The Future of Insulin Therapy for Patients

With Type 2 Diabetes Mellitus

Joseph M. Tibaldi, MD

From the Albert Einstein College of

Medicine in Flushing, New York.
This article is based on a continuing
medical education symposium held
on October 10, 2012, during the
American Osteopathic Associations
2012 annual Osteopathic Medical
Conference & Exposition in
San Diego, California. This article was
developed with assistance from
Global Directions in Medicine.
The author has approved
the article and all of its content.
Financial Disclosures:
Dr Tibaldi is on the speakers
bureaus for Daiichi Sankyo Company,
Merck & Co, Inc, and Novo Nordisk Inc.
He is also a consultant for
Novo Nordisk Inc.
Address correspondence to
Joseph M. Tibaldi, MD,
Queens Diabetes and

Insulin therapy has been the mainstay of therapy for patients

Endocrinology Associates,

with type 2 diabetes mellitus for the past 90 years. This trend

59-45 161st St,

is likely to continue as new formulations are developed to more

Flushing, NY 11365-1414.

closely mimic physiologic insulin secretion and to provide

E-mail: jtibaldi@aol.com

patients who have diabetes with more convenient options for

integrating this therapy into their lifestyle. The present article
reviews how the role of insulin continues to evolve, from its
earlier use in the treatment paradigm (even at first diagnosis)
to its role in combination therapy with incretin-based therapies, as well as new formulations that provide more-convenient
forms of insulin replacement therapy.
J Am Osteopath Assoc. 2013;113(4 suppl 2):S29-S39

A Supplement to The Journal of the American Osteopathic Association

April 2013 | Vol 113 | No. 4 | Supplement 2

S29

he number of patients with type

cated and patient-friendly agents.2 The

patients with T2DM, the normal post-

2 diabetes mellitus (T2DM) far

present review article discusses ini-

prandial suppression of glucagon secre-

exceeds the number of endo-

tiation of insulin replacement therapy at

tion is inadequate, leading to increased

crinologists and diabetes specialists

the time of diagnosis, basal insulin ther-

hepatic glucose output that worsens

available to treat them. The majority

apy used in combination with incretin

hyperglycemia. In turn, chronic hyper-

of patients are treated in primary care

therapy, and second-generation basal

glycemia leads to glucose toxicity that

environments, and by virtue of the com-

insulin analog therapy, using a case

paradoxically results in reduced syn-

mon comorbidities that travel with

study to demonstrate clinical applica-

thesis and secretion of insulin.6 Native

diabetes, including hypertension, dys-

tion. Other means of enhancing delivery

glucagon-like peptide-1 (GLP-1) is an

lipidemia, and obesity or overweight,

of insulin to patients are also discussed.

incretin hormone secreted by the gut

comprehensive and holistic approaches

to care are required. Osteopathic physi-

acts on the pancreas to stimulate glu-

a result of improvements in health care

Pathophysiologic
Profile of T2DM Drives
Treatment Choices

and increases in longevity, patients are

Insulin is instrumental in managing T2DM,

may result in the abnormal regulation

more likely to require insulin therapy at

which is a complex, multihormonal, and

of insulin and glucagon secretion that

some point during the progression of

progressive chronic disease. Our ap-

characterizes T2DM.8 Like insulin, GLP-1

T2DM. With advances in insulin therapy

proach to the treatment of patients with

and glucagon are important targets of

still occurring, it is well worth keeping

T2DM requires an understanding of the

pharmacologic treatment strategies for

up to date on trends in the use of this

pathophysiologic profile of this condition

improving glycemic control.9

powerful glucose-lowering agent.

to determine when and how to use the

many pharmacologic agents available.

cians are likely to encounter more and

more such patients in their practices. As

Patients with T2DM are insulin resis-

cose-dependent insulin secretion, and

suppresses the release of glucagon.7
Incretin deficits or incretin resistance

tant, have relatively low insulin produc-

tion, or have both characteristics. Most

the abnormal secretion or abnormal

patients with T2DM eventually require

actions of key hormones that regulate

Use of Insulin Therapy

Early in the T2DM
Treatment Paradigm

insulin if other medications fail to control

glucose production by the liver and glu-

Insulin remains integral to the treatment

their blood glucose levels adequately.

