams glucose information via
radio-frequency waves to the monitor. The monitor can dis-
play trends in glucose levels in real time and has a program-
mable threshold alarm which informs users of impending
hypoglycemia or hyperglycemia and, therefore, permits
immediate or planned adjustments to insulin therapy. Glucose
data can also be accessed retrospectively which is beneficial
when considering changes in lifestyle and insulin manage-
ment. Clinical studies comparing CGM with SMBG have
shown modest reductions in HbA1c of approximately 0.26 %
[10], although greater improvements in HbA1c (0.9 %) and
reduced risk of hypoglycemia can be expected in those who
use CGM sensors more frequently and with a higher baseline
HbA1c (>10 %) [11]. However, the cost-effectiveness of
using CGM has not been fully elucidated.
5.2.3 Sensor-Augmented Insulin Pump Therapy
In recent years, integrating real-time glucose data with insulin

pumps has paved the way for sensor-augmented pumps (SAPs).
SAPs can improve glycemic control and reduce (but not com-
pletely eliminate) hypoglycemia in select adult individuals with
T1DM [10]. SAPs integrate a sensor monitoring device (e.g.,
CGM) with an insulin pump. Manual input and adjustment of
insulin basal rates and boluses are still required. This combina-
tion provides detailed information about glucose patterns to
enable both pump users and their health-care provider to moni-
tor treatment and respond through internet-based software.
Improvements in glycemic control with SAP are observed in
individuals with poorly controlled diabetes who are naive to

insulin pump therapy [12] (Fig. 5.2). SAPs with a threshold sus-
pend feature which interrupts insulin delivery at predetermined
glucose sensor thresholds have also shown beneficial reduc-
tions in nocturnal hypoglycemia [13, 14]. However, clinical
b
Excursion summary
Sun Dec 1 Mon Dec 2 Tue Dec 3 Wed Dec 4 Thu Dec 5 Fri Dec 6 Sat Dec 7 Average/Total
# Excursions 2 9 3 6 2 1 4 27
High excursions 2 9 2 5 1 1 3 23
Low excursions 0 0 1 1 1 0 1 4
AUC above limit 23.1 27.4 65.9 23.8 82.2 55.9 21.7 48.6
AUC below limit 0.0 0.0 1.1 0.8 0.3 0.0 0.2 0.3
Duration distribution (hh:mm)
Above 140 16:45 70% 7:20 32% 13:25 63% 12:35 54% 15:05 64% 23:20 98% 9:25 42% 97:55 61%
Within (70-140) 7:15 30% 15:30 68% 6:45 31% 9:30 40% 7:40 33% 0:25 2% 12:20 55% 59:25 36%
Below 70 0:00 0% 0:00 0% 1:15 6% 1:25 6% 0:40 3% 0:00 0% 0:45 3% 4:05 3%
Figure 5.2 An example of continuous glucose monitoring data (a, b)

which can also be integrated with an insulin pump. AUC area under-
curve, MAD mean absolute difference
5.3 Insulin Regimens in Type 1 Diabetes 139
benefits are mostly derived with consistent use and recognized

barriers include frequent sensor alarms which can disrupt nor-
malcy of daily life, discomfort at sensor insertion site, and body
image issues [15]. Examples of SAP devices include the
Paradigm Veo (Medtronic, Fridley, Minnesota) and the
Animas Vibe (Animas Corporation, West Chester,
Pennsylvania) insulin pumps.
5.3 Insulin Regimens in Type 1 Diabetes

The aim of insulin therapy in T1DM is to match physiological
insulin requirements both in the fasting and postabsorptive
period and optimize an anticipated rise in blood glucose after
a carbohydrate meal. Insulin therapy should be initiated
immediately (within 6 h if ketonuria is present) after diagnosis
to prevent hyperglycemic crises. The total daily dose of insulin
may depend upon age, may differ between individuals, and
may change over time as well as on a day to day basis due to
exercise, physical activity, stress, and hormonal changes such
as evolution of insensitivity to insulin during puberty and
therefore requires regular reassessment of individual insulin
needs [16]. Children and young people with newly diagnosed
T1DM may also experience partial remission (or honey-
moon period) during which lower insulin doses (0.5 units/kg
body weight/day) are sufficient to maintain euglycemia.
Over the last decade, intensive regimens such as multiple-
daily injections (MDI) and continuous subcutaneous insulin
infusion (CSII) insulin regimen compared to less intensive
regimens of one to two injections of basal insulin singly or in
combination with prandial insulin are increasingly being
employed [17]. Although intensive regimens provide flexibil-
ity with eating habits and social and family life, they also
require high levels of patient motivation, patient education,
increased health-care input, and resources. Furthermore,
insulin omissions (or nonadherence) and lack of dose adjust-
ment can impact glycemic control [18]. Premixed insulin is
generally not recommended in pediatric age groups, although
if a twice-daily regimen is used, free mixing of regular and

neutral protamine Hagedorn (NPH) insulin is preferred.
However, variations in the preferred starting insulin regi-
men exist. Factors such as individual preference, experience
of local diabetes teams, higher parental education, higher
family income, and access to private health care may explain
variations in insulin management [19]. Factors which influ-
ence choice of an insulin regimen in T1DM include:
Age
Physical and psychological maturity
Weight gain
Risk of hypoglycemia
Individual preference of insulin delivery (e.g., subcutane-
ous injections, pump therapy) or frequency of desired
injections
Lifestyle considerations (diet and eating habits, physical
activity and sport, study and/or work commitments, health
beliefs, and culture)
Table 5.1 illustrates the insulin regimen commonly used in
individuals with T1DM.
5.3.1 Conventional Insulin Regimen
Conventional insulin regimen consists of two or three injec-

tions a day, which includes administration of an intermediate-
acting insulin (e.g., NPH) at least twice daily as basal insulin
and a rapid- or short-acting insulin with meals. Both free
mixing of basal and prandial insulin and premixed, fixed
combination insulin mixtures are available for use. Twice-daily
premixed insulin is suitable in initiating regimen in prepubes-
cent children with fairly rigid meal patterns and for those who
are not compliant with multiple-dose injections. However,
lack of flexibility in the timing of injections and meals may
increase the risk of hypoglycemia. This may be a particular
problem in adolescents who exhibit poorer glycemic control
using premixed insulin [19]. This regimen can also induce
Table 5.1 Insulin regimens in type 1 diabetes

Insulin regimen in
T1DM Glycemic target Comments
Conventional therapy
Two-injection Intermediate- Benefits individuals
or three- acting insulin with a fixed meal/
injection regimen targets FPG and activity schedule
which involves postabsorptive
May not suit those
administration of blood glucose
(e.g., adolescents)
(basal) intermediate- excursions
with active or
acting insulin (e.g., whereas prandial
erratic lifestyle
NPH) at least twice insulin targets
and eating habits
daily and a short- PPG
or rapid-acting May involve
(prandial) insulin snacking (and
two or three times hence potential
a day weight gain)
Available as to avoid
premixed or free hypoglycemia
mixing of short- or
rapid-acting and
intermediate-acting
insulin at the time of
administration
Multiple-daily injections (MDI) or basalbolus insulin regimen
One or two insulin Intermediate- Offers more
injections of or long-acting flexibility with
intermediate-acting insulin to injections
insulin or long-acting target FPG and
Benefits
insulin analog plus postabsorptive
individuals with
prandial short-acting blood glucose
variable mealtimes
insulin or rapid- excursions and
and erratic
acting insulin analog prandial insulin
lifestyles
to targets PPG
Requires frequent
SMBG
(continued)

Insulin regimen in
T1DM Glycemic target Comments
Continuous subcutaneous insulin infusion (CSII) or insulin
pump therapy
Programmable Controlled Greater flexibility
pump device with subcutaneous and accuracy with
an insulin storage infusion of rapid- insulin dosing and
reservoir containing acting insulin frequency without
rapid-acting insulin analog covers need for frequent
analog or short- basal insulin subcutaneous
acting insulin which requirements injection
enables continuous targeting administration
insulin delivery via a FPG and
subcutaneous needle postabsorptive Multiple basal
or cannula blood glucose insulin rates/carb/
excursions. Bolus insulin ratios
insulin doses benefit individuals
are delivered with erratic
manually to lifestyles and
target PPG eating habits
Expensive and
requires high
level of individual
engagement
FPG fasting plasma glucose, NPH neutral protamine Hagedorn, PPG
postprandial plasma glucose, SMBG self-monitoring of blood glucose
snacking between meals to prevent hypoglycemia, for exam-

ple, the peak of rapid-acting insulin given with breakfast cou-
pled with the peak of intermediate-acting insulin administered
in the morning can have a cumulative effect in reducing blood
glucose and, if unmatched with a mid-morning carbohydrate
snack, can result in hypoglycemia. Snacking between meals
can potentially induce weight gain and some patients may
require at least three injections a day to achieve satisfactory
glycemic control.
5.3.1.1 Efficacy and Real-Life Experience

with Conventional Insulin Regimen
Some studies have reported good results with an intensive

twice-daily injection approach. Results from the Hvidoere
Study Group on Childhood Diabetes which examined ado-
lescents from more than 20 pediatric diabetes centers
worldwide between March and October 2005 showed that
HbA1c achieved using twice-daily free mixing (soluble/
regular plus NPH insulin) was 7.9 %, which was lower com-
pared to groups using a basalbolus (8.2 %) or CSII regi-
men (8.1 %) [20]. However, these findings were center
specific, merely suggesting more effective use of conven-
tional insulin regimen in certain centers. Data from the
Hvidoere Study in Young Children in 2009 [21] also showed
that lower HbA1c levels (7.3 %) were achieved with a free
mixing twice-daily conventional regimen compared to a
premix twice-daily insulin regimen (8.5 %) and other com-
plex, intensive insulin regimens (HbA1c range between 7.8
and 8.0 %). However, frequency of severe hypoglycemia
was highest with free mixing insulin regimens. These data
underscore the importance of training in insulin self-man-
agement skills and management of complications, ongoing
education and support, even with simplistic insulin regimens
both for young individuals with T1DM and, where appropri-
ate, for their families.
5.3.1.2 Indications to Change or Intensify Insulin

Therapy from a Conventional Insulin
Regimen
Individuals who fail to achieve HbA1c targets of <7.5 %

(58 mmol/mol) on an optimized conventional insulin regimen
may be considered for a MDI or CSII regimen. Other indica-
tions include disabling hypoglycemia while aiming for tight gly-
cemic targets or individual preference or individuals who desire
greater flexibility with injections due to lifestyle considerations.
5.3.2 Multiple-Daily Injections or BasalBolus

