Professional Documents
Culture Documents
Janet Jarvis
Melanie J. Davies
Handbook of
Insulin Therapies
Handbook of Insulin
Therapies
Handbook of Insulin
Therapies
Winston Crasto
Janet Jarvis
Melanie J. Davies
vii
xi
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.
Europe
Western
South East Pacific
Asia
Figure 1.3 The role of insulin hormone in human metabolism. GH growth hormone, FFA free fatty acid,
T2DM type 2 diabetes mellitus
8 Chapter 1. Introduction to Insulin Therapies
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)
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
1.6 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:
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;493:241–5.
Further Reading
Amiel SA. Hypoglycemia: from the laboratory to the clinic. Diabetes
Care. 2009;32:1364–71.
2.1 Introduction
Intermediate NPH suspensions 2–4 h 4–8 14–16 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)
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
2.4.2.1 Glargine
2.4.2.2 Detemir
50µm
Capillary
2+
membrane Phenol Zinc Protracted absorption
Insulin in blood
(continued)
Table 2.4 (continued)
30
Peak Duration
Onset of of of action
Analog insulin Physicochemical properties action action (hours) Other comments
Detemir Formed by deletion of 0–2 h No Less than Duration of action lasts
Chapter 2.
diabetes
Mean
change in
Mean Risk of body
Study difference hypoglycemia weight
Chapter 2.
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
Chapter 2.
[23] included 28–47 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; 11–27 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 6.9–9.5 %;
to −0.03)b BD vs.
weeks BMI =
NPH
23.1– Det OD/
OD:
28.0 kg/m2 BD vs.
−5.51
Existing Insulin Therapies
NPH OD:
(−6.56 to
−0.36(−0.59
−4.46)b
to –0.19)b
Gla OD
vs. NPH
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
diabetes
Mean
change in
Mean Risk of body
Study difference in hypoglycemia weighta
Chapter 2.
b
Indicates significance at P < 0.05
2.4.2.5 Summary
2.4.3.1 IDegAsp
BIAsp 30 bid showed comparable Inferior in reducing FPG (treatment difference= 0.7 mmol/L (95 % CI,
efficacy for HbA1c lowering to 0.3–1.0); [12.0 mg/dL; 95 % CI, 6.0–18.1])
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 basal–bolus regimen Superior reductions in FPG (treatment difference= –1.1 mmol/L; 95 %
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)
Table 2.9 (continued)
46
2.5 Summary
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.
References
1. Brange J, Ribel U, Hansen JF, Dodson G, Hansen MT,
Havelund S, et al. Monomeric insulins obtained by protein
engineering and their medical implications. Nature.
1988;333:679–82.
2. Wendt D. Two tons of pig parts: making insulin in the 1920s.
Smithsonian Institute Website. http://americanhistory.si.edu/
blog/2013/11/two-tons-of-pig-parts-making-insulin-in-the-1920s.
html. Accessed July 18, 2016.
3. Goeddel DV, Kleid DG, Bolivar F, Heyneker HL, Yansura DG,
Crea R, et al. Expression in Escherichia coli of chemically syn-
thesized genes for human insulin. Proc Natl Acad Sci U S A.
1979;76:106–10.
4. Thim L, Hansen MT, Norris K, Hoegh I, Boel E, Forstrom J, et al.
Secretion and processing of insulin precursors in yeast. Proc Natl
Acad Sci U S A. 1986;83:6766–70.
5. Starke AA, Heinemann L, Hohmann A, Berger M. The action
profiles of human NPH insulin preparations. Diabet Med.
1989;6:239–44.
6. Richter B, Neises G. ‘Human’ insulin versus animal insulin in
people with diabetes mellitus. Cochrane Database Syst Rev.
2005;(1):CD003816.
7. Cameron CG, Bennett HA. Cost-effectiveness of insulin analogs
for diabetes mellitus. CMAJ. 2009;180:400–7.
8. Reutrakul S, Wroblewski K, Brown RL. Clinical use of U-500
regular insulin: review and meta-analysis. J Diabetes Sci Technol.
2012;6:412–20.
9. Crasto W, Jarvis J, Hackett E, Nayyar V, McNally PG, Davies MJ,
et al. Insulin U-500 in severe insulin resistance in type 2 diabetes
mellitus. Postgrad Med. 2009;85:219–22.
10. Fireman P, Fineberg SE, Galloway JA. Development of IgE
antibodies to human (recombinant DNA), porcine, and bovine
insulins in diabetic subjects. Diabetes Care. 1982;5 Suppl 2:
119–25.
11. Airey CM, Williams DR, Martin PG, Bennett CM, Spoor
PA. Hypoglycemia induced by exogenous insulin--‘human’ and
animal insulin compared. Diabet Med. 2000;17:416–32.