cose uptake in the peripheral muscle

of patients with diabetes.10 For patients

Insulin replacement therapy lets pa-

and adipose tissue. In patients with

with T1DM, insulin therapy is essential

tients know that a key component of

established T2DM, insulin secretion is

and lifesaving. For patients with T2DM,

their natural glucose-regulating system

reduced because of progressive loss

use of insulin therapy was formerly

is being restored. When insulin replace-

of pancreatic -cell function. Plasma

relegated to use during later stages of

ment therapy was introduced more than

glucose levels increase as insulin

the disease. This approach is being

90 years ago, it was a lifesaving option

deficiency and insulin resistance reduce

reexamined as more recent treatment

for patients with type 1 diabetes mellitus

normal insulin activity, leading to dimin-

paradigms encourage earlier use of in-

(T1DM), even though the formulations

ished stimulation of peripheral glucose

sulin treatment algorithms for patients

used were relatively crude. During past

uptake and decreased inhibition of he-

with T2DM.11 On the basis of guidelines

decades, major advances in our abil-

patic glucose production.

from the American Association of Clini-

ity to synthesize more reproducible and

Glucagon normally helps maintain

cal Endocrinologists, insulin therapy

physiologic formulations have enabled

fasting plasma glucose levels by stim-

clearly is recommended for patients

the production of much more sophisti-

ulating hepatic glucose production. In

with severe hyperglycemia and for pa-

S30

that normally slows gastric emptying,

Type 2 diabetes mellitus results from

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April 2013 | Vol 113 | No. 4 | Supplement 2

420

tients receiving oral antidiabetic drugs

who have glycated hemoglobin (HbA1c)

360

Of particular interest are data as-

sessing the use of insulin as a first-line

treatment option for T2DM, often in patients who initially have very high levels

Glucose, mg/dL

levels greater than 9%.12

of glucose toxicity. This treatment op-

Before insulin therapy

270
Immediately after insulin therapy
180

1 year after insulin therapy

90

tion was reviewed by Rolla13 in 2009,

and additional data have since been

published. Several studies 14-16 have

30

60

90

120

150

180

Time, min

shown prolonged remission of T2DM

in patients receiving intensive insulin
600

therapy for 2 weeks. A 2- to 3-week

course of intensive insulin therapy can

500

lay the foundation for prolonged good

diagnosed T2DM who have elevated
fasting glucose levels. Figure1 shows
an example of the effects of short-term
intensive insulin therapy on glucose and
insulin levels.14

In a more recent study, the use of

Insulin, pmol/L

glycemic control in patients with newly

400
300

1 year after insulin therapy

200

Immediately after insulin therapy

Before insulin therapy

100

low-dose insulin therapy (given as premixed insulin in one study) for patients
with newly diagnosed T2DM led to evi-

30

60

90

120

150

180

Time, min

dence of -cell recovery, as documented by plasma insulin and C-peptide levels.17 It appears that reversing glucose
toxicity may result in a rapid improvement in -cell function, which then allows the cell to start to function and
to secrete adequate amounts of insulin
for clinically significant periods of up to
1 year.14-16 This series of events is also
known as a second-wind phenomenon
for the cell.13 After symptom relief oc-

Figure 1.
Glucose and insulin levels before insulin therapy, immediately
after insulin therapy, and 1 year after insulin therapy,
demonstrating the effects of short-term intensive insulin therapy
in patients with newly diagnosed type 2 diabetes mellitus.14
Reprinted with permission from the American Diabetes
Association, from Ryan EA, Imes S, Wallace C. Short-term
intensive insulin therapy in newly diagnosed type 2 diabetes
mellitus. Diabetes Care. 2004;27(5):1028-1032; permission
conveyed through Copyright Clearance Center, Inc.

curs and glucose levels are normalized

in such patients, oral agents often can
be added to therapy, and it may be possible to withdraw insulin.