Insulin Regimen
An MDI regimen involves four or more subcutaneous insulin
injections a day. Basal insulin is administered once- or twice-
daily with bolus (prandial) insulin injections added to each
main meal. Insulin dose adjustments (particularly prandial
insulin) can be made depending on meal content, time of day,
anticipated activity, stress, and preexisting blood glucose
measurements. The ability to count the carbohydrate content
of a meal with concurrent insulin dose adjustment allows for
dietary freedom with unrestricted food choices, and its appli-
cability in routine health care has shown greater improve-
ments in glycemic control and quality of life [22]. Correction
bolus can also be administered for unintended hyperglyce-
mia, significant ketonuria, or ketonemia.
Findings from the DCCT studies have provided unequivo-
cal evidence for the superiority of MDI regimens over con-
ventional regimens in T1DM [3]. CSII or insulin pump
therapy is a viable alternative to MDI regimen in the man-
agement of T1DM and may be of particular benefit in indi-
viduals with increased frequency of severe hypoglycemia on
an MDI regimen. Early studies using an all-analog insulin
approach in an MDI regimen have shown satisfactory glyce-
mic improvements over long-term follow-up [23]. With the
advent of newer, long- and ultra-long-acting, peakless basal
insulin analogs, and rapid-acting analogs, it is anticipated that
more physiological insulin replacement may result in supe-
rior metabolic outcomes, lower risk of complications, and
better quality of life (Table 5.2) [24, 25].
5.3.2.1 Indications to Change or Intensify Insulin

Therapy from an MDI Regimen
Alternative insulin regimens, including twice-daily premixed

insulin regimens or CSII, may be considered for individuals
on an MDI regimen who fail to achieve HbA1c targets of
Table 5.2 Multiple-dose insulin or basalbolus insulin regimen

When to consider When initiating an insulin regimen in type 1
diabetes
Individuals with suboptimal HbA1c targets
using conventional insulin regimen [3]
How to initiate Calculate total daily insulin dose 0.30.5 units/
and self-manage kg and divide 50 % as basal insulin (preferably
at bedtime) and 50 % as prandial insulin to
cover three meals
Approach when transferring from a twice-
daily premixed insulin regimen to a basal
bolus regimen:
Add up total daily dose of premixed
regimen and reduce by 20 % (may not
apply if blood glucose readings/HbA1c
are significantly elevated)
Give 50 % as basal insulin and 50 %
divided to cover main meals
Clinical evidence Superior HbA1c lowering effect was observed
(key studies) using both rapid- and long-acting analogs in
a basalbolus regimen compared to similar
regimen using regular and basal human
insulin [24]
Reduced risk of all-day, nocturnal, and
severe hypoglycemia with long-acting
analogs compared to NPH insulin [25]
Reduced risk of weight gain with long-
acting analogs (particularly insulin
detemir), compared to human insulin
Advantages Flexible mealtimes, greater dietary freedom,
flexibility with insulin dose adjustments
Correction bolus can be taken to correct
unintended hyperglycemia
(continued)

Disadvantages Greater frequency of injections can interfere
with daily activities and quality of life
Requires regular and frequent SMBG
Knowledge and skills to self-adjust insulin
doses based on carbohydrate counting of
meals and using insulin carbohydrate ratios is
required
HbA1c glycated hemoglobin, NPH neutral protamine Hagedorn,
SMBG self-monitoring of blood glucose
<7.5 % (58 mmol/mol) or experience disabling hypoglycemia

while aiming for tight glycemic targets or have difficulty
adhering to multiple-daily injections despite an integrated
care package consisting of structured education with regular
health-care professional support.
5.4 Continuous Subcutaneous Insulin

Infusion or Insulin Pump Therapy
The concept of CSII commonly referred to as insulin pump
was conceived in the early 1970s with the aim of achieving
near-normoglycemia to prevent microvascular complications
in individuals with T1DM (Fig. 5.3) [26, 27].
CSII closely approximates the physiological pattern of
insulin secretion and is an alternative to the MDI strategy.
CSII is delivered via a portable, battery-powered electrome-
chanical device with a programmable user interface and a
refillable reservoir of rapid-acting insulin analog attached to
an infusion set (narrow tubing with needle and cannula) for
subcutaneous insertion [28].
The pump delivers a controlled subcutaneous infusion of
rapid-acting insulin analog which covers basal insulin require-
ments. Basal insulin infusion rates can be manually adjusted
on an hourly basis and temporary adjustments can be pro-
grammed into the pump, which are of particular benefit in
5.4 Continuous Subcutaneous Insulin Infusion 147
Figure 5.3 The first insulin pump for continuous subcutaneous

insulin infusion (called the Mill Hill infuser) Designed by John
Pickup, Harry Keen, and John Parsons at the National Institute for
Medical Research, Mill Hill and Guy's Hospital, London, England,
1976 (Reproduced with permission from Pickup [27] Wiley)
optimizing nocturnal glycemia, an early morning rise in blood

glucose (dawn phenomenon), hyperglycemia in the postab-
sorptive state, and during sporting activities and intercurrent
illness. Accelerated insulin infusion delivers bolus or mealtime
insulin with the push of a button and can be predetermined by
the user/health-care provider taking into consideration exist-
ing blood glucose measurements, carbohydrate and caloric
content of meals, and recent or planned activity.
Modern insulin pumps (Fig. 5.4, as an example) have a
range of prandial insulin delivery profiles. For example, a
dual-wave bolus profile delivers a pre-meal bolus followed by
an extended (or square-wave) bolus that is uniformly deliv-
ered over several hours. Insulin pump bolus calculators are
also available which guide prandial insulin calculation.
Delivery of insulin with an insulin pump is, therefore, more
exact, flexible, and customized to meet the needs of the indi-
vidual. In recent years, patch pumps, made from less obtru-
sive tubing-free devices that download pump data to a
computer, and sensor-augmented pumps, which integrate the
pump with a real-time CGM, have been developed.
From a clinical point of view, CSII compared with both
analog or NPH-based MDI regimen offers superior improve-
ments in glycemic control, reduction in frequency of severe
hypoglycemia, greater quality of life gains due to improved
Figure 5.4 An example of a combination insulin pump system.

Remote programming of the pump is carried using data from the
blood glucose combo meter which can also be transferred to a com-
puter. Bolus doses can be delivered with assistance from a customiz-
able bolus calculator on the combo meter (Reproduced with
permission from Accu-Chek Accu-Chek)
lifestyle flexibility, treatment satisfaction, and less fear of

hypoglycemia [29]. Recent evidence suggests that initiating
CSII for poor glycemic control and/or disabling hypoglycemia
on MDI is a cost-effective use of health-care resources [30].
5.4.1 Determining Appropriateness

and Indications of CSII Therapy
Insulin pump therapy should be initiated by a multidisci-
plinary team comprising a diabetologist, nurse specialist, and
dietitian with a specialist training in insulin pumps. Individuals
5.5 Technological Advances in Insulin Pump Therapy 149
for CSII therapy should be carefully selected and have par-

ticipated in a formal structured education program, are adept
with insulin dose adjustment based on carbohydrate count-
ing, able and willing to learn insulin pump technology, and
can engage with the multidisciplinary team. Referral to a
psychologist may be needed to assess motivation, cognitive
and problem-solving skills, maturity level, financial stability,
and social support systems. Insulin pump use is contraindi-
cated in individuals with significant psychological or psychi-
atric problems and may not suit individuals engaged in
contact sports. A summary of international guidelines can be
found in Fig. 5.5 and an overview of clinical use in Table 5.3
and Fig. 5.6 [3139].
Health-care providers may consider discontinuation of
CSII if the individual is not compliant with blood glucose
monitoring and/or ketone testing, shows reluctance to con-
tinuously wear the pump device, or develops mental health
problems or visual impairment which may limit optimal and
safe use of the pump device. Working in extreme climates,
activities related to prolonged underwater immersion, and
exposure to high electromagnetic fields may also preclude
use of insulin pumps.
5.5 Technological Advances in Insulin Pump

Therapy: Moving Close to the Artificial
Pancreas
The concept of an artificial pancreas was first conceived by
Arnold Kadish in 1964 who developed a portable, closed-loop
insulin delivery system. The device was cumbersome, required
constant supervision, and did not achieve tight blood glucose
control. The roadmap to creating a fully functional artificial
pancreas was launched by the Juvenile Diabetes Research
Foundation (JDRF), a global charity organization which
funds research in T1DM, to standardize and accelerate the
artificial pancreas technology program. A brief description of
the six-step plan is outlined in Fig. 5.7 [40]. The first-generation
NICE UK guidelines [31]

Attempts to reach the targeted HbA1c levels with multiple injections result in the person having
disabling hypoglycemia (ie, hypoglycemia episodes occurring frequently and without warning so
that the person is constantly anxious about another episode occurring, which has a negative
impact on their quality of life).
HbA1c levels remain high (8.5%) with multiple injections despite the person and/or their carer
carefully trying to manage their diabetes.
Can be offered to children <12 years of age if MDI is considered to be impractical or
inappropriate.
American Association of Diabetes Educators guidelines for suitability of insulin pump therapy [32]
Use in patients with frequent and unpredictable fluctuations in blood glucoseand when patient
perceptions that diabetes management impedes the pursuit of personal or professional goals.
US Centers for Medicare & Medicaid Services (CMS) insulin pump patient eligibility criteria [33]
Patient has completed a comprehensive diabetes education program and has been managed on
MDI insulin regimen with frequent self-adjustments for at least 6 months.
Patient has documented SMBG frequency on average of 4 times per day during the previous 2
months.
Patient must also meet 1 of the following criteria:
HbA1c >7.0%
History of recurrent hypoglycemia
Wide fluctuations in blood glucose before mealtime
Dawn phenomenon with fasting plasma glucose frequently >200 mg/dL or a history of severe
glycemic excursions.
Figure 5.5 Indications for CSII (insulin pump) therapy in individu-

als with type 1 diabetes mellitus. HbA1c glycated hemoglobin, NICE
National Institute for Health and Care Excellence, MDI multiple-
dose insulin, SMBG self-monitoring of blood glucose
Table 5.3 Clinical guidance for choosing continuous subcutaneous

insulin infusion (CSII) or insulin pump therapy
When to Trial of CSII is appropriate if an optimized
consider CSII MDI insulin regimen alongside structured
or insulin pump patient education and self-monitoring of blood
therapy glucose fails to achieve HbA1c target of <7.5 %
either due to frequent unpredictable and
disabling hypoglycemia
May be considered in pregnant T1DM
women who cannot achieve tight glycemic
control despite optimized MDI regimen and
experience recurrent, disabling, severe, and
non-severe hypoglycemia
How to initiate Determining initial pump basal rates [34]:

