Improving Glucagon-like Peptide-1

Dynamics in Patients With Type 2

Diabetes Mellitus

Jeffrey S. Freeman, DO
The increased number of cases of type 2 diabetes mellitus (both
diagnosed and undiagnosed) parallels the current epidemic of
obesity in the United States. Despite receiving treatment, many
patients do not achieve established therapeutic goals. Type 2 diabetes mellitus is a progressive disease characterized by multiple abnormalities that extend beyond -cell dysfunction and
insulin resistance. Incretin-based agents, including glucagonlike peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase4 (DPP-4) inhibitors, have become important options in the therapeutic paradigm for patients with type 2 diabetes mellitus.
The author reviews physiologic mechanisms of the incretin
system and discusses the practical application of GLP-1 receptor
agonists and DPP-4 inhibitors in improving GLP-1 dynamics in
patients with type 2 diabetes mellitus.
J Am Osteopath Assoc. 2012;112(1 suppl 1):S2-S6

ccording to the Centers for Disease

Control and Preventions National
Diabetes Fact Sheet published in 2011,
25.8 million children and adults in the
United States (8.3% of the population)
have diabetes mellitus.1 Among these
people, 18.8 million have been diag-

From the Division of Endocrinology and Metabolism in the Department of Internal Medicine
at the Philadelphia College of Osteopathic
Medicine in Pennsylvania.
This article was developed with assistance
from DIME, the Discovery Institute of Medical
Education. The author approved the article and all
of its contents.
Financial Disclosures: Dr Freeman discloses that
he is on the speakers bureaus for Amylin Pharmaceuticals, Inc; Boehringer Ingelheim Pharmaceuticals, Inc; GlaxoSmithKline PLC; Lilly USA, LLC;
Merck & Co, Inc; and Novo Nordisk, Inc.
Address correspondence to Jeffrey S. Freeman,
DO, 4190 City Ave, Suite 324, Division of Endocrinology and Metabolism, Philadelphia College of
Osteopathic Medicine, Philadelphia, PA 191311633.
E-mail: jeffreyfreemando@aol.com

nosed as having diabetes mellitus, and

7.0 million have undiagnosed diabetes.
In 2010, 1.9 million people aged 20 years
or older were diagnosed as having diabetes mellitus on the basis of both
fasting hemoglobin and glycosylated
hemoglobin (HbA1c) criteria. The epidemic of type 2 diabetes mellitus
(T2DM) in the United States and other
Western countries parallels the epidemic
of obesity and physical inactivity in
those nations.1
The importance of lowering glucose
levels in patients with diabetes mellitus
has been well established in several landmark studies. For example, in a 10-year
follow-up of 867 patients enrolled in the
United Kingdom Prospective Diabetes
Study, or UKPDS,2 reducing fasting
plasma glucose (FPG) levels below 108
mg/dL with intensive treatment pro-

S2 JAOA Supplement 1 Vol 112 No 1 January 2012

vided a 25% reduction in relative risk of

microvascular complications, compared
with conventional treatment.
Data from the National Health and
Nutrition Examination Survey
(NHANES)3 for 1999 to 2000 suggested
that only 37% of US adults with T2DM
reached the established American Diabetes Association (ADA) goal of HbA1c
level of less than 7%. Progress was made
by the time of NHANES 2003-2004,
when 52% of US adults with T2DM met
the ADAs HbA1c goal.4 The proportion
of NHANES participants who achieved
an HbA1c level of less than 7.0% was significantly lower among those receiving
triple therapy (31.9%) than among those
receiving metformin monotherapy
(62.2%) (P<.01).4 These data indicate the
need for new agents that will help
improve glycemic control when used

This supplement is supported by an independent educational grant

from Novo Nordisk Inc.

Freeman Improving GLP-1 Dynamics in Patients With Type 2 Diabetes Mellitus

either alone or in combination with

existing agents.
The author reviews the pathophysiologic mechanisms of core defects in
patients with T2DM, including mechanisms involving incretin hormones,
which are peptides originating in the gastrointestinal tract that contribute to
insulin secretion. The author also discusses the application of administering
glucagon-like peptide-1 (GLP-1) receptor
agonists and dipeptidyl peptidase-4
(DPP-4) inhibitors to improve GLP-1
dynamics in patients with T2DM.