12. Garber AJ, Davidson JA, Krosnick A, Beaser RS, Anderson Jr
JH. Impact of transfer from animal-source insulins to biosyn-
thetic human insulin (rDNA E coli) in patients with diabetes
mellitus. Clin Ther. 1991;13:627–36.
technology with the potential Early metabolic effect, as well as pronounced late metabolic
for once-daily dosing effect, compared to biphasic analog
57
(continued)
Table 3.1 (continued)
58
Type of ultra-
rapid-acting
insulin Brief description Clinical studies and development
Concentrated BIOD-531: a concentrated BIOD-531 (at 1.0 U/kg and 0.5 U/kg) compared to Humulin®R
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
Chapter 3. Emerging Insulin Therapies
baseline 8.1 %: 0.04 % (0.10–0.19)a added to OADs in individuals previously treated with basal insulin
Comparative glycemic efficacy compared (EDITION 2 studya [19])
to Gla-100 in a basal–bolus 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-naïve 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
(0.10–0.19)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
Table 3.2 (continued)
62
Gla-100
Gla-300 glargine 300 units/mL, Gla-100 glargine 100 units/mL, OAD oral antidiabetic drugs, RR rate ratio
a
95 % confidence interval
3.1.4.1 IDegLira
3.1.4.2 LixiLan
a b
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
70 Chapter 3. Emerging Insulin Therapies
product.
(continued)
74
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
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
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.
References
1. Krasner A. Safety and efficacy of ultra-rapid-acting human insu-
lin formulation BIOD-123 in patients with type 1 diabetes.
Webcast presented at 74th ADA Scientific Sessions, San
Francisco; June 13-14, 2014.
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.
Further Reading
Berger M. Oral insulin 1922–1992: the history of continuous ambi-
tion and failure. In: Berger M, Gries FA, editors. Frontiers in
insulin pharmacology. Stuttgart: Thieme Publishing Group;
1993:144–8.
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;85:257–67.
Heller S, Kozlovski P, Kurtzhals P. Insulin’s 85th anniversary—an
enduring medical miracle. Diabetes Res Clin Pract. 2007;78:
149–58.
4.1 Introduction
Type 2 diabetes mellitus (T2DM) is a progressive disease
typically characterized by insulin resistance and diminishing
β-cell reserve, eventually leading to insulin deficiency. In
addition to insulin resistance within the muscle, liver, brain,
and β 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 sodium–glucose 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
• 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].
Figure 4.1 Clinical inertia in people with type 2 diabetes requiring insulin therapy. OAD (oral antidiabetic) (Adapted
(continued)
89
Table 4.1 (continued) 90
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
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 ~10–12 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 5.5–6.6 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 3–4
interval days between adjustments. Consider nocturnal
hypoglycemia if FPG readings remain consistently high
If SMBG below FPG target or unexplained hypoglycemia,
reduce by 2–4 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
(continued)
95
Table 4.3 (continued)
96
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.
3-2-1 ATLANTUS Starting basal insulin dose differed between physician-led and The starting basal insulin dose for
patient-led algorithms insuline-naïve 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-naïve
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
0–2 0–2
(≥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) 6–8 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
4.3
Met + insulin improved glycemic control (mean difference in <45 and stopping therapy when
HbA1c = 0.40 %; 0.25–0.55) 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, 14.36–24.91; or 0.18 IU/kg; 95 % CI, 0.12–0.23)
39 % reduced risk of macrovascular disease (hazard ratio 0.61; 95 %
CI, 0.40–0.94)
(continued)
99
Table 4.4 (continued)
100
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, 0.76–1.29) 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, 1.43–2.56) therapies have not been established
Efficacy of GLP-1RA added to basal Contraindications: history of acute pancreatitis,
insulin vs. basal–bolus 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
(continued)
Insulin added to
novel glucose-
lowering drugs Selected trials illustrating glycemic efficacy and safety Comments
Efficacy of LixiLan (lixisenatide 1 μg/glargine 2 units)
vs. glargine alone [32]:
Chapter 4.
SGLT2 inhibitors
Insulin added to
novel glucose-
lowering drugs Selected trials illustrating glycemic efficacy and safety Comments
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 ß-cell
function and therefore
does not confer a high
risk of hypoglycemia
Treatment with the
gliflozins is well tolerated
weeks
No differences in hypoglycemic events between treatment groups
109
(continued)
Table 4.6 (continued)
110
Insulin added to
novel glucose-
lowering drugs Selected trials illustrating glycemic efficacy and safety Comments
Efficacy and safety of empagliflozin as add-on therapy to MDI
Chapter 4.
*
P < 0.01
4.3 Insulin Regimens 111
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)
4.3 Insulin Regimens 115
(continued)
(continued)
(continued)
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 basal–bolus
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
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.
