The Role of Incretin-Based Therapies: Reconstructing
Treatment Approaches in Type 2 Diabetes CME
Robert R. Henry, MD Author Information and Disclosures
The effective management of type 2 diabetes mellitus (T2DM) is a constant challenge
to physicians. It is an epidemic which places a huge burden on national economies and
medical care systems with its acute and chronic complications. The International
Diabetes Federation estimates that the global diabetic population is 246 million people
and that 7.3% of the world's population, ages 20-79, have diabetes. These numbers
are expected to grow significantly in the next few decades. By 2025, the number of
people with diabetes is forecast to exceed 380 million. Even with access to numerous
hypoglycemic drugs and counseling in life-style changes, it is estimated that 2 of every
3 T2DM patients are unable to reach the hemoglobin A1c (HbA1c) target of less than
7% set by the American Diabetes Association (ADA). The availability of newer drugs
such as the incretin mimetics and the dipeptidyl peptidase-IV (DPP-4) inhibitors has
grown the therapeutic armamentarium for T2DM, providing the possibility of further
improved glycemic control that may eventually lead to a positive impact on the
seemingly inevitable complications of T2DM.
The morbidity and mortality associated with diabetic complications contribute to a large
proportion of patients with chronic illnesses. T2DM is responsible for 44% of new cases
of kidney failure diagnosed each year, cardiac disease and stroke cause 65% of deaths
among diabetic patients, more than 60% of lower limb amputations occur in people with
diabetes, and diabetes is the leading cause of blindness among adults.
The main objectives in the treatment of diabetes include prevention or slowing of
disease progression, including the prevention of microvascular and macrovascular
complications, as well as improving mortality. It is now recognized that the onset of
T2DM may occur up to 10 years prior to clinical diagnosis. Indeed, it is postulated that
nearly one third of all people with diabetes are not yet diagnosed because of the
insidious nature of the disease.
Diagnostic criteria for T2DM as defined by the ADA include a fasting plasma glucose ≥
126 mg/dL, confirmed on repeat testing, or a 2-hour plasma glucose ≥ 200 mg/dL
during an oral glucose tolerance test (OGTT), or symptoms of hypoglycemia and a
casual plasma glucose ≥ 200 mg/dL. Two core defects are known to underlie the
pathophysiology of T2DM. Insulin resistance is 1 such defect, occurring in 80-85% of
these patients. Obesity and a sedentary lifestyle contribute to the development of
insulin resistance, but the inheritance of the genetic potential for insulin resistance does
not require obesity to become functional. The second abnormality is impaired
pancreatic beta-cell function, which is progressive over time. In type 2 diabetes,
insufficient insulin supply occurs in a setting of increased insulin demands, a situation
known as chronic insulin resistance. It has been demonstrated that abnormalities in
insulin secretion and insulin sensitivity are present long before type 2 diabetes
develops. Moreover, both insulin resistance and failing insulin secretion are
progressive over the course of many years.
Evidence from studies by Buchanan and Ferrannini and colleagues suggest that the
signal provided by circulating plasma glucose levels in relation to the underlying
deterioration in beta-cell function is initially low and becomes stronger only when the
beta-cell function has deteriorated markedly. The essence of these and other studies
clearly shows that, by the time diabetes has been diagnosed, the disease is well under
way and the processes leading to the various complications have already begun. Data
from the United Kingdom Prospective Diabetes Study (UKPDS) study showed that
patients with newly diagnosed type 2 diabetes had only 50% of their beta-cell function.
As these patients were followed over a 6-year period, there was a linear reduction in
this function. In addition to the decline in beta-cell function, there is also a decline in
beta-cell mass caused by increased apoptosis (cell death), although new islet
formation and beta-cell replication are normal. The UKPDS study also demonstrated
that the addition of metformin, sulfonylureas, or a change to a more healthy diet were
not sufficient to arrest the decline in beta-cell function. Treatment that would slow or
stop the progression of beta-cell loss, or even reverse it, would dramatically alter the
landscape of diabetes management.