A Supplement to The Journal of the American Osteopathic Association

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S31

Other recent data show that -cell

thinking that he might have diabetes.

Harry, 2-Year Follow-Up

function can be preserved for at least

After talking with the owner, Harry real-

Harrys diabetes treatment regimen

3.5 years with the use of early and in-

ized that he had unquenchable thirst.

now includes basal insulin as well as

tensive T2DM therapy involving admin-

He promptly made an appointment to

metformin. During the 2 years since

istration of either insulin plus metfor-

see his primary care physician, even

Harry was first seen in the physicians

min or triple oral therapy after an initial

though he had been negligent in doing

office, he has been self-titrating his bas-

3-month period of insulin-based treat-

so for the past year.

al insulin and has generally been able

ment. These data support the premise

The findings from Harrys visit to

to keep his HbA1c level at less than 7%.

that insulin should not be relegated to

his physician were notable. He had a

However, despite engaging in exercise

use as a last-line therapy but, rather,

weight loss of 15 lbs, a nonfasting glu-

on a relatively consistent basis, he has

could be used earlier in the disease

cose level of 430 mg/dL, an HbA1c level

gained 11 lbs. For the past 6 months,

paradigm, when some -cell function

of 12%, and trace levels of ketone bod-

however, his HbA 1c level has been

remains intact. Insulin therapy can be

ies in his urine sample. Insulin replace-

8.3%, in spite of fasting blood glucose

discontinued in patients who have early

ment therapy was recommended as

levels between 90 and 115 mg/dL.

disease, and it can be restarted when

initial treatment.

Harrys goal is to once again attain an

necessary or continued in conjunction

HbA1c level of less than 7%.

with other oral agents or GLP-1 recep-

clearly indicated. He had T2DM, clini-

tor agonists.

cally significant hyperglycemia, and

insulin therapy will ultimately require

signs of catabolism (weight loss), and

treatment intensification. Notably, the

no oral agent or other noninsulin agent

HbA 1c level reflects not only fasting

would begin to bring him close to his

blood glucose levels but also postpran-

Harry

goal HbA1c level. Pathophysiologic find-

dial glucose levels.19 Adding a sulfonyl-

Harry is a 52-year-old man who, for the

ings revealed that his liver was secret-

urea to insulin-based therapy increases

past 6 months, has been struggling with

ing excess glucose that was unable to

the risk of hypoglycemia without pro-

a new job that has required his attention

enter the muscle. His problematic glu-

viding much benefit. Sulfonylureas

during most of his waking hours. His

cose levels occurred in part because

also lower fasting glucose levels much

past medical history includes hyperten-

Harry has diminished insulin levels.

more than postprandial glucose levels,

sion, for which he takes a diuretic, and

However, it also occurred because Har-

so they may not be the best treatment

mixed hyperlipidemia managed with a

ry has a GLP-1 deficit, and because,

option for Harry. At this point, the clini-

modest dose of a statin.

with that deficit, he was producing too

cal decision traditionally is to switch to

much glucagon.

a premixed insulin or move toward a

his medications, but his job keeps him

It is gratifying to treat a patient like

basal-bolus regimen (which is often

at his desk most of the time. His only

Harry, who arrives at the office feeling

done by sequentially adding prandial

exercise is walking to the local fast food

poorly but who, after approximately 3 to

insulin before meals as needed and as

restaurant where he buys most of his

6 months, is in much better health and

tolerated).11,20-22 This clinical decision

meals. The owner of the restaurant

can have blood glucose levels that are

is certainly a well-validated and effec-

noted that Harry was returning more

close to normal. Chronic hyperglycemia

tive treatment strategy, but there are

frequently and buying more juice and

leads to reduced insulin secretion

drawbacks for some patientsnamely,

soda. The owners wife had diabetes,

(Figure2).6 By reversing glucotoxicity,

an increased risk of hypoglycemia,

so the owner gently questioned Harry

it is possible for the body to resume

weight gain, and number of complica-

about his thirst levels and weight loss,

insulin secretory capacity.