Pathophysiologic Mechanisms
of Core Defects
Type 2 diabetes mellitus is a progressive
disease characterized by multiple abnormalities, including insulin resistance,
declines in -cell function, and defects
in -cell function.
There are pathophysiologic abnormalities, which typically manifest before
T2DM is diagnosed and continue
throughout the disease process.5 Skeletal
tissue insulin resistance, a contributor to
hyperglycemia, is evident in early stages
of the disease. Insulin resistance has been
attributed to impaired binding of insulin
to its cellular receptors and to postbinding defects, contributing to impaired
glucose transport. These defects also
include diminished glucose phosphorylation, impaired glycogen synthase
activity, insulin signal transduction
abnormalities, and decreased insulin
tyrosine kinase activity.5
Early in the course of T2DM, the
pancreatic cells compensate for peripheral insulin resistance by secreting more
insulin. This progressive augmentation of
insulin secretion by cells eventually
leads to an inability of these cells to compensate for insulin resistance. It has been
estimated that as much as 80% of cells
have lost their insulin secretory function
by the time of diabetes mellitus diagnosis.6
The array of metabolic abnormalities
contributing to the pathogenesis of
T2DMextending beyond insulin resistance and -cell dysfunctionhas been
referred to as the Ominous Octet
(Figure). 7 For example, patients
adipocytes demonstrate accelerated lipolysis, the kidneys increase glucose uptake

Decreased insulin secretion

Inefficient glucose uptake
(skeletal muscle)

Increased hepatic glucose

production

Hyperglycemia

Decreased incretin effect

Increased glucagon secretion

Increased free fatty acids
Neurotransmitter dysfunction
Increased glucose reabsorption

Figure. The array of metabolic abnormalities that contribute to the pathogenesis of type 2
diabetes mellitusreferred to as the Ominous Octet. Adapted with permission of the
American Diabetes Association, from DeFronzo RA. From the triumvirate to the ominous octet:
a new paradigm for the treatment of type 2 diabetes mellitus [Banting Lecture]. Diabetes.
2009;58(4):773-7957; permission conveyed through Copyright Clearance Center, Inc.

and reabsorption, and the brain exhibits

impaired insulin function.7 Patients with
T2DM also have inappropriately elevated
levels of glucagons, which are produced
by pancreatic cells. As a result, the liver
releases excessive amounts of glucose,
further contributing to hyperglycemia.
The diagnosis of T2DM is established with several hyperglycemic
parameters (ie, FPG, 126 mg/dL;
random glucose, >200 mg/dL; and
HbA1c, >6.5%).8 Although available
medications can lower levels of FPG,
postprandial plasma glucose (PPG), and
HbA1c, several of these agents are associated with risks of hypoglycemia and
weight gain.8 Therefore, a need exists for
exploration and implementation of
newer treatments, which, on a physiologic basis, improve defects of -cell and
-cell function, and, on a clinical basis,
improve glycemic control without
adverse effects.

Physiologic Effects of Incretin

Hormones
An understanding of the dynamics of

Freeman Improving GLP-1 Dynamics in Patients With Type 2 Diabetes Mellitus

insulin secretion are important when

evaluating new treatments such as
incretin-based agents. These agents are
becoming important options in the diabetes mellitus therapeutic paradigm.
About 80 years ago, La Barre9 observed
that plasma insulin levels were greater in
patients with diabetes mellitus after oral
ingestion of glucose, compared to intravenous infusion of comparable amounts
of glucose.10 This difference was ascribed
to the incretins, a class of gut-derived
hormones. It was subsequently determined that incretins are secreted after
oral ingestion of glucose but generally
not after intravenous infusion of glucose.9
This physiologic difference was referred
to as the incretin effect. An estimated
50% to 70% of insulin secretion can be
attributed to the effects of incretins.11
There are 2 major types of incretins
in humans: GLP-1 and glucose-dependent insulinotropic peptide (GIP).
Although GIP, which is produced by
duodenal and jejunal K cells, was identified before GLP-1 as having an important impact on insulin response in