Slide 1. ADA/EASD Consensus Algorithm for Type 2 Diabetes Mellitus (2006)
The treatment algorithm for the management of individuals with T2DM has been
established by opinion leaders on both sides of the Atlantic. The American Diabetes
Association/European Association for the Study of Diabetes (ADA/EASD) consensus
algorithm, published in 2006, stresses the need for the rapid additions of medications
and transition to new medications when glycemic targets are not met or sustained.
Comparison of plasma glucose, insulin, and glucagon levels in non-diabetic and
diabetic subjects following administration of an OGTT shows clear differences in
response between the 2 groups. The non-diabetic subjects show an increase of plasma
glucose of approximately 3 mM, whereas the increase measured in diabetic subjects
was approximately 8 mM. This finding was accompanied by a much greater increase in
plasma insulin and a decrease in plasma glucagon in the non-diabetic subjects. In the
diabetic subjects, plasma insulin did not achieve the same concentration as the non-
diabetic group; the rise was much slower, and the consequent return to basal levels
was also extended. In contrast to non-diabetics, plasma glucagon levels in the diabetic
subjects showed a small transitory increase in response to the OGTT before returning
to basal levels. Using radiolabeled glucose, Mitrakou and colleagues ascertained that
the increased systemic glucose delivery in diabetic subjects was primarily due to a
reduced suppression of hepatic glucose output and, to a lesser extent, a reduced
splanchnic uptake of glucose. Similar changes in plasma glucose, plasma insulin, and
plasma glucagon are seen following a carbohydrate meal rather than the standard
OGTT when comparing non-diabetic and diabetic subjects.
Glucose homeostasis, in its simplest terms, is the rate at which glucose enters and
leaves the circulation. In normal individuals, the plasma concentration of glucose is
maintained within a narrow range previously thought to be controlled primarily by
insulin and glucagon. However, this concept has now been expanded to include other
glucoregulatory hormones including amylin, glucagon-like peptide-1 (GLP-1), and
glucose-dependent insulinotropic polypeptide (GIP). It has been known for many years
that administration of an oral glucose challenge elicits a stronger insulin response than
an equivalent intravenous glucose challenge. This effect has been termed the incretin
effect and led to the hypothesis that gut-derived factors are important modulators of
insulin secretion and glucose homeostasis. It is now established that 2 gut-derived
hormones, GLP-1 and GIP, are responsible for most of the incretin effect. Creutzfeldt
introduced the term incretin, which is derived from Intestinal Secretion of Insulin.
Slide 2. Incretin Effect
A seminal report by Nauck and colleagues showed that 70% of post-glucose insulin
secretion is due to the incretin effect and that the incretin effect is diminished in T2DM.
A later study published by Toft-Neilsen and colleagues demonstrated that
postprandial GLP-1 levels are decreased in T2DM subjects following an OGTT.
GLP-1 is synthesized and secreted by L cells of the ileum and colon and stimulates
glucose-dependent insulin release with a concomitant suppression of hepatic glucose
output by inhibiting glucagon secretion. Furthermore, it improves beta-cell
responsiveness to glucose by increasing the expression of glucose-transporter-2 and
glucokinase together with a decrease in the proinsulin to insulin ratio. It also inhibits
gastric emptying and has a central nervous system effect resulting in reduced food
intake and a decrease in body weight. In animal models and human islets, it has been
shown to enhance beta-cell proliferation and survival. The latter effect is due to a
combination of induction of beta-cell proliferation, neogenesis, and an anti-apoptotic
Slide 3. GLP-1 Modulates Numerous Functions in Humans
GIP is produced by K cells in the proximal gut and also stimulates glucose-dependent
insulin release. In contrast to GLP-1, it has a little or no effect on gastric emptying and
no significant effect on satiety or body weight. It may potentially enhance beta-cell
proliferation and survival in islet cell lines.