tions for patients in terms of the number

18

Case Study

S32

Harry has been fastidious in taking

In Harrys case, insulin therapy was

A Supplement to The Journal of the American Osteopathic Association

Many patients who receive basal

April 2013 | Vol 113 | No. 4 | Supplement 2

Chronic
hyperglycemia

Oxidative stress (ROS)

Glucose

Pancreatic cell

Glucokinase activity

PDX-1 activity
Insulin biosynthesis

Insulin secretion

Figure 2.
The mechanism of insulin secretion reduction caused by glucose toxic effects.
The binding capacity of PDX-1 decreases as a result of oxidative stress caused
by hyperglycemia, while insulin biosynthesis and secretion also decrease.
Reprinted from Kawahito et al.6 Abbreviations: PDX-1, pancreatic duodenal
homeobox-1; ROS, reactive oxidative species.

of injections needed and the complex-

efficacy in lowering glucose levels.24-27

lower postprandial glucose levels, with

ity of titrating both basal and prandial

The benefit of using these approaches

a low associated risk of hypoglycemia

insulin doses.23

is that incretin-based therapies work

and without weight gain (an advan-

in a glucose-dependent manner (ie,

tage over prandial insulin analogs).28-33

only in the presence of hyperglycemia).

However, basal insulin doses may need

They also are weight neutral (dipepti-

to be adjusted downward or sulfonyl-

dyl peptidase-4 [DPP-4] inhibitors) or

ureas may need to be discontinued.34

Basal Insulin Therapy

in Combination With
Incretin-Based Therapy

are associated with weight loss (GLP-1

Table1 provides a summary of some

Another approach used to augment

receptor agonists).

of the available published literature on

insulin therapy is to add incretin-based

DPP-4 inhibitors used in combination

agents to the treatment regimens of

as both liraglutide and short-acting

with insulin therapy.28,29,35

patients who are receiving basal in-

exenatide, are approved for use with

sulin therapy but who are no longer

long-acting basal insulin analogs in pa-

bination with insulin therapy for post-

achieving treatment goals. Although

tients with T2DM who are not achiev-

prandial glucose control also may

these approaches are similar, they

ing their goals for glycemic control. In-

result in some weight loss. 33 Some

have important differences (Figure3).

cretin-based therapies primarily target

clinicians prefer to start with a GLP-1

Glucagon-like peptide-1 receptor ago-

postprandial hyperglycemia (although

agonist or an incretin-based therapy

nists provide supraphysiologic levels of

longer-acting GLP-1 agonists also af-

early in the treatment paradigm, before

the incretin hormone and have greater

fect fasting plasma glucose levels) and

initiating insulin.36,37

Currently, DPP-4 inhibitors, as well

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The use of GLP-1 agonists in com-

April 2013 | Vol 113 | No. 4 | Supplement 2

S33

Table 1.
Outcomes of Select Studies of Dipeptidyl Peptidase-4 Inhibitors
in Combination With Insulin Over 24 Weeks Duration
Source Agent Comparison

Patients

Outcome

Hong et al,
Sitagliptin
Add-on to insulin vs
Patients with T2DM (n=140);
201228
an insulin dose increase
baseline HbA1c level, 9.2%

Compared with a 25% increase

in the insulin dose, adding
sitagliptin to an insulin-based
regimen was more effective
at lowering HbA1c levels and
was associated with less
hypoglycemia and weight gain

Barnett et al, Saxagliptin

201235

Insulin alone or insulin

plus metformin, addition
of saxagliptin vs placebo

Patients with T2DM (n=455);

baseline HbA1c level,
7.5% to 11%

Addition of saxagliptin improved

glycemic control and was
generally well tolerated

Vilsboll et al, Sitagliptin

201029

Add-on to basal or
premixed insulin vs
placebo

Patients with T2DM (n=451);

baseline HbA1c level,
7.5% to 11%

Addition of sitagliptin improved

glycemic control and was
generally well tolerated

Abbreviations: HbA1c, glycated hemoglobin; T2DM, type 2 diabetes mellitus.