JAOA Supplement 1 Vol 112 No 1 January 2012 S3

humans, its effects are less well characterized than those of GLP-1.
Glucagon-like peptide-1 appears to
be the major incretin hormone relevant to
glucose homeostasis. This hormone is
produced by the proglucagon gene,
which is expressed in the enteroendocrine L cells of the distal ileum and
colon.11 It has a half-life of approximately
1 to 2 minutes as a result of rapid inactivation by the ubiquitous enzyme DPP-4.
Glucagon-like peptide-1 increases insulin
secretion from cells in a glucose-dependent manner, ensuring appropriate
insulin response after a meal. Glucagonlike peptide-1 exerts multiple actions in
cells that affect various signaling pathways and gene products.12 This hormone
also appears to improve -cell glucose
sensing, thereby suppressing inappropriate basal and postprandial glucagon
secretion.13
Furthermore, GLP-1 has pleiotropic
actions. It delays gastric emptying and
secretion, and it promotes satiety and
weight lossas evidenced by weight
loss observed with the use of GLP-1
receptor agonists.11 In animal models,
GLP-1 induces -cell neogenesis and proliferation and inhibits -cell apoptosis.14
Therefore, GLP-1 may exert protective
effects on cells. Effects of GLP-1 on the
central nervous system include enhanced
memory and neuronal survival and activation of aversive pathways, which
causes nausea and vomiting.14
Receptors for GLP-1 are expressed
throughout the cardiac system. 15
Glucagon-like peptide-1 has been
demonstrated to improve cardiovascular
function after ischemia and to reduce the
extent of cardiac myocyte death after
experimental injury.16
Type 2 diabetes mellitus results in
defects in incretin secretion and action
and in decreased sensitivity of cells to
GLP-1. In initial investigations, shortterm intravenous GLP-1 infusions
demonstrated glucose-lowering effects
in patients with T2DM.17 Achieving supraphysiologic levels of GLP-1 through
sustained subcutaneous infusions
restores glucose-induced insulin secretion and elicits other beneficial effects.
Modulating GLP-1 levels or activity
through the production of insulin analogs
or mimetics is currently a major focus of

investigation.17 In addition, inhibition of

DPP-4 is being used to increase circulating levels of GLP-1.17 Various properties of GLP-1 receptor agonists and DPP4 inhibitors are shown in Table 1.

Available and Emerging

Incretin-Based Treatments
GLP-1 Receptor Agonists
The development of GLP-1 receptor agonists began with the discovery of
exendin-4 in the saliva of the Gila monster. Exendin-4 is 53% homologous to
human GLP-1.18 Exenatide, the synthetic
form of this compound, has been available clinically since 2005 as a twice-daily
subcutaneous injection. It is indicated for
use as adjunct therapy to diet and exercise, as well as monotherapy. The half-life
of exenatide is 2.4 hours, necessitating
twice-daily dosing before meals.18
Clinical trials have established the
beneficial effects of exenatide on patients
glycemic control and body weight.19 The
major adverse effects of exenatide are
nausea and vomiting, which appear to be
dose-dependent. In approximately half of
the patients who receive exenatide, antibodies with weak binding affinity and
low titers develop, although these antibodies do not seem to impair the antidiabetes effects of this drug.19
A long-acting release (LAR) form of
exenatide, exenatide LAR, has been
developed by incorporating biodegradable polymeric microspheres. This onceweekly formulation is approved in
Europe and is being considered by the
US Food and Drug Administration