References
1. DeFronzo RA. Banting Lecture: From the triumvirate to the
ominous octet: a new paradigm for the treatment of type 2 dia-
betes mellitus. Diabetes. 2009;58:773–95.
2. Matthews DR, Cull CA, Stratton IM, Holman RR, Turner
RC. UKPDS 26: Sulphonylurea failure in non-insulin-dependent
diabetic patients over six years. UK Prospective Diabetes Study
(UKPDS) Group. Diabet Med. 1998;15:297–303.
3. Vora J. Combining incretin-based therapies with insulin: realiz-
ing the potential in type 2 diabetes. Diabetes Care.
2013;S226–32.
4. Khunti K, Wolden ML, Thorsted BL, Andersen M, Davies
MJ. Clinical inertia in people with type 2 diabetes: a retrospec-
tive cohort study of more than 80,000 people. Diabetes Care.
2013;36:3411–7.
5. Strain WD, Cox X, Hirst M, Vencio S, Mohan V, Vokó Z, et al. Time
to do more: addressing clinical inertia in the management of type
2 diabetes mellitus. Diabetes Res Clin Pract. 2014;105:302–12.
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;85:257–67.
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;30:512–24.
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 ß-cell death is variable and individuals are usually clini-
cally symptomatic when nearly 70–80 % of pancreatic ß 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?
Figure 5.1 New cases of type 1 diabetes (0–14 years per 100,000
children per year), 2013 (Reproduced with permission from the
International Diabetes Federation (IDF) [1] ©IDF)
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
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%
American Association of Diabetes Educators guidelines for suitability of insulin pump therapy [32]
• Use in patients with ’frequent and unpredictable fluctuations in blood glucose’and 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 ³4 times per day during the previous 2
months.
Patient must also meet ³1 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.
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 Project’s six-step plan to develop a fully automated multihormone artificial pan-
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 (1869–1962), 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.
References
1. Cnop M, Welsh N, Jonas JC, Jörns A, Lenzen S, Eizirik
DL. Mechanisms of pancreatic β cell death in type 1 and type 2
diabetes: many differences, few similarities. Diabetes. 2005;54
suppl 2:S97–107.
2. The Diabetes Control and Complications Trial (DCCT) Research
Group. The effect of intensive treatment of diabetes on the
development and progression of long-term complications in
insulin-dependent diabetes mellitus. N Engl J Med.
1993;329:977–86.
3. Nathan DM, DCCT/EDIC Research Group. The Diabetes
Control and Complications Trial/Epidemiology of diabetes
interventions and complications study at 30 years: overview.
Diabetes Care. 2014;37:9–16.
4. Kähler P, Grevstad B, Almdal T, Gluud C, Wetterslev J, Lund SS,
et al. Targeting intensive versus conventional glycemic control
for type 1 diabetes mellitus: a systematic review with meta-
analyses and trial sequential analyses of randomised clinical tri-
als. BMJ Open. 2014;4:8 e004806.
5. Fullerton B, Jeitler K, Seitz M, Horvath K, Berghold A,
Siebenhofer A. Intensive glucose control versus conventional
glucose control for type 1 diabetes mellitus. Cochrane Database
Syst Rev. 2014;(2):CD009122.
6. Pickup JC. Insulin-pump therapy for type 1 diabetes mellitus. N
Engl J Med. 2012;366:1616–24.
7. Hanghoj S, Boisen KA. Self-reported barriers to medication
adherence among chronically ill adolescents: A systematic
review. J Adolescent Health. 2014;24:121–38.
8. Kilpatrick ES, Rigby AS, Goode K, Atkin SL. Relating mean
blood glucose and glucose variability to the risk of multiple epi-
sodes of hypoglycaemia in type 1 diabetes. Diabetologia.
2007;50:2553–61.
9. Hoeks LB, Greven WL, de Valk HW. Real-time continuous glu-
cose monitoring system for treatment of diabetes: a systematic
review. Diabet Med. 2011;28:386–94.
Further Reading
Frese T, Sandholzer H. The epidemiology of type 1 diabetes mellitus.
In: Escher A, editor. Type 1 diabetes. Rijecka: In Tech; 2013.
Hovorka R. Continuous glucose monitoring and closed-loop sys-
tems. Diabet Med. 2006;23:1–12.
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.
6.3.1 Verification
6.3.2 Storage
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)
6.3.3.2 Priming
a b
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.
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
a b
Cannula inserted
03/08/2008 – 08/09/2008 into LH
550
500
450
Glucose (mg/dL)
400
350
300
250
200
150
100
50
a b
a b
4 mm needle
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
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
Chapter 6.
No
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)
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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Siminerio L, Kulkarni K, Meece J, Williams A, Cypress M, Haas L, et al;
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