Table 2.
Comparison of Onset, Peak, and Duration of Longer-Acting Basal Insulins
Basal Insulin

Case Study Revisited

Harry Follow-Up

Harry was presented with options to

Onset

Peak

Duration

1-2 h

4-8 h

8-12 h

Glargine

30-60 min

Relatively peakless

16-24 h

Detemir

30-60 min

Relatively peakless

16-24 h

treatment option that could achieve this

Degludec

30-90 min

Peakless

>24 h

goal is the addition of prandial insulin

Neutral protamine
Hagedorn

Source: Reprinted from Nasrallah SN, Reynolds LR. Insulin degludec, the new generation basal insulin
or just another basal insulin? Clin Med Insights Endocrinol Diabetes. 2012;5:31-37.38 Copyright 2012,
with permission from Libertas Academica Ltd.

help him return to his goal HbA1c level of

7%. A DPP-4 inhibitor would be a simple treatment option but would not allow him to attain this goal. A successful

injections at mealtimes.

Harry was also concerned about

losing weight, so it was decided to use

GLP-1 receptor agonists. Because Harry was traveling a great deal and eating at irregular times (usually at a restaurant), he wanted a simple treatment
plan that involved the least number of
injections and a medication that did not
require strict dosing in relation to meals.
Therefore, once-daily liraglutide was selected. Liraglutide is administered once
daily, without regard to mealtime, but it

S34

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April 2013 | Vol 113 | No. 4 | Supplement 2

Brain

Muscle

Glucose

Liver

Adipose tissue

I
ce

ns

lls

uli

Native GLP-1

Glucagon

In

Pancreas

( cells)

su
(

lin
ce

lls

Amylin
( cells)

Figure 3.
Different approaches to enhancing the effects of the naturally
occurring incretin hormonepharmacologic replacement or minimizing
degradation.9 Abbreviation: GLP-1, glucagon-like peptide 1.

should be administered at approximate-

GLP-1 receptor agonists, the need for

using the insulin pen. At that visit,

ly the same time each day, if possible.

lower doses of insulin has been ob-

mild nausea had occurred; however,

Short-acting exenatide is administered

served. There also is the possibility

it abated 3 weeks later. Harry had a

twice daily before meals. It should be

that patients may transiently eat less if

weight loss of 5 lbs, and he noted that

noted that the once-weekly formulation

nausea is problematic, which may in-

his fasting blood glucose level was still

of exenatide is not currently approved

crease the possibility of insulin-related

between 80 and 120 mg/dL.

by the US Food and Drug Administra-

hypoglycemia developing. Furthermore,

tion (FDA) for use with insulin.

by means of mechanisms independent

ter Harry had been receiving the new

The next follow-up visit occurred af-

The physician discussed the possi-

of adverse gastrointestinal effects, pa-

medication for 12 weeks. At that time,

bility of nausea occurring in association

tients treated with GLP-1 receptor ago-

he had lost an additional 4 lbs, and his

with initiation of GLP-1 receptor agonist

nists experience greater satiety than

HbA1c level was 6.8%.

therapy. The nausea tends to be mild

placebo-treated patients, and their food

to moderate and of a transient nature.

intake may decrease.

Harry was told that if severe nausea or

abdominal pain were to occur, he would

insulin pen delivery device, so he was

Ultra-Long-Acting Basal

need to call the physicians office right

told to start with a dose of 0.6 mg of

Insulin in Development

away, because the presence of these

insulin given subcutaneously daily.

Current research efforts are focusing

symptoms might be a sign of a more se-

One week later, Harry increased the

on improving the pharmacokinetics and

rious condition, such as pancreatitis.

insulin dose to 1.2 mg given subcuta-

pharmacodynamics of long-acting insu-

Harrys basal insulin dose was re-

neously daily.

lin analogs to make them even less vari-

duced by 20%, from 40 U to 33 U, at

A follow-up appointment was sched-

able and longer acting (ie, make them

night. When basal insulin is used with

uled for 6 weeks after Harry started

truly once-daily insulin analogs). These

Harry already knew how to use an

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What Else Is New?