(FDA). The ongoing DURATION trials20

are designed to assess the efficacy and
safety of exenatide LAR as monotherapy
and as part of combination therapy, as
well as to compare it with insulin
glargine and liraglutide. Characteristics
of exenatide LAR and other investigational GLP-1 receptor agonists are shown
in Table 2.
The use of albumin binding to
decrease the dosing frequency of GLP-1
receptor agonists has been investigated.
Liraglutide, the most recent GLP-1 agent
to receive FDA approval, has 97% homologic similarity to human GLP-1 and contains a fatty acid molecule (palmitoyl)
that enables it to bind to albumin.21 These
molecular characteristics of liraglutide
limit its susceptibility to DPP-4 degradation, prolong its absorption from the
injection site, and reduce its renal clearance, thereby increasing the duration of
action of GLP-1. Liraglutide has an elimination half-life of 12.6 hours, supporting
once-daily dosing.21 Liraglutide reduces
levels of FPG, PPG, and HbA1c and
induces weight loss in patients.22 The
most common adverse effects of this
drug are nausea and vomiting.
The investigational agent albiglutide was developed through the fusion of
human GLP-1 (7-36) amide to recombinant human albumin, with a single
amino acid substitution conferring DPP4 resistance.23 Because of its prolonged
half-life, albiglutide is being investigated
for once-weekly administration. Furthermore, albiglutide has low permeability in the central nervous system,

Table 1.
Clinically Relevant Properties of Currently Available GLP-1 Receptor Agonists
and DPP-4 Inhibitors18,21,25
Property

DPP-4 Inhibitors

GLP-1 Receptor Agonists

Currently available agents

Linagliptin, saxagliptin,
sitagliptin

Exenatide, liraglutide

Administration

Oral

Subcutaneous injection

Glucose-dependent
insulin secretion

Yes

Yes

Effects on GLP-1

Prevent degradation of
physiologic GLP-1

Elevate pharmacologic levels

of GLP-1

Adverse effects

Minimal

Gastrointestinal (nausea and

vomiting)

Effects on body weight

Neutral

Weight loss

Abbreviations: DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1.

S4 JAOA Supplement 1 Vol 112 No 1 Janaury 2012

Freeman Improving GLP-1 Dynamics in Patients With Type 2 Diabetes Mellitus

Table 2.
Characteristics of Exenatide
and Other Investigational GLP-1 Receptor Agonists20,23,24
Structure

Agent

Dosing Frequency

Exendin-4Based GLP-1
Exenatide long-acting
release

Peptide incorporated in
biodegradable polymeric
microspheres

Once weekly

Lixisenatide

Modified with additional

C-terminal lysine residues

Once or twice daily

Genetically fused to human

serum albumin; single amino
acid substitution to confer
dipeptidyl peptidase-4
resistance

Once weekly

Novel Combinations
and Applications

Human GLP-1
Albiglutide

Abbreviation: GLP-1, glucagon-like peptide-1.

which may improve gastrointestinal tolerability.23

Another GLP-1 receptor agonist in
clinical development is once-daily,
exendin-4based lixisenatide.24

DPP-4 Inhibitors
Inhibition of the DPP-4 enzyme, which
rapidly inactivates GLP-1, provides
another approach to increasing GLP-1
levels in patients with T2DM. Dipeptidyl
peptidase-4 inhibitors increase GLP-1
levels to a peak of 30 pmol/L, compared
to the 60 pmol/L peak level attained with
GLP-1 receptor agonists.25 Three oral
DPP-4 agents are available in the United
States: sitagliptin, saxagliptin, and, most
recently, linagliptin. Differences of agent
actions within this class can be attributed
to variations in metabolism and excretion.
Sitagliptin, the first DPP-4 inhibitor
to receive FDA approval, entered the US
market in 2006 as an adjunctive treatment to diet and exercise. It is administered as a single daily oral dose and is
excreted renally, with approximately 79%
of the drug excreted unchanged in individuals with normal renal function.26 As
such, dose adjustments are required in
patients with moderate to severe renal
impairment.
Subsequent to sitagliptins availability, saxagliptin received FDA
approval. Saxagliptin is also administered orally once daily and is indicated as
an adjunct to diet and exercise. 27
Saxagliptin undergoes hepatic meta-