and self-
Calculate the total daily dose (TDD): Pre-
manage
pump TDD 0.75 or weight in kg 0.5
(lb 23)
Calculate basal rate: pump TDD 0.5/24
or 4060 % of TDD. Use one basal rate
initially and adjust according to glucose
estimates over 2 or 3 days. Add further
basal rate variations depending on diurnal
glucose trends
Insulin-to-carbohydrate (I/C) ratio: 500/
TDD. Adjust ratios based on carb content
of meals with 1020 % increments as
needed
Sensitivity factor/correction: 1500/
TDD. Adjust to keep glucose levels within
30 mg/dL (1.7 mmol/L) of desired target
Bolus insulin dose [34]:
The user enters current BG value and
carbohydrate content consumed. The
pump calculates a bolus dose based on
preset I/C ratio and sensitivity factor
and calculates the insulin onboard from
previous boluses (algorithms may differ
between pump devices)
Special bolus profiles (e.g., extended
combination bolus) are available for
different meals (e.g., high fat, high
carbohydrate), part insulin dose given as
immediate bolus and remainder over an
extended period
Pump shutoff or temporary basal
reduction can reduce risk of hypoglycemia
in special situations
(continued)
Clinical CSII vs. MDI using both rapid- and long-acting

evidence insulin analogs [35]
(recent key
CSII and MDI exert similar glycemic
studies)
efficacy, with HbA1c reduction 0.61.7 %
from baseline
CSII vs. MDI: systematic review (2008) [35]
CSII provides superior HbA1c lowering,
with greatest glycemic improvements seen
among individuals with highest HbA1c
levels on MDI
Severe hypoglycemia rate is markedly
reduced with CSII with the greatest
reduction in those with most severe
hypoglycemia on MDI and with the
longest duration of diabetes
CSII vs. MDI in children aged 121 years:
systematic review (2009) [36]
CSII provides superior HbA1c lowering
(mean difference -0.24 %; 95 % CI: 0.41
to 0.07) compared to MDI
No differences were observed in the
incidence of DKA or severe hypoglycemia
between both regimens
(mean difference 0.3 %; 95 % CI: 0.1 to
0.4) compared to MDI
Severe hypoglycemia was reduced with
CSII; no differences were observed for
non-severe hypoglycemia
Greater improvements in quality of life
seen with CSII compared to MDI regimen
(mean difference 0.3 %; 95 % CI: 0.58 to
0.02) compared to MDI
Advantages Greater flexibility and accuracy with insulin

dosing and frequency (permits insulin dose
changes in smaller fractions) without need for
frequent subcutaneous injection administration
Calculates active insulin on board (IOB),
which is the amount of active insulin
remaining after a previous bolus correction
for hyperglycemia. This avoids insulin
stacking and safer bolus corrections
Establishing appropriate basal insulin levels
is important with intensive insulin regimen
and multiple basal insulin rates/carb/
insulin ratios benefit individuals with erratic
lifestyles and eating habits (Fig. 5.6)
Disadvantages Risk of rapidly developing DKA due to
technical or mechanical fault (e.g., failure of the
cannula to prime after change, kink, blockage
or leak in cannula, dislodgment of the infusion
set, low battery, mechanical or electrical failure
with alarms)
Infusion site problems such as local skin
infection and lipohypertrophy or lipoatrophy
can occur
CI confidence interval, DKA diabetic ketoacidosis, MDI multiple-
dose insulin
systems are not fully automated (non-closed-loop) and include

low glucose suspend and predictive low glucose suspend
devices. The second-generation systems (stages 4 and 5) pro-
vide automated insulin delivery with or without mealtime
manual assist bolus insulin delivery. The third-generation
(stage 6) systems are fully automated multihormonal (MH)
closed-loop delivery devices, which in addition to insulin use
glucagon or amylin to aid more perfect glucoregulation.
Figure 5.6 Variations in average hourly basal insulin requirements

by age group and gender in T1DM individuals on CSII therapy
(Reproduced with permission from Scheiner and Boyer [39]
Elsevier)
5.5.1 Non-closed-Loop Systems (First

Generation)
5.5.1.1 Very Low-Glucose Insulin Off Pump
In a very low-insulin off pump system, the SAP automatically

suspends insulin release when a preset low glucose threshold
(e.g., 6070 mg/dL or 3.33.9 mmol/L) is detected in order to
mitigate onset of hypoglycemia and then resumes after 2 h.
Initially, the pump emits an alarm as glucose levels drop but
if the user does not respond to the alarm, the insulin delivery
is suspended. The user can intervene at any stage in this 2 h
period to either continue suspension or resume insulin deliv-
ery after which basal insulin delivery resumes.
In clinical trials, SAP therapy with automated insulin sus-
pension compared to standard insulin pump therapy reduced
the combined rate of severe and moderate hypoglycemia as
well as nocturnal hypoglycemia in individuals with T1DM. The
adjusted incidence rate per 100 patient-months for severe and
First generation Second generation Third generation
1 2 3 4 5 6
Very-low-glucose Hypoglycemia Hypoglycemia/ Automated Fully automated Fully automated
insulin off pump minimizer hyperglycemia basal/hybrid insulin closed multi-hormone
Pump shuts off Predictive minimizer closed loop loop closed loop
when user not Hypoglycemia Same as #2 but Closed loop at Manual meal-time
responding to causes alarms added feature of all times with bolus eliminated
low-glucose alarm followed by allowing insulin meal-time manual
reduction or dosing above high assist bolusing
cessation of insulin threshold (eg,
delivery below low 200 mg/dL)
threshold
Figure 5.7 The Artificial Pancreas Projects six-step plan to develop a fully automated multihormone artificial pan-
creas. The project is a multi-year initiative launched by the Juvenile Diabetes Research Foundation (JDRF)
5.5 Technological Advances in Insulin Pump Therapy
(Reproduced with permission from JDRF [40] JDRF)

155
moderate hypoglycemia was 34.2 (95 % CI, 22.053.3) for the

pump-only group versus 9.5 (95 % CI, 5.217.4) for the low-
glucose suspension group. No significant differences in HbA1c
were reported [41, 42]. The main concern with this system is
the risk of hyperglycemia and associated metabolic ketosis.
These types of devices incorporate a threshold or low
glucose suspend system and are available for commercial
use (e.g., MiniMed or Paradigm Veo; Fig. 5.8).
5.5.2 Predictive Low-Glucose Management

System
In a Predictive Low-Glucose Management (PLGM) system,
The insulin pump is set to suspend basal insulin delivery
upon prediction of impending hypoglycemia and resumes
insulin delivery when this risk is attenuated. The CGM and
pump device communicate with a laptop computer that con-
tains a hypoglycemia prediction algorithm which estimates
the level and rate of change of sensor glucose. Basal insulin
delivery is suspended if glucose is predicted to fall <80 mg/
dL (4.4 mmol/L) within a 30 min time interval. Additional
suspension/restart rules include, for example, no suspension if
sensor glucose >230 mg/dL (12.7 mmol/L). A PLGM system
trialed within a home setting can substantially reduce over-
night hypoglycemia [43]. There are predictive low-glucose
management systems with regulatory approval for use out-
side the United States.
5.5.2.1 Hypoglycemia Hyperglycemic Minimizer
A hypoglycemia hyperglycemic minimizer (HHM) system

has a predictive low-glucose management, as well as auto-
matic insulin dosing to reduce hyperglycemia exposure. A
feasibility study using this system showed that insulin deliv-
ery can be modulated based on CGM readings and was effec-
tive in taking preemptive action to mitigate near-future
below-zone excursions by delivering less insulin than the
Figure 5.8 The MiniMed 640G (Image reproduced with permis-

sion from Medtronic. Medtronic)
corresponding preprogrammed basal rates [44]. HHM is not

yet available for commercial use.
5.5.3 Closed-Loop Control Systems (Second

Generation)
There are three major functional components of a closed-
loop system: CGM, an insulin pump, and a controller that is
capable of interpreting blood glucose levels in real time and
adjusting insulin administration using a preset algorithm. This
effectively closes the loop because insulin delivery is auto-
mated without the need for external supervision. A schematic
view is shown in Fig. 5.9 [28].
Figure 5.9 An illustrative representation of a closed-loop insulin

delivery system. (a) The sensor transmits information about intersti-
tial glucose levels to a handheld device about the size of a cell phone
(red box) which holds a control algorithm and interacts with the
user. An insulin pump (blue box in the pocket) delivers a rapid-
acting insulin analog subcutaneously. Insulin delivery is modulated
by the control algorithm. (b) The communication between the sys-
tem components is wireless. The control algorithm can also reside
within the insulin pump (Adapted with permission from Thabit and
Hovorka [28] Elsevier)
Closed-loop control systems differ from non-closed-loop

systems and conventional insulin pump therapy since they can
automatically regulate insulin delivery using a control algo-
rithm based on sensor glucose readings. The basic requisites of
a clinically effective closed-loop control system therefore
depend on an effective delivery device, glucose sensor, a math-
ematical module that looks at trends in glucose, and a rapid-
acting insulin analog. Closed-loop control (CLC) systems have
been tested both within controlled and unrestricted outpatient
environments. The uni-hormonal system uses insulin only with
a complex, control algorithm and the bihormonal approach
(bionic endocrine pancreas) uses insulin, glucagon, and a con-
trol algorithm to automatically adapt insulin dosing to achieve
safe and effective glycemic control. Control algorithms for
closed-loop control systems include four main models:
Proportionalintegralderivative (PID)
Model predictive control
Fuzzy logic
Adaptive control
The basic function of the control algorithm is to compute
the amount of insulin to be delivered without intervention
by the pump user. For example, the PID algorithm adjusts
basal insulin delivery by assessing the difference in measured
glucose from target glucose (proportional component), the
area under-curve between measured and target glucose
(integral component) and the rate of change in measured
glucose (derivative component). Prandial insulin delivery in
CLC systems may be fully automated and is based solely on
the evaluation of glucose excursions or may occur in a semi-
closed-loop or closed-loop with meal announcement sys-
tem where information on the timing and size of the meal is
provided to the controller and prandial insulin dose is deliv-
ered manually by the pump user.
5.5.3.1 Hybrid Closed-Loop System