April 2013 | Vol 113 | No. 4 | Supplement 2

S35

Table 3.
Published Trials of Ultra-Long-Acting Insulins

Source

Insulin
Agent

Patient
Insulin
Characteristics Comparator

Design

Outcomes

Rosenstock LY2605541
T1DM; basal-bolus
Glargine
8-wk randomized,
et al, 201356 (pegylated
therapy
phase 2, open-label,

insulin lispro)
22 crossover study

Greater improvements in glycemic

control, increased total hypoglycemia,
reduced nocturnal hypoglycemia,
reduced weight, and lowered insulin
doses at mealtime

Bergenstal LY2605541
et al, 201257 (pegylated

insulin lispro)

Comparable glucose control; total

hypoglycemia rates, reduced intraday
variability, and lower nocturnal hypoglycemia, as well as weight loss,
relative to glargine

T2DM (HbA1c level

Glargine
12-wk, randomized,
10.5%); metformin
open-label, phase 2
and/or sulfonylurea
study
with glargine or NPH
insulin once daily

Birkeland
Degludec
T1DM; mean HbA1c Glargine
16-wk randomized,
et al, 201143
level 8.4%
phase 2 controlled trial

Comparable glucose control at

similar doses, with reduced rates
of hypoglycemia

Heise et al, Degludec/

T2DM; background
Glargine
16-wk, open-label trial
201145
aspart
metformin therapy

Comparable glucose control at

similar doses, similar low rates
of hypoglycemia, and better
glucose control after dinner

Zinman et al, Degludec

201250

T2DM; background
Glargine
therapy for OAD;
baseline HbA1c level
7% to 10%

1-year treat-to-target,
open-label, randomized
trial

Comparable glucose control,

much lower rates of nocturnal
hypoglycemia

Heller et al, Degludec

201246

T1DM; basal-bolus
Glargine
insulin therapy;
HbA1c level 10%

1-year treat-to-target,
open-label, randomized
trial

Comparable glucose control and

much lower rates of nocturnal
hypoglycemia

Garber et al, Degludec

201244

T2DM; basal-bolus
Glargine
insulin; HbA1c level,
7% to 10%

1-year treat-to-target,
open-label, randomized
trial

Comparable glucose control and

much lower rates of overall and
nocturnal hypoglycemia

Niskanen
et al, 201258

Degludec/
T2DM; HbA1c level
aspart (twice 7% to 11%
daily) and an
alternative
formulation

Biphasic
16-wk, open-label,
insulin aspart randomized,
twice daily
treat-to-target trial

Comparable glucose control and

lower rates of hypoglycemia

Abbreviations: HbA1c, glycated hemoglobin; NPH, neutral protamine Hagedorn; OAD, oral antidiabetic drugs; T1DM, type 1 diabetes mellitus;
T2DM, type 2 diabetes mellitus.

S36

longer-acting insulin analogs will be

analogs at a consistent time each day,

reduced risk of hypoglycemia and more

more forgiving of the busy schedules of

on the basis of their duration of action.

convenience for the patient.39,40

patients, because they have little to no

Table2 provides a comparison of the

impact on glucose levels if there is some

pharmacodynamics of longer-acting

clinical development of both insulin

variation in the time of administration.

insulin analogs.38 The goal of ongoing

degludec (administered alone or in

Optimal glycemic benefits are achieved

research is to come close to achieving

combination with insulin aspart) and

with the injection of current basal insulin

glycemic control while benefitting from a

pegylated insulin lispro. Insulin de-

A Supplement to The Journal of the American Osteopathic Association

Advances have been made in the

April 2013 | Vol 113 | No. 4 | Supplement 2

gludec has been submitted to the FDA

tively. Low rates of hypoglycemia were

Technosphere insulin (MannKind Cor-

for review. This ultra-long-acting basal

noted with both regimens. This trial

49

poration, Valencia, California), another

insulin has a flat and stable glucose-

showed that insulin degludec can be

inhaled insulin, was compared with sub-

lowering effect,

and it is associated

administered at varying times without

cutaneous regular human insulin in a

with a much lower risk of nocturnal

resulting in either a loss of glycemic

randomized, open-label study of their

hypoglycemia than insulin glargine, as

control or the development of hypogly-

efficacy and safety in covering prandial

has been demonstrated in studies of

cemia to accommodate changes in a

insulin needs.54,55 Technosphere insulin

patients with T1DM and T2DM.