bolism and is predominantly excreted in

the kidneys. Dosage adjustments are
required in patients with severe renal
insufficiency.27
Linagliptin is a selective, competitive DPP-4 inhibitor that the FDA
approved in May 2011.28 Linagliptin is
administered orally as a single daily dose
(5 mg), with no dose titration needed for
patients with renal insufficiency. This
xanthine-based agent is a potent, longacting nonpeptidomimetic -secretase
inhibitor that is predominantly eliminated in feces, with minimal renal excretion compared with other DPP-4
inhibitors.29
When used as monotherapy or in
combination with metformin, DPP-4
inhibitors result in modest reductions in
levels of FPG, PPG, and HbA1c, with neutral effects on body weight.30-33 The DPP4 inhibitors have a reduced incidence of
hypoglycemia compared with sulfonylureas, primarily because of their glucose-dependent effects on insulin secretion. The most common adverse effects of
DPP-4 inhibitors are nasopharyngitis,
respiratory tract infection, and
headache.30-33
Although DPP-4 inhibitors effectively reduce HbA1c levels, the durability
of their glycemic control and their protective effects on b-cell function have not
been evaluated in long-term clinical trials.
These agents do not appear to increase
cardiovascular risk.34 However, clinical
trials are under way to assess the effects
of DPP-4 inhibitors on cardiovascular

Freeman Improving GLP-1 Dynamics in Patients With Type 2 Diabetes Mellitus

outcomes (eg, Liraglutide Effect and

Action in Diabetes: Evaluation of Cardiovascular Outcome ResultsA Long
Term Evaluation [LEADER]; Saxagliptin
Assessment of Vascular Outcomes
Recorded in Patients with Diabetes
Mellitus Trial [SAVOR-TIMI 53];
Sitagliptin Cardiovascular Outcome
Study [TECOS]).

A common question in the clinical application of incretin-based treatments is,

Can a GLP-1 receptor agonist and a
DPP-4 inhibitor be administered in combination? Although, to my knowledge,
there have been no clinical studies evaluating such combinations, it is suspected
that the combinations would produce
minimal benefits on glycemic control and
potentially cause adverse effects.
Recent studies have examined the
use of incretins in combination with
insulin as treatment for patients with
T2DM.35,36 The rationale for such a combination is that the different therapeutic
approaches have complementary effects.
Insulin controls FPG and nocturnal glucose levels, while GLP-1 receptor agonists and DPP-4 inhibitors control PPG
levels and, to a lesser extent, FPG levels.
Insulin tends to increase body weight,
whereas incretins typically have neutral
or beneficial effects on weight. Accumulating data indicate that concomitant
insulin and incretin therapy results in
improvements in several measures of
glycemic control, compared with that of
either therapy alone.35,37,38 Furthermore,
such a combination does not increase
rates of hypoglycemia, and the weightneutral or weight-reduction features of
incretins persist despite the use of
insulin.35,37,38
The GLP-1 receptor agonists have
also been investigated in patients with
type 1 diabetes mellitus. In small, preliminary studies, exenatide and liraglutide resulted in reductions in the HbA1c
level, insulin dose, and glucose excursions in such patients.39,40 In addition,
ongoing trials are investigating the combination of GLP-1 receptor agonists and
insulin in a single delivery device.
Recognition that GLP-1 plays a role
in satiety and food intake led to interest

JAOA Supplement 1 Vol 112 No 1 January 2012 S5

in using GLP-1 receptor agonists in the

treatment of obese patients without diabetes mellitus. However, as of late 2011
there were few published data on the
use of GLP-1 receptor agonists for the
management of obesity.41 These agents
are also being investigated as part of combination therapies with other hormones
that regulate appetite.

Conclusion
Incretin-based agents play an increasingly important role in the therapeutic
paradigm for patients with T2DM. Incorporating GLP-1 receptor agonists into
treatment can improve the physiologic
role of GLP-1, which is impaired in
patients with T2DM. The beneficial
effects of these agents extend beyond
glucose control and include weight loss
and potential restoration of -cell function.

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Freeman Improving GLP-1 Dynamics in Patients With Type 2 Diabetes Mellitus