The hybrid closed-loop system (HCL) is a fully integrated
system to modulate basal insulin delivery continuously during
day and night based on glucose sensor readings. It has a pro-

portionalintegralderivative with insulin feedback algorithm
incorporated within the insulin pump. A supplementary
phone or computer to store the algorithm is not required and
hence avoids potential interruption in communication
between devices. The pump requires meal announcement with
carbohydrate counting and manual delivery of mealtime
bolus insulin. An investigational study with the HCL system
has not demonstrated improved glucose control compared
with sensor-augmented pump therapy [45]. HCL systems are
in development and not yet commercially available.
5.5.3.2 Fully Automated Insulin Delivery/Fully

Closed-Loop System
The fully closed loop (FCL; or fully automated insulin deliv-

ery) is a wireless, fully automated, closed-loop system with
minimal human interaction. The prediction algorithm is either
based on a prediction algorithm (fuzzy logic, proportional
integrativederivative) which integrates information derived
from past glucose levels, insulin delivery, and insulin pharma-
codynamics. Real-time alarms alert for impending hypoglyce-
mia and prolonged hyperglycemia. In a crossover trial in
young people with T1DM at an overnight diabetes camp, FLC
artificial pancreas system reduced hypoglycemia with tighter
control of nocturnal glycemia compared to an SAP [46]. FCL
devices are still in the investigational stage of development.
5.5.4 Third-Generation APD Systems
5.5.4.1 Multihormone InsulinGlucagon System/

Bionic Pancreas
The multihormone (MH) system is a fully automated, bihor-

monal, bionic pancreas which makes automated dosing deci-
sions for subcutaneous insulin and glucagon administration
with the use of a control algorithm. The administration of
glucagon helps to counter the effects of insulin and increases
5.6 Summary 161
glucose production by the liver, stabilizing glucose concentra-

tions after meals and preventing hypoglycemia.
Compared with conventional insulin pump therapy, a
bihormonal bionic pancreas improved mean glycemic levels
with less frequent hypoglycemic episodes in adolescents and
adults with T1DM [47, 48]. In free-living conditions (outside
a hospital setting), bionic pancreas has demonstrated less
nocturnal hypoglycemia and tighter glucose control com-
pared to SAPs [46, 49]. MH system devices are still in the
investigational stage of development.
5.6 Summary
The management of T1DM requires an individualized approach
keeping in mind that the condition affects a wide spectrum
of individuals from prepubertal children, adolescents, and
adults who require insulin for survival. Maintaining tight gly-
cemic control is important to avoid long-term complications;
however, the use of intensive insulin regimens must also be bal-
anced against ensuring lower risk of complications, complete
avoidance of hypoglycemia, and a positive impact on quality
of life. Drugs used in T2DM such as metformin are often used
off-label with insulin therapy to improve insulin sensitivity and
reduce insulin dose requirements, particularly in obese individuals
with T1DM [50]. The SGLT2 inhibitors, which exert a glucuretic
effect, may be efficacious in reducing hyperglycemia in T1DM
and trials with these drugs are underway in this setting [51].
The diabetic who knows the most lives the longest. Dr Eliot
Joslin (18691962), US physician, on the role of self-management
education in diabetes
Key Messages
Any insulin regimen has to be considered in the wider
context of a total diabetes management package, which
must include dietary management, exercise and physical
activity, blood glucose monitoring, initial and ongoing edu-
cation, regular medical follow-up, and psychological care.
The development of new technology has created new

opportunities in the management of T1DM, and the chal-
lenge is to ensure that these treatment options are afford-
able, equitable, and targeted at those individuals who are
most likely to benefit.
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Chapter 6
Practical Aspects of Insulin
Therapy
6.1 Introduction
For millions of individuals with type 1 diabetes mellitus
(T1DM) and those with type 2 (T2DM) who require insulin
as a treatment option, coping with the complexities of insu-
lin therapy is often challenging. The number of newer insu-
lin formulations, combination insulin therapies, insulin
delivery devices, and blood glucose monitoring systems
have made this process increasingly complex. However, a
holistic management approach aimed at improving glycemic
control and ensuring a good quality of life should not focus
solely on the right insulin formulation and regimen but
must also make provisions to empower individuals to self-
manage their own insulin therapy via formal education on
the practical aspects of insulin use. This chapter will discuss
the practical aspects and common complications associated
with insulin use and briefly summarize insulin therapies in
special groups, including older patients, pregnant women,
and patients with chronic kidney disease (CKD), as well as
provide advice for insulin management during exercise, fast-
ing, travel, and driving.

DOI 10.1007/978-3-319-10939-8_6,
170 Chapter 6. Practical Aspects of Insulin Therapy
6.2 Insulin Injection Practices in Diabetes

Improving procedural knowledge around insulin use includes
targeted training around injection practices, advice on rotation
of sites, and needle use and reuse, which are critical elements of
self-care for those on insulin therapy and associated with greater
improvements in glycemic control, treatment satisfaction, and
treatment adherence [1, 2]. However, comprehensive structured
training programs on the practical aspects of insulin therapy are
lacking. In 2014, the Forum for Injection Technique published
evidence-based best practice recommendations for health-care
professionals and people with diabetes using injectable thera-
pies, which have now been rolled out to many global diabetes
health centers [3]. It is conceivable, therefore, that widespread
dissemination and implementation of high-quality injection
practices and structured education programs can improve injec-
tion practices in insulin-requiring individuals with diabetes.
6.3 Insulin Initiation

Once the decision to commence insulin therapy has been taken,
insulin initiation and practical training on insulin delivery are
usually delivered by a diabetes specialist nurse or trained health-
care professional. The initial consultation may be conducted on a
one-to-one basis in the presence of a relative or carer (if required)
to help the health-care provider assess the patients individual
learning style and needs. At this stage, insulin support groups may
provide a supportive environment by allowing patients to share
experiences and are cost- and resource-effective option, particu-
larly in a community setting [4, 5]. Broadly, the initial consultation
should be comprehensive and aim to cover the following topics:
Metabolic actions of insulin in normal individuals and
those with diabetes
Indications, benefits, and difficulties experienced with
insulin therapy and opportunity to disclose any apprehen-
sions about the injection process and insulin therapy
Discussion on healthy eating practices (portion sizes,
healthy food choices), regular activity, weight management,
6.3 Insulin Initiation 171
and self-monitoring of blood glucose to deal with effects of

food, physical activity, and medication
Choice of insulin type and regimen
Choice and management of devices, including insulin vials,
pens, and needles
Choice, care, and self-examination of injection sites
Injection techniques including injection angle and site rotation
Recognition and avoidance of injection-related
complications
Safe disposal of sharps (used syringes)
Recognition and management of complications such as
hypo- and hyperglycemic crises
General advice on insulin therapy while driving, traveling,
and fasting
Common insulin administration errors
6.3.1 Verification
It is good practice to check that the right type and dose of

insulin is prepared prior to every insulin injection. The expiry
date on the vial or insulin pen must be inspected because use
after the expiry date can affect sterility of the insulin product.
6.3.2 Storage
Proper storage and handling of insulin products is an integral

part of routine insulin management [6]. Persistently high blood
glucose readings can occur due to reduction in insulin potency
from faulty storage. In general, insulin should be inspected for
clumping, frosting, precipitation, or discoloration prior to use.
Insulin should be stored between 2 and 8 C (approx. 3646 F)
either in a refrigerator or cool storage area protected from
direct light. However, opened or used insulin pens should not be
stored in a refrigerator. Importantly, insulin should not be stored
in the freezer compartment of a refrigerator, and temperature
extremes of <2 C/36 F and >30 C/86 F must be avoided. If
the contents of a vial or pen are frozen, it should be discarded.
Insulin products are viable at room temperature (<25 C/77 F)
for up to a month.After this period and regardless of refrigeration,
the efficacy and potency of insulin can be compromised and

should be discarded. In settings where refrigerator storage is
unavailable, insulin can be stored in plastic bags kept cool in an
earthen pitcher, clay pot, or water container (Fig. 6.1) [7].
6.3.3 Injection Technique and Administration
The initial injection technique can be demonstrated using an

injection pad by which individuals can practice and gain con-
fidence with needle insertion and injection technique (Fig. 6.2).
Figure 6.1 Clay pots (as depicted) are used for insulin storage in areas
where cold storage facilities are lacking. The crucial way of using it is to
half filled with sand or soil, surrounded with water. The water evapo-
rates through the unglazed clay dropping the temperature inside
(Image provided courtesy of Professor Geoff Gill Geoff Gill)
6.3.3.1 Preparing the Device
Drawing up insulin with a needle and syringe is a straight-

forward process. After removing the cap off the needle, the
plunger is pulled back to fill the syringe with air. The needle
is inserted into the rubber stopper of the insulin vial and air
is injected into the vial. The insulin vial is held upside down
and in a smooth motion the plunger is pulled back to draw
up insulin. The barrel of the syringe is then gently tapped to
eliminate air bubbles. The procedure can be repeated a few
times if necessary. Air bubbles are harmless but should be
avoided because the displaced volume of the bubbles can
cause errors in insulin dose. Injecting air into the vial also
prevents a vacuum from being created, which pulls back
insulin into the vial and makes it difficult to draw insulin
Figure 6.2 Injection training pad (Reproduced with permission

from DiaMedical USA)
out with ease. Another useful method is venting, where

the plunger is removed from the syringe barrel and the
needle is inserted into the insulin vial. After a few moments,
air equalizes and removes any vacuum inside the insulin
bottle.
Insulin delivery devices containing cloudy insulin (e.g.,
neutral protamine Hagedorn [NPH] and premixed insulin)
must be rolled gently approximately ten times between the
palms of the hand and inverted (not shaken because excess
physical agitation can cause degradation of insulin) until the
crystals go back into suspension, and the solution appears to
be a milky white color (Fig. 6.3). Excess physical agitation
can cause degradation of insulin.
Steps for preparing an insulin pen cartridge are shown in
Fig. 6.4. Insulin pens do not generally develop air bubbles.
However, if a needle is left on the pen, it can lead to air
bubbles.
6.3.3.2 Priming
With a new disposable pen, cartridge in a reusable pen, and

insulin syringe needle, priming the device (an air shot) is
carried out with the first dose. With the needle pointing up,
a b
Figure 6.3 (a, b) Mixing cloudy insulin (Reproduced with permis-

sion from Lilly Diabetes)
a b
c d
Figure 6.4 Steps to using an insulin cartridge. (a) Remove pen cap.
(b) Twist cartridge holder anticlockwise to detach. (c) Insert car-
tridge into cartridge holder. (d) Push cartridge holder into pen body.
(e) Reattach by twisting clockwise (Reproduced with permission
from Lilly Diabetes)
two units of insulin are expelled into the air. This ensures that
the device is primed and ready for use.
6.3.3.3 The Injection Process
Insulin is injected below the skin into subcutaneous fatty tis-