In patients with T2DM, the incretin effect is either greatly impaired or absent and it is
assumed that this finding could be a contributing factor to the inability of these patients
to adjust their insulin secretion to their needs. In studies examining the mechanism of
this impaired effect, the data show that GIP secretion is unimpaired and levels of intact
GIP are actually increased in response to a glucose challenge. In contrast, the
secretion of GLP-1 is attenuated. The abnormal incretin effect in T2DM can be
described as one of diminished GLP-1 secretion and diminished GIP responsivity.
Thus, T2DM patients have a GLP-1 secretory defect, and with a known physiologic
defect in the GLP-1 pathway comes the opportunity to leverage its therapeutic potential
by correcting it. As T2DM is a progressive disease, there is considerable interest in
whether or not incretin-based therapies might be able to prevent the onset of the
disease or even reverse its progress by an impact on the transition from normal
glucose tolerance, through a state of impaired glucose tolerance to fully developed
GLP-1 has been administered to diabetic patients before meals by means of
subcutaneous injection causing a significant decrease in postprandial glucose levels.
However, the insulin response to the meal was not greatly enhanced and the effect on
postprandial glucose concentration was primarily due to a reduction in gastric emptying
following the injection of GLP-1. An important finding from a study by Rachman and
colleagues where GLP-1 was given by a continuous infusion to T2DM subjects was
not only the normalization of postprandial glucose but the normalization of blood
glucose during the hours when the patients were asleep. Thus, incretin action is not
simply required for the control of postprandial glucose but for 24-hour blood glucose
control as well. Zander and co-workers then administered GLP-1 for 6 weeks by
subcutaneous infusion to 10 patients with T2DM. After 1 week's treatment, they
observed a marked increase in insulin secretion in response to a 30 mmol/L
hyperglycemic clamp, an effect that persisted throughout the 6-week period. In tandem
with this increase in insulin secretion, there was a marked reduction in basal plasma
glucose levels and a substantial reduction in HbA1c levels. An additional benefit was a
mean weight loss of more than 2 kg. This study demonstrated that chronic GLP-1
administration over 6 weeks results in sustained effects on insulin secretion, and A1C.
Additionally, it served as proof of concept for the potential therapeutic application of
GLP-1 within the diabetic population.
A major disadvantage of using GLP-1 to treat T2DM patients is its short half-life (1-2
min) due to rapid catabolism by the ubiquitous enzyme dipeptidyl peptidase-IV
(DPP-4), thus requiring it be given by continuous intravenous infusion. Clearly, this
method of administration is not practical or economical. Therefore, researchers have
synthesized GLP-1-based compounds, some currently available and others at various
stages of clinical development, which have a more prolonged duration of activity and a
more convenient method of administration. These compounds include the GLP-1
receptor agonists with extended biological half-lives such as exenatide and exenatide
LAR, GLP-1 analogues such as liraglutide, and DPP-4 inhibitors (incretin enhancers)
such as sitagliptin and vildagliptin.
DPP-4 is a glycoprotein consisting of 766 amino acids and is a catalytic enzyme. It is
highly concentrated in the capillaries close to the intestinal cells where GLP-1 and GIP
are produced, and it is widely distributed throughout the body. The rationale for DPP-4
inhibition as a target for the treatment of T2DM is that the degradation of endogenously
released GLP-1 could be attenuated. This would allow prolonged circulating
concentrations of the active form of endogenous GLP-1.
Sitagliptin (Januvia, Merck) is an orally administered DPP-4 inhibitor recently approved
for use in T2DM. It was approved for use either as monotherapy, or as combination
therapy when added to either metformin, a sulfonylurea, or a thiazolidinedione (PPAR-
gamma agonist) such as rosiglitazone or pioglitazone. Additionally, The Food and Drug
Administration (FDA) has recently approved a fixed-dose combination of sitagliptin and
metformin, called Janumet, to be taken twice daily for patients not achieving adequate
control on either therapy taken alone or for those patients already taking sitagliptin and
metformin. The most common adverse experience in sitagliptin monotherapy reported
regardless of investigator assessment of causality in ≥ 5% of patients and more
commonly than in patients given placebo was nasopharyngitis.