41

patients daily schedule.

substantially improved postprandial glu-

pharmacodynamic variability of insulin

Another new agent, pegylated in-

cose levels and had a more favorable

degludec is much lower than that of in-

sulin lispro, is currently moving into

pharmacodynamic profile than subcuta-

sulin glargine.41,48 Insulin degludec has

phase 3 of clinical development. This

neous regular human insulin. The Tech-

received an approvable status from an

agent appears to be associated with

nosphere insulin system is currently

FDA regulatory panel and has been ap-

less variability, less nocturnal hypogly-

undergoing phase 3 trials.

proved for use in Europe.

cemia, perhaps slightly more overall

Because insulin degludec has a sta-

hypoglycemia (which may be related to

culty of working with complex proteins,

ble and prolonged time-action profile,

some dosing and titration issues), and

such as hormones, and highlight the

coupled with low within-subject variabil-

some interesting effects on weight. To

successes that have been achieved

ity, it allows for more-flexible once-daily

my knowledge, few data on this com-

with current and emerging formula-

dosing. Insulin degludec has a flat and

pound have been published in the peer-

tions as they continue through the

stable glucose-lowering effect that is not

reviewed literature to date.

approval process.

affected by dose.48 This concept was

tested in patients with T2DM participat-

clinical trials is shown in Table3.43-46,50

Oral Insulin

ing in a 26-week randomized trial49 in

Overall, these exciting developments

The physiologic barriers of the gastro-

which insulin degludec (administered

may be used by physicians to improve

intestinal tract pose a major challenge

in variable dosing intervals in a flexible

glycemic control and to increase pa-

for the optimal delivery of any hormone,

regimen) was compared with insulin

tient acceptance of and adherence to

including insulin. Oral insulin would pro-

glargine (administered at the same time

insulin therapy.

vide a convenient method of adminis-

42-47

The

All of these efforts illustrate the diffi-

A summary of available data from

each day). Both insulins were added

tration, potentially leading to improved

to an existing regimen of oral glucose-

Inhaled Insulin

glycemic control for patients with poor

lowering therapy, as in the case study

Inhaled insulin has been under devel-

adherence to subcutaneous insulin

described here, and study patients

opment for many years, but a product

regimens.2

were titrated to achieve fasting plasma

that actually reached market (Exubera,

glucose levels of less than 90 mg/dL.

an insulin human [recombinant DNA

The once-daily regimen of insulin de-

origin] inhalation powder; Pfizer, New

Conclusion

gludec involved a compulsory, rotating

York, New York) was eventually with-

Development of insulin replacement

morning-and-evening schedule of dos-

drawn because of poor market up-

therapy is ongoing. Physicians need to

ing that created 8- to 40-hour dosing

take,51 perhaps because of the complex

understand the central role of insulin in

intervals. From a baseline HbA1c level

requirements for its administration.

52

the pathophysiologic profile of diabetes,

of 8.4%, HbA1c values were reduced by

Other inhaled insulin agents that have

how it can be used early or late in the

1.28% and 1.26% with the use of insulin

been investigated have been found

disease process, and how it comple-

degludec and insulin glargine, respec-

to produce nocturnal hypoglycemia.53

ments other agents. As more insulin

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products become available, an understanding of the relative characteristics,

benefits, and potential of these agents
in helping us to improve glycemic control in patients currently coping with
unsatisfactory glycemic control cannot
be overstated.

13. Rolla AR. What about insulin as an immediate

first step for type 2 diabetes? Diabetes Obes
Metab. 2009;11(suppl 5):19-22.
14. Ryan EA, Imes S, Wallace C.
Short-term intensive insulin therapy
in newly diagnosed type 2 diabetes.
Diabetes Care. 2004;27(5):1028-1032.

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2013 American Osteopathic Association

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