sue at a selected injection site. Use of alcohol swabs is
generally not required if the injection site is acceptably clean.
In general, 4 mm needles are preferable for all age groups,
including obese individuals. With smaller-sized needle use
(between 4 and 6 mm), pinching to create a skinfold (pinch-

up) prior to injection is not required [6]. However, a pinch-
up technique applies for needle sizes of 8 mm to avoid
injecting directly into muscle, which can induce hypoglycemia
(Fig. 6.5) [3]. The needle is inserted in a quick smooth move-
ment through the skin, and insulin is injected slowly (count
up to 10) until the plunger (syringe) or thumb button (insulin
pen) is fully depressed. If the skin is pinched up, it should be
released prior to withdrawing the needle. After the injection,
the needle is removed from the pen/vial and replaced by a
cover. Needles should be discarded after each use. Exercise,
massaging the site before or after the injection, and an
increased local temperature can speed up insulin absorption.
6.3.3.4 Injection Sites
In general, recommended insulin injection sites are the entire

surface of the abdomen/flanks, anterolateral aspect of the
upper thigh from the hip, outer thigh, and back of the upper
arms (Fig. 6.6) [6]. Injections or cannulae must be sited at
a b c
Figure 6.5 Correct (a) and incorrect (b, c) ways of performing the
skinfold (Reproduced with permission from Peter Lamb [3] Lamb
Medical Illustration)
a b
Figure 6.6 (a, b) Recommended insulin injection sites
least 1 cm away from previously injected areas. Each injec-

tion site has a different absorption pattern, with the most
rapid absorption occurring from the abdomen due to
increased local density of capillaries. Injecting into or close to
a mole or scar should be avoided.
6.3.4 Common Problems Encountered

with Insulin Injections
6.3.4.1 Dermatological Complications
Common skin complications associated with insulin injec-

tions include scarring, erythema, subcutaneous nodules,
lipohypertrophy, lipoatrophy, localized skin infection, and
abscesses (Figs. 6.7 and 6.8) [8]. Local allergic reactions to
insulin are usually erythema, pruritus, and induration. These
allergic reactions are usually short-lived and resolve sponta-
neously within a few weeks.
Lipohypertrophy appears as soft, subcutaneous swellings
or bumps at an insulin injection or infusion site (Fig. 6.9).
Initial skin changes can be subtle, appearing as discrete, thick-
ened subcutaneous areas that can be easily missed on visual
a b
Figure 6.7 Examples of visible lipohypertrophy. (a) Bilateral upper

abdomen. (b) Bilateral lower abdomen (Reproduced with permis-
sion from Grassi et al [2] Elsevier)
Figure 6.8 Insulin injection site abscess (Reproduced with permis-

sion from Thukral et al [8] American Diabetes Association)
Cannula inserted
03/08/2008 08/09/2008 into LH
550
500
450
Glucose (mg/dL)
400
350
300
250
200
150
100
50
05/08/2008 12/08/2008 19/08/2008 26/08/2008 02/09/2008 09/09/2008

Date
Figure 6.9 Glycemic excursions seen when insulin pump cannula is

inserted into areas of lipohypertrophy. LH (lipohypertrophy)
(Reproduced with permission from Strauss [9] Publiscripts)
inspection and, hence, require careful palpation to reveal the

diagnosis. Detection is important because insulin absorption
from these sites is unpredictable and can lead to glycemic
variability and unpredictable hypoglycemia, leading to poor
glucose control. As areas of lipohypertrophy are painless,
patients tend to inject in the same area rather than move to a
new, relatively more painful site. Large areas can become
cosmetically embarrassing for patients. The exact cause of
lipohypertrophy is unclear but is associated with duration of
diabetes, repeated needle trauma, failure to rotate injection
or infusion sites, reuse of injection needles, leaving a cannula
in situ longer than recommended, or direct local anabolic
insulin action [9]. Greater emphasis should be directed
toward effective injection site rotation rather than merely
advising to switch injection sites [9].
Lipoatrophy is a wasting of the subcutaneous tissue at an
injection site. It is rarely seen, but injecting into such tissue
should be avoided because insulin absorption might be more
rapid (and unpredictable) in comparison to normal injection
areas as insulin molecules are in closer proximity to the

underlying capillary vasculature [10]. In severe cases, topical
dexamethasone injections may be effective [11, 12].
6.3.4.2 Needle Phobia and Discomfort with Insulin

Injections
Insulin injection anxiety (needle phobia) is a barrier to initia-

tion and compliance with insulin therapy. Although true
needle phobia is rare, studies suggest that nearly one-third of
individuals with T1DM intentionally miss taking insulin and
fail to refill insulin prescriptions [13, 14]. In individuals with
T1DM, it can lead to acute diabetic complications such as
diabetic ketoacidosis and is linked to poor glycemic control.
Needle phobia can be addressed by demonstrating a dry
injection, demonstrating that insulin needles are small, thin,
and less painful compared to the larger needles used for intra-
muscular injections or inoculation. Other strategies include
using an autoinject device or needle shield, which can be used
with a pen device (Fig. 6.10). Additionally, behavioral coping
techniques such as relaxation training, guided imagery, and
graded exposure can be employed to good effect [15].
a b
Figure 6.10 Devices to consider for patients with needle phobia or

anxiety. (a) An autoinjector conceals the syringe and needle. (b) An
autoshield safety pen needle conceals the needle, which enables
effective drug delivery and can positively patient compliance in
individuals with needle phobia (Reproduced with permission from
Owen Mumford and Beckton, Dickinson and Company)
6.4 Insulin Delivery Devices 181
6.3.4.3 Painful Injections
Pain from an injection usually results from multiple use of the

same pen needle or direct injection into a muscle. Children
have a lower threshold for pain than adults and sometimes
find injecting insulin uncomfortable. Useful strategies to
avoid injection discomfort include regularly changing needles
after each injection, using the pinch-up skin folding tech-
nique prior to injecting, using shorter needles, and injecting
insulin at room temperature.
6.3.4.4 Insulin Leaking at Injection Site
Significant amounts of insulin can leak after subcutaneous

injection if the needle is removed too quickly. Hence, insulin
should be injected slowly and a count to ten performed
before withdrawing the needle. If a significant insulin leak is
visible, insulin must not be re-injected but rather blood glu-
cose levels should be monitored closely.
6.4 Insulin Delivery Devices

6.4.1 Insulin Syringes
Insulin syringes are suitable if free mixing of insulin (short-

and intermediate-acting insulin) is desired, for those injecting
insulin doses greater than 6080 units a day and/or as a
backup device. It requires manual dexterity and visual acuity
to ensure accurate insulin doses can be drawn up for injection.
They may be preferred by some individuals who can visualize
insulin being delivered and are reassured by the process.
6.4.2 Insulin Pens
Insulin pens are available as prefilled disposable insulin pens

or reusable models with refillable cartridges. An insulin pen
has a short, fine needle and a dose counter window with a
dial that can be rotated in increments of one or two units to

the required insulin dosage. Currently available insulin pens
are mostly discreet, durable, have attractive exterior designs,
require less injection force, and some have an integrated
memory function which is particularly useful in children or
forgetful patients (Fig. 6.11, as an example). Insulin pens are
available for all analog insulin and most human insulin for-
mulations. Most insulin pens are proprietary devices and are
designed to be used with insulin made by the same manufac-
turer. Hence, the choice of insulin pen is usually determined
by the choice of a specific insulin. Generally, prefilled dispos-
able pens are preferred as they are light, small, easy to use,
and do not require cartridge loading.
Pen devices are particularly useful for children and indi-
viduals who require insulin dose adjustment by half-unit
increments (Fig. 6.12 shows examples, but there are others
also approved for use that are not pictured).
Insulin pens provide several advantages to the syringe and
vial method of insulin delivery. They are easy to use, insulin
dosing is more accurate, and they are convenient to carry
Figure 6.11 Example of available insulin pen. The NovoPen incor-

porates a memory function and allows users to check the last dose
unit and the hours lapsed since injection (Reproduced with permis-
sion from Novo Nordisk)
a b
Figure 6.12 Examples of pen devices which can dispense half-unit

increments of insulin. (a) The NovoPen ECHO is an example of an
insulin pen designed to meet the needs of children with diabetes. It pro-
vides half-unit dosing and incorporates a memory function that records
the dose and time passed since the last injection. (b) HumaPen Luxura
HD also allows for 1/2 unit increments (Reproduced with permission
from Novo Nordisk and Lilly Diabetes)
when insulin is required to be injected outside home or in

certain social settings (Fig. 6.13). Some studies suggest
improved adherence and patient satisfaction to insulin ther-
apy with insulin pens [16].
For older patients, those with visual impairment, or indi-
viduals with reduced manual dexterity, insulin pens provide a
distinct advantage because insulin dose measurements are
easily visible, audible clicks indicate the number of dose units
injected, and it eliminates the process of manually drawing up
insulin with a syringe. Despite their advantages, accidental
administration of incorrect insulin (e.g., short-acting instead
of long-acting insulin) can occur because pen devices which
contain different insulin formulations may bear a similar
external appearance. This highlights the importance of proper
identification of insulin type and pen prior to use.
Furthermore, free mixing of insulin is not possible and
device malfunction can occur. Therefore, patients using an insu-
lin pen should have a spare pen with them at all times. Although
insulin delivery with pens are more costly compared to the
vial and syringe option, the relative cost differential may be
offset by lower treatment-related costs and higher treatment
adherence [17]. Insulin pens are covered under health benefits
Figure 6.13 Insulin pens come in a variety of formulations and

require careful, appropriate identification prior to administration to
prevent an insulin error (Reproduced with permission from Novo
Nordisk)
in Europe and countries such as Japan, which is reflected by

higher uptake in these areas.
6.4.3 Insulin Needles
Insulin needles are available in many lengths from 4 to

12.7 mm. As the average skin thickness extends from 1.9 to
2.4 mm irrespective of age, body habitus, or gender, insulin
needles between 4 and 6 mm needles can be used for subcu-
taneous insulin administration without the need for a lifted
skinfold approach prior to injection [18] (Fig. 6.14).
For children and adolescents, needles no longer than 6 mm
should be used [19]. If 8 mm size pen needles are used, it is
important to lift the skinfold in order to avoid inadvertent
injection into muscle. Insulin injection needles are for single
use only, as repeated use can blunt or bend the needle tip and
even break inside the skin (Fig. 6.15). It is important to edu-
cate insulin users that disposing of insulin needles after every
single use is not wasteful and reduces pain, needle contami-
nation, and tissue damage [20].
6.4.3.1 Disposal of Sharps
All health-care professionals, individuals with diabetes, and

their carers must be aware of the importance of safe disposal
of insulin needles due to the risk of needlestick injury, which
can affect people in nearby surroundings (children, relatives)
and remotely (refuse workers). Used insulin syringes also
pose a hazard for cross infection and can be picked up by
illicit drug users to be used for their own purposes. Advice on
the safe disposal of needles and insulin syringes into a speci-
fied disposal container should be reinforced and made freely
available to all insulin and blood glucose meter users at insu-
lin initiation. A needle clipper is useful to reduce waste vol-
ume (Fig. 6.16).
4 mm needle
Skin NOT Here
Subcutaneous
tissue Here
Muscle
NOT Here
b
12.7 mm x 29g
8 mm x 31g
6 mm x 32g
5 mm x 31g
4 mm x 32g
Figure 6.14 Skin thickness in adults (a) and commercially available

insulin needle sizes (b)
Unused needle at 370 magnification* Reused needle at the same magnification
Figure 6.15 Blunting of needle after reuse (Reproduced with per-

mission from Becton, Dickinson and Company)
Figure 6.16 An example of a needle clipping device (Reproduced

with permission from Becton, Dickinson and Company)
6.5 Common Problems with Insulin Therapy
6.5.1 Weight Gain
Weight gain is a recognized problem with insulin use and a

psychological barrier to initiation and adherence to treatment,
particularly in individuals with T2DM and health-care profes-
sionals involved in their care [21, 22]. It is associated with
therapy intensification and improvements in glycemic control,
both in individuals with T1DM and T2DM [23, 24]. Weight gain
may also be influenced by a particular insulin regimen. For
example, a basal-only insulin regimen in individuals with
T2DM is associated with less weight gain compared to com-
plex insulin regimens (e.g., premixed or basalbolus) [25].
Postulated mechanisms include changes in energy expenditure
(more efficient calorie utilization from reduction in glycos-
uria), anabolic effects of insulin, defensive snacking to prevent
hypoglycemia, and a nonphysiological insulin profile [26, 27].
However, weight gain with insulin therapy can be limited.
Judicious use of insulin formulations and limiting insulin dos-
age by using insulin-sparing agents including metformin,
glucagon-like peptide-1 (GLP-1) agonists, and sodiumglucose
cotransport 2 (SGLT2) inhibitors in T2DM are useful strategies.
Insulin detemir has a weight-sparing effect due to its unique
hepatoselective action and influence on satiety centers in the
central nervous system [28]. In individuals with T2DM, clinical
trials have shown a lower mean weight difference of 0.91 kg
(95 % CI, 1.21 to 0.61 kg) with insulin detemir compared to
insulin glargine, despite similar HbA1c levels and similar rates
of hypoglycemia. Similarly, in children and adolescents with
T1DM, the use of insulin detemir does not appear to be associ-
ated with weight gain when compared with NPH insulin [29].
6.5.2 Hypoglycemia with Insulin Therapy
Clinically, hypoglycemia is characterized by low plasma glu-

cose, physical symptoms (e.g., shaking, palpitations), and res-
olution of symptoms with treatment. The American Diabetes
6.5 Common Problems with Insulin Therapy 189
Association Workgroup definition of hypoglycemia is an

alert value of 3.9 mmol/L (70 mg/dL) [30]. A detailed clas-
sification is summarized in Table 6.1.
Hypoglycemia is an unpleasant experience which, in
severe cases, can cause morbidity and death [31]. From a
societal perspective, higher utilization of health-care
resources, loss of work-related productivity, and occupa-
tional- and driving-related hazards are all indirect costs of
hypoglycemia [32]. Fear of hypoglycemia is a deterrent to
insulin initiation (both from a health-care professional and
Table 6.1 Definition of hypoglycemia

Stage of
hypoglycemia Definition
Severe An event requiring assistance of another person
hypoglycemia to actively administer carbohydrate, glucagon,
or other resuscitative actions
Neurological recovery attributable to
restoration of plasma glucose to normal is
sufficient evidence that the event was induced
by low plasma glucose
Documented Typical symptoms (e.g., palpitations, trembling,
symptomatic shaking, hunger, tingling of the lips, going pale,
hypoglycemia palpitations, dizziness) with measured plasma
glucose concentration 3.9 mmol/L (70 mg/dL)
Asymptomatic No symptoms but measured plasma glucose
hypoglycemia concentration 3.9 mmol/L (70 mg/dL)
Probable Typical symptoms not accompanied by a plasma
symptomatic glucose determination (but presumably caused
hypoglycemia by a plasma glucose concentration 3.9 mmol/L
(70 mg/dL)
Relative An event during which a person with diabetes
or pseudo- reports typical symptoms of hypoglycemia
hypoglycemia interpreted as indicative of hypoglycemia but
with a measured plasma glucose concentration
>3.9 mmol/L (>70 mg/dL)
Adapted from Seaquist [30] American Diabetes Association
patient perspective) and adherence to treatment and often

prompts individuals on insulin to curtail the risk by main-
taining blood glucose at higher than physician-recom-
mended levels [33].
Hypoglycemia is a common problem with insulin ther-
apy. Potentiating factors include suitability of insulin regi-
men and formulation (e.g., nocturnal hypoglycemia with
human insulin [NPH] can be partly mitigated with basal
insulin analogs); errors in dose, timing, or delivery of insu-
lin; strenuous or unplanned exercise; dietary changes such
as insufficient food consumption or an abrupt switch to
low-starch foods; excess alcohol without adequate carbohy-
drate consumption; injection into lipohypertrophy sites;
concomitant administration of glucose-lowering medica-
tions (e.g., sulfonylureas) in individuals with T2DM; and
comorbidities such as liver and kidney disease. Individuals
with poor appetite or erratic lifestyles and eating patterns,
significant weight loss, longer duration of diabetes, neuro-
cognitive decline, and older patients are at a higher risk of
hypoglycemia.
Frequent self-monitoring of blood glucose (3 times a
day, preferably after meals) is helpful to avoid hypoglyce-
mia. Other recommendations include checking injection
sites regularly (erratic absorption can induce hypoglyce-
mia), taking recommended doses at mealtimes, appropriate
insulin dose adjustments before and after exercise, and
ensuring that a carbohydrate supplement and blood glucose
meter are easily accessible. Advances in insulin infusion
pump therapy and continuous glucose monitoring are useful
adjuncts to the management of T1DM. Degludec and
glargine U300 are newer long-acting basal analogs with
more physiological basal profiles and provide a lower risk of
nocturnal hypoglycemia compared to existing basal analogs,
detemir, and glargine, respectively. In individuals with
T1DM, degludec significantly lowered rates of confirmed
nocturnal hypoglycemia when compared to glargine (esti-
6.6 Insulin Therapy in Special Groups 191
mated rate ratio [degludec/glargine]= 0.75, 95 % CI, 0.60

0.94) [34] and, when compared to detemir, resulted in a
33 % lower rate of nocturnal hypoglycemia (estimated rate
ratio [degludec/detemir]= 0.67, 95 % CI, 0.510.88) [35].
Pooled patient-level data for self-reported hypoglycemia
from randomized controlled phase III trials in individuals
with T2DM and T1DM further confirm a lowering of noc-
turnal hypoglycemia risk with insulin degludec compared to
glargine [36].
The acute treatment of hypoglycemia depends on the
severity of hypoglycemia and level of consciousness
(Fig. 6.17). The prevention and management of hypoglyce-
mia requires a supportive care plan with individualization of
glycemic targets. Intensification of therapy must be balanced
against the increased risk of cardiovascular events and all-
cause mortality due to hypoglycemia [37]. Structured patient
education, skills on insulin self-management, and training
hypoglycemia recognition and avoidance are important and
cost-effective measures in hypoglycemia prevention and
management [38].
6.6 Insulin Therapy in Special Groups
6.6.1 Insulin Therapy in Older Patients
The pathophysiology of diabetes in older individuals is char-

acterized by reduced endogenous insulin secretion due to
declining -cell function and insulin resistance due to obesity,
physical inactivity, and low skeletal muscle mass [39, 40]. The
management of diabetes in the elderly is complex, challeng-
ing, and requires consideration of:
Physical, behavioral, and cognitive functioning
Life expectancy
Lifestyle, diet, and eating habits
Treating Hypoglycemia
192
Treating hypoglycemia Give one of the following: If after 5 minutes the blood glucose level
- 150 mL of non-diet cola (small can) is still less than 4 mmol/L, repeat the treatment.
- 200 mL of pure smooth orange juice (small carton)
Is patient conscious and
Yes - 100 mL of sports drink (eg, Lucozade) Once the blood glucose is above 4 mmol/L,
able to swallow?
- 4 glucotabs give a starchy snack such as banana,
- 5 to 6 dextrose tablets glass of milk, or biscuits unless a meal will
be eaten in the next 1 to 2 hours
No
For patients on PEG feeds Repeat this procedure every 5 minutes

Stop the feed and insert one of the following until the blood glucose is above 4 mmol/L
Is patient conscious and into the feeding tube:
Yes - 30 mL undiluted fruit drink Afterwards, resume the feed
not able to swallow?
- 150 mL non-diet cola
- 100 mL sports drink
No
If unconscious: Once conscious (usually after approx 10 minutes),

Put the patient in the recovery position and maintain airway - do not put glucose give patient one of the following:
in to the mouth. Give 1 mg glucagon intramuscularly if available and carer is - 150 mL non-diet cola
trained to do so. - 100 mL sports drink
Follow with a starchy snack such as a banana
If glucagon is not available or is ineffective, and intravenous access is available, or 2 slices of bread
give 75-80 mL of 20% glucose over 10-15 minutes. If not available, call paramedics.
Note: glucagon may not be effective in people with liver disease

Chapter 6. Practical Aspects of Insulin Therapy
After an episode of hypoglycemia:

Review management plan with the patient (and relatives) to clarify/confirm goals of diabetes management.
Figure 6.17 Management of hypoglycemia in individuals with diabetes (Reproduced with permission from Leicester
Diabetes Centre. www.leicestershirediabetes.org)
Associated comorbidities including stroke, coronary heart

disease, and renal impairment [41]
Frailty, polypharmacy, reduced ability to self-manage insu-
lin therapy, impaired vision, confusion, and short-term mem-
ory loss leading to omission, injecting the same dose twice, or
insulin product mix-ups are some of the problems frequently
encountered in this age group. Older patients may have a
marked subjective unawareness of hypoglycemia due to slow
reaction times and may fail to seek help or respond quickly
to hypoglycemia [42].
The evidence base for glucose-lowering therapies in
the elderly population with diabetes is relatively poor
[43]. Management principles depend on whether the per-
son is functionally independent and can potentially pur-
sue tighter glycemic goals (HbA1c 77.5 %; 5359 mmol/L)
or is functionally dependent, which may require a prag-
matic relaxation of treatment targets (HbA1c 78 %;
5364 mmol/mol) to avoid hypoglycemia and unaccept-
able hyperglycemia [ 41 ].
Insulin therapy is effective in older individuals with T2DM
and is particularly indicated in individuals with osmotic symp-
toms [44]. However, the harmful effects of severe hypoglyce-
mia due to intensive treatment most often observed with
sulfonylureas or insulin therapy often exceed the potential
benefits in individuals with multiple serious comorbidities and
functional limitations [45]. It is, therefore, important to set
appropriate, individualized glycemic targets in this patient
population. Self-management education and educating carers,
family members, and relatives to monitor blood glucose and
recognize signs and/or symptoms of hypoglycemia are of para-
mount importance.
Insulin pen devices are recommended due to their simplic-
ity of use. Insulin analogs offer increased convenience with
the ability to time injections to meals and a lower risk of
hypoglycemia when compared to human insulin. Basal-only
insulin regimen is a suitable initial approach in older indi-
viduals with T2DM that require insulin. A prandial insulin
can be added to the meal with the greatest glycemic excur-
sion (typically dinner) to intensify treatment. Rapid-acting

insulin analogs allow flexibility because they can be injected
immediately after a meal is consumed, ensuring that the insu-
lin dose is commensurate with ingested food, particularly
when intake is variable. A twice-daily premixed insulin regi-
men is more convenient than a basalbolus regimen (3
injections/day) due to reduced injection frequency but
requires regimented mealtimes and lifestyle. A basalbolus
regimen is suited to older patients with busy lifestyles and
erratic meal eating habits who can appropriately adjust insu-
lin doses; they are also helpful in nursing homes where meal-
times often do not correspond to scheduled medicine
administration times. Finally, newer long-acting basal insulin
analogs (e.g., insulin degludec and glargine U300) have low
glycemic variability and less propensity to cause hypoglyce-
mia and are useful treatment options in the management of
older people with diabetes.
6.6.2 Insulin Therapy and Pregnancy

Tight glycemic control (HbA1c <6.0 %) in pregnancies com-
plicated either by gestational or preconceptional diabetes can
reduce the risk of adverse fetomaternal outcomes provided
this can be achieved with negligible risk of recurrent or dis-
abling hypoglycemia [46]. Insulin requirements are highly
variable and increase as pregnancy progresses, averaging 0.8
u/kg/day in the first trimester to 1.0 u/kg/day in the second
trimester to 1.2 u/kg/day in the third trimester. Hence, women
on insulin therapy require frequent dose titration to achieve
adequate glycemic targets. Insulin resistance drops rapidly
with delivery of the placenta, and women gradually become
more insulin sensitive, with significantly less insulin required
in the peripartum period, which must be anticipated to avoid
hypoglycemia.
Self-monitoring of blood glucose is preferable because
HbA1c values do not accurately reflect glycemic control due
to rapid red blood cell turnover during pregnancy. Glycemic
targets in women with overt or gestational diabetes include

fasting plasma glucose of <5.3 mmol/L (<95 mg/dL), 1 h post-
prandial plasma glucose of <7.27.8 mmol/L (<130140 mg/
dL), or 2 h postprandial plasma glucose of <6.7 mmol/L
(<120 mg/dL) [46]. Early initiation of insulin is indicated if an
ultrasound suggests the possibility of hydramnios or fetal
macrosomia [46].
During labor, basal insulin should be withheld and an insu-
lin infusion ( dextrose, if needed) is commenced to maintain
blood glucose levels between 4 and 7 mmol/L (72126 mg/
dL). Basal insulin requirements can be met either with NPH
or detemir insulin, although the latter may provide greater
improvements in fasting glucose levels without an increased
incidence of hypoglycemia [47, 48].
If glycemic control has been satisfactorily maintained with
a basal insulin analog (detemir or glargine) before pregnancy,
they can be continued during pregnancy. However, insulin
glargine is not approved by the Food and Drug Administration
(FDA) in the United States for use during pregnancy and any
initiation or continuation during pregnancy must be dis-
cussed with the concerned individual. Insulin lispro and
aspart are safe for use during pregnancy and generally pre-
ferred because they provide greater improvements in post-
prandial hyperglycemia compared to short-acting human
insulin [47]. Data on the safety of insulin glulisine in preg-
nancy is lacking and it is not recommended for use [47].
6.6.3 Insulin Therapy in Gestational Diabetes

Mellitus
Safe glucose-lowering therapies for use during pregnancy are
limited and include insulin and metformin. A recent systematic
review concluded that glibenclamide should not be used for
the treatment of gestational diabetes if insulin or metformin is
available [49]. Metformin is commonly employed after lifestyle
interventions [50] and may particularly benefit obese women
and those who are reluctant to inject insulin. It also acts as an
insulin-sparing agent. If recommended glycemic targets are

difficult to achieve, insulin therapy should be considered [51].
Women with diabetes on insulin therapy desiring preg-
nancy should be offered the choice of multiple daily dose
insulin (basalbolus) regimen which offers flexibility,
precise dose adjustment, and, consequently, a greater
chance of achieving optimal glycemic targets [52]. In
women with T1DM during labor, intravenous dextrose and
insulin infusion should be considered from the onset of
established labor with the aim of maintaining blood glu-
cose between 4 and 7 mmol/L (72126 mg/dL) [53]. Insulin
pump therapy is a viable option and may represent a more
efficacious route of insulin delivery if glycemic control can-
not be achieved using various insulin strategies, including
basalbolus regimen [54]. Insulin pump therapy is associ-
ated with an increased risk of temporary worsening of
glycemic control, ketoacidosis, and hypoglycemia and
requires careful monitoring. However, women with satis-
factory glycemic control on an insulin pump prior to con-
ception should continue with this treatment option during
pregnancy [52].
6.6.4 Insulin Therapy in Chronic Kidney Disease
CKD commonly affects individuals with T2DM and is a

major cause of end-stage kidney failure [55]. Aggressive gly-
cemic control in the early stages of diabetic nephropathy can
reduce vascular complications and progression of CKD, but
benefits in end-stage kidney failure are less obvious. The
pharmacokinetics of glucose-lowering therapies are influ-
enced by whether the individual has mild- to moderate-stage
CKD, severe kidney impairment, or end-stage kidney failure
(CKD stages 4 and 5) that requires renal replacement ther-
apy [56]. Insulin therapy is commonly employed in estab-
lished kidney failure, though frequent insulin dose adjustments
are required. With progressive loss of kidney function, the
half-life of insulin is prolonged due to reduced insulin clear-

ance, which increases the risk of hypoglycemia [57]. Hence,
the starting dose of insulin dose should be reduced and
titrated cautiously. Despite its shortcomings, HbA1c is used
for estimating diabetes control in advanced CKD, though
insulin dose recommendations should be carried out after a
review of self-monitored blood glucose readings [58]. In indi-
viduals undergoing hemodialysis, daily insulin requirements
may also change due to improvements in insulin sensitivity
and clearance. Hence, it is prudent to reduce the basal insulin
dose by approximately 25 % post-dialysis compared to the
day before the procedure [59].
6.6.5 Insulin Therapy and Long-Distance Travel
Insulin self-management during overseas or long-distance

travel, particularly across time zones, requires detailed
advanced planning [60]. There is an increased risk of hypo- or
hyperglycemia during or after long-haul travel in insulin-
treated individuals with diabetes due to changes in quality
and timing of meals [61]. Therefore, a comprehensive review
of diabetes care with formal checks of insulin supplies and
accessories with a health-care professional or diabetes nurse
specialist is beneficial prior to embarking on long-distance
travel [60, 62].
Insulin storage during travel is important, as insulin may
lose efficacy in higher temperatures (e.g., hot tropical cli-
mates); storage in insulated containers or proprietary evapo-
rative cooling bags is recommended, and insulin should not
be left for long periods in the glove compartment of a car. The
shelf life of insulin should be adequate for the duration of the
trip, and spare insulin pens or vials should be carried so that
therapy is not interrupted if there is malfunction of insulin
delivery device. Insulin supplies should be carried in hand
luggage because aircraft luggage holding areas are often not
climate controlled and insulin may freeze, making it unsuit-
able for use. Insulin, syringes, a glucose testing kit, and a

hypoglycemia (hypo) kit containing dextrose or a sugary
drink must be readily available. Wearing identification (e.g.,
medical bracelet which indicates diabetic status and taking
insulin) and an emergency contact number is particularly
helpful to first responders during an emergency. A letter from
a health-care provider to allow use of needles on flight may
be needed when traveling with certain aircraft carriers.
Airport security X-ray machines or body scanners can dam-
age insulin pumps or continuous glucose monitors, and so it
is advisable to disconnect the pump and hand it to security
staff or remove batteries before entering the scanner [61].
Frequent blood sugar testing during travel is recommended
to prevent or detect impending hypoglycemia. In some coun-
tries, blood glucose meters measure readings in mg/dL (not
mmol/L), which can impact decisions on diabetes treatment.
For conversion from mg/dL to mmol/L, the value in mg/dL is
divided by 18 and for conversion from mmol/L to mg/dL, the
value in mmol/L is multiplied by 18. Delayed gut absorption
of carbohydrates can occur at high altitudes, which predis-
poses an individual to postprandial hypoglycemia. Hence,
insulin should be taken with or immediately after
meals. A basalbolus regimen offers greater flexibility in
matching insulin to diet, activity, and travel plans and should
be considered on a short-term basis. Variations in the length of
the day while traveling across time zones can impact insulin
needs. In general, westward travel requires patients take more
insulin or split the basal insulin dose, and eastward travel
requires less insulin.
Traveling at high altitudes can produce air bubbles in an
insulin pump cartridge due to drop in ambient pressures,
which can cause unintended insulin delivery. Thus, sugges-
tions for insulin pump users during flight travel include keep-
ing the pump cartridge slightly underfilled (approximately
1.5 mL of insulin), disconnecting the pump before takeoff,
and reconnecting when the aircraft reaches cruising altitude.
After landing, the pump should be disconnected, a tubing or
cannula prime of 2 units carried out, and then the pump can
be reconnected. In case of cabin decompression, the insulin

pump should be disconnected [63].
6.6.6 Driving and Insulin-Treated Diabetes
Driving is an important consideration in people with diabe-

tes. Although insulin-treated individuals do not present a
greater risk for road accidents compared to those not on
insulin therapy, driving motorized transport, large goods
vehicle, airplane, train, boat, or working underwater or at
height poses a significant hazard if hypoglycemia intervenes
and compromises neurocognitive function [64]. Factors asso-
ciated with diabetes such as hypo- or hyperglycemia, impaired
visual acuity, peripheral neuropathy, and sleep apnea are also
known to increase accident risk [65].
Driving regulations may differ in various countries but are
generally quite stringent for insulin-treated diabetes. In recent
years, regulatory bodies have adopted a flexible approach, and
insulin therapy is not an absolute contraindication for employ-
ment in at risk occupations providing strict criteria for
safety are met. Fitness for driving criteria by most licensing
agencies generally requires complete hypoglycemia aware-
ness, no more than one episode of severe hypoglycemia in the
preceding 12 months,and intact visual acuity.Recommendations
for drivers on insulin therapy or glucose-lowering therapies
that may induce hypoglycemia suggest they should test their
blood glucose prior to the start of a journey to ensure that
blood glucose readings are 5.0 mmol/L (90 mg/dL) while
driving and at approximately 2-hour intervals on long jour-
neys. Drivers should also keep fast-acting carbohydrates and
a blood glucose meter within reach and refrain from driving if
blood glucose is <4 mmol/L (<72 mg/dL) [65, 66]. Driving can
be commenced following a period of hypoglycemia after
approximately 45 min but only if testing shows normalization
of blood glucose. While it is important that driving regulations
and safe practices are discussed at regular consultations, medi-
cal assessment for fitness to drive should be undertaken on an
Table 6.2 Safe driving advice for drivers with insulin-treated

diabetes
Keep a blood glucose meter, testing strips, and an adequate
supply of glucose tablets or sweets within easy reach during
driving
Check blood glucose no more than 1 h before the start of the
first journey and every two hours (on a longer journey)
Blood glucose should ideally be >5.0 mmol/L (90 mg/dL) while
driving. If blood glucose is 5.0 mmol/L or less, a snack must be
consumed
Do not drive if blood glucose is <4.0 mmol/L (72 mg/dL) or
feeling hypoglycemic
If hypoglycemia develops while driving, stop the vehicle in
a safe location as soon as possible. Do not drive for at least
45 min after blood glucose has returned to normal
Carry personal identification to indicate that you have diabetes
and are taking insulin
Monitor blood glucose more often after increased physical
activity or exercise, altered meal routine, changes to insulin
regimen, or insulin dose and during pregnancy
Take regular meals, snacks, and periods of rest on longer
journeys. Do not drink alcohol before or while driving
individualized basis to enhance safety of life and property on

land, air, and sea (Table 6.2).
6.6.7 Insulin Therapy During Prolonged

Religious Fasting
Fasting as part of religious customs is observed by many
religious faiths including Islam, Christianity, Judaism, and
Hinduism. Long-term fasting during the month of Ramadan
presents a particular challenge for Muslims with diabetes
and their health-care providers. Ramadan occurs in the
ninth lunar month of the Islamic calendar and during this
time, Muslims do not consume food or drink from predawn

(suhur) to sunset (iftar). Fasting is not obligatory for Muslim
people with diabetes because it can negatively impact health
due to disruptions in glycemic control, increased risk of
severe hypoglycemia, dehydration, and thrombosis [67]. This
may be particularly relevant in high-risk individuals with
recent, unexplained severe hypoglycemia or hypoglycemic
unawareness, recent diabetic ketoacidosis, hyperglycemic
hyperosmolar state, acute illness, pregnancy, and comorbidi-
ties such as end-stage kidney failure, advanced dementia, or
uncontrolled epilepsy [68].
However, for those who intend to fast despite medical
advice, Ramadan-focused care planning and education are
important [69]. This includes emphasis on more frequent
blood glucose testing during the day which does not consti-
tute breaking the fast and importance of knowing when to
break the fast due to hypoglycemia if it endangers health,
which is acceptable and in keeping with the tenets of Islam.
At sunset and predawn, foods containing high dietary fiber
(e.g., whole grains, fruits, vegetables) and low glycemic index
rating (e.g., beans and pulses) should be consumed. Dates are
traditionally consumed for breaking fast at sunset; how-
ever, they have a high glycemic index and limited consump-
tion is advised. In individuals with T1DM on a basalbolus
regimen, one approach is to calculate 70 % of the total pre-
Ramadan insulin dose and divide it in to 60 % intermediate-
or long-acting basal insulin in the evening and 40 % as
rapid-acting insulin analog given with the meal at sunset and
predawn [70]. A correction bolus of rapid-acting insulin ana-
log is advised at midday if blood glucose readings are
>7 mmol/L.
In individuals with T2DM requiring insulin, hyperglycemic
excursions can be controlled with a similar basalbolus regi-
men. Alternatively, premixed insulin lispro with neutral prot-
amine lispro in a 50:50 ratio with evening meal and premixed
analog in a 30:70 ratio at predawn meals can be used to
achieve optimal effect [71].
6.6.8 Insulin Therapy at End of Life
Diabetes management at end of life or when palliative

treatment is commenced requires careful consideration of
individual needs and broader discussions with family and
members of the health team. Frequent blood testing can be
onerous and a complex insulin regimen should be avoided.
The aim of management is a dual approach which should
seek to avoid osmotic symptoms of hyperglycemia (e.g., thirst,
dehydration) and symptomatic hypoglycemia [72, 73]. Insulin
requirements may be reduced due to poor nutritional intake,
weight loss, or kidney failure. In individuals with T1DM, unless
specifically instructed by the patient, withdrawing insulin will
lead to early demise; a more pragmatic approach is to consider
a twice-daily mixed insulin regimen or once-daily intermedi-
ate- or long-acting basal insulin. In individuals with T2DM
without symptomatic hyperglycemia, insulin treatment can
be withdrawn and managed with oral glucose-lowering drugs.
With steroid use, the recommended approach is to administer
a single dose of isophane insulin to counter hyperglycemia
[72]. However, the overarching principle surrounding the man-
agement of these individuals is to offer a care plan which is the
least intrusive and avoids treatment-related adverse effects.
6.7 Summary
Individuals on insulin therapy, depending on their circum-
stances, need to make practical decisions every day to self-
manage their condition and achieve near-normal glycemia.
While some of these decisions are based on ad hoc learning
or personal experience, diabetes education and effective
self-management can improve patient treatment behavior
and adherence to treatment. However, it requires investing
time, effort, and trained health-care teams to deliver this.
The provision of information, education, and psychological sup-
port that facilitates self-management is the cornerstone of diabe-
tes care. National Service Framework for Diabetes (Department
of Health UK, 2001)
References 203
Key Messages
Effective patient self-management when taking insulin
requires patient education, treatment adherence, and
involvement of trained health care professionals.
Insulin therapies in special patient population groups
require a multidisciplinary team approach with careful
attention to providing individualized care.
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Further Reading
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18 Jul 2016.

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Winston Crasto

ISBN 978-3-319-10938-1 ISBN 978-3-319-10939-8 (eBook)

Library of Congress Control Number: 2016946349

Springer International Publishing Switzerland 2016

Printed on acid-free paper

This Adis imprint is published by Springer Nature

1 Introduction to Insulin Therapies . . . . . . . . . . . . . . . . . 1

3.1.2 Long-Acting Basal Insulin Peglispro . . . . . 55

5.2.1 Adherence to Insulin Therapy

6.4.2 Insulin Pens . . . . . . . . . . . . . . . . . . . . . . . . . . 181

Winston Crasto, MBBS, MRCP, MD is a Consultant Physician

Janet Jarvis, RN, BSc (Hons), MSc is a Nurse Research Fellow

Melanie J. Davies, CBE, MB, ChB, MD, FRCP is an honorary

type 2 diabetes, screening and prevention of type 2 diabetes,

W. Crasto et al., Handbook of Insulin Therapies, 1

Table 1.1 Classification of different types of diabetes with impor-

Table 1.1 (continued)

1.3 The Global Burden of Diabetes

North America and

South and Central Africa

IDF 2013 2035 INCREASE

Figure 1.1 International Diabetes Federation (IDF) regions and

in Europe have been diagnosed with T2DM, a disease previ-

1.4 The Human Insulin Molecule

Figure 1.2 Biochemical structure of insulin

1.4.1 Effect of Insulin on Metabolism

Insulin is directly released from the pancreatic cells in a

In brief, insulin facilitates glucose transport in liver and

1.5 History of Insulin Therapy

Table 1.2 Discovery of insulin timeline

1.5.1 The New Era of Insulin Therapies

analogs created by recombinant DNA technology, including

1.5.2 Insulin Management: Combining Art

although sometimes these choices can be arbitrary. The real-

After a certain level of technical skill is achieved, science and art

6. Curry DL, Bennett LL, Grodsky GM. Dynamics of insulin

The insulin hormone is normally synthesized and stored as

W. Crasto et al., Handbook of Insulin Therapies, 15

Rapid or quick acting (aspart, lispro, glulisine)

2.2 Animal Insulin

Figure 2.1 Process of insulin extraction in the early ninetieth cen-

Figure 2.2 A bottle of insulin produced in 1923 (Reproduced with

vials or cartridges as a white suspension of porcine/bovine

Table 2.1 Pharmacokinetics and pharmacodynamics of currently

2.3 Human Recombinant Insulin

2.3.1 U-500 Insulin

U-500 is a five-time concentrated formulation of human insu-

2.3.2 Animal Versus Human Insulin

As the animal versus human insulin debate on clinical supe-

Intermediate NPH suspensions 24 h 48 1416 Usually used for basal insulin

Type of human Onset Peak of Duration

IM intramuscular, NPH neutral protamine Hagedorn, s/c subcutaneous

and ceased production by major insulin manufacturers have

2.4 Insulin Analogs

(glargine, detemir) form the first-generation insulin analogs.

2.4.1 Rapid-Acting Analogs

Rapid-acting analogs are prandial (or mealtime) types of insu-

Figure 2.3 Insulin analogs: pharmacodynamics and pharmacokinet-

lowering of prandial glucose, reduced risk of nocturnal hypo-

2.4.2 Long-Acting Insulin Analogs

Long-acting insulin analogs are used to provide basal or back-

Table 2.3 Rapid-acting insulin analogsa clinical outcomes in type 1

Table 2.3 (continued)