Sitagliptin is rapidly and almost completely absorbed, with a bioavailability of 87%, and
has a half-life of approximately 12.4 hours. In clinical trials, it has been given as
monotherapy, comparing it to placebo and in combination when added to other current
therapies for T2DM. In all cases, the primary measure of efficacy was the change in
Slide 4. Sitagliptin Studies: Summary
Nonaka conducted a 12-week study comparing sitagliptin 100 mg daily to placebo in
151 Japanese patients. There was a 1.05% reduction in HbA1c for patients treated
with sitagliptin compared to placebo. Raz studied the effect of 2 doses of sitagliptin
versus placebo treated for 18 weeks in 521 T2DM patients. The doses of sitagliptin
were 100 mg daily or 200 mg daily, resulting in a decrease in HbA1c, when compared
to placebo, of 0.6% and 0.48%, respectively. Both decreases were statistically
significant. Aschner and colleagues conducted a study comparing sitagliptin 100 mg
and 200 mg daily versus placebo in 741 T2DM when treatment was administered for
24 weeks. The reductions in HbA1c relative to placebo were 0.79% and 0.94% for
the 100-mg dose and 200-mg dose of sitagliptin, respectively, and were statistically
significant. In all 3 studies, there was a reduction in fasting plasma glucose (FPG) for
those patients treated with sitagliptin, whereas all the placebo dose groups had a mean
increase in FPG.
Goldstein and colleagues conducted a 24-week randomized, placebo controlled,
parallel group study to evaluate the efficacy of sitagliptin when added to metformin in
T2DM patients who had inadequate glycemic control with diet and exercise. A total of
1091 patients were randomized to 1 of 6 treatments: sitagliptin 100 mg + metformin
1000 mg, sitagliptin 100 mg + 2000 mg metformin, 1000 mg of metformin, 2000 mg of
metformin, 100 mg of sitagliptin, or placebo. At week 24, all active treatments produced
significant reductions from baseline (P < .001) in HbA1C relative to placebo. All active
treatments also produced significant (P < .001) reductions in FPG from baseline when
compared to placebo. The magnitude of FPG reduction by coadministration treatment
was additive relative to individual monotherapies. Significant improvement (P < .05)
was also observed in other measurements for fasting efficacy such as proinsulin/insulin
ratio and homeostasis model assessment beta-cell function (HOMA-B) and HOMA-
insulin resistance in the coadministration treatment groups.
In a study reported by Nauck and colleagues, sitagliptin was compared to glipizide in
a randomized, parallel group study of 1172 patients with T2DM receiving monotherapy
with metformin, but who were considered to have inadequate glycemic control.
Subjects were treated for 52 weeks with either sitagliptin 100 mg daily or glipizide 5 mg
daily (titrated up to a maximum of 20 mg/day) in addition to their metformin therapy. At
the end of the 52-week period, the mean HbA1c levels between the 2 groups were
compared in a non-inferiority analysis. The reduction in HbA1c from baseline was
0.67% in both treatment groups, confirming that sitagliptin was non-inferior to glipizide.
There was a significantly higher proportion of glipizide-treated patients who reported at
least 1 episode of hypoglycemia (5% sitagliptin, 32% glipizide, P < .001) highlighting
the difference in mechanism of action between the sulfonylureas and the DPP-4
inhibitors. There was a mean weight gain of 1.1 kg in the glipizide group compared to a
mean weight loss of 1.5 kg in the sitagliptin group. Overall, with the exception of the
incidence of hypoglycemia, there was no difference between the groups in drug-related
Slide 5. Sitagliptin and Measures of Beta-Cell Function
Rosenstock and co-workers conducted a study to ascertain the effect of adding
sitagliptin or placebo to patients already receiving pioglitazone. The addition of
sitagliptin resulted in significant reductions compared with placebo in HbA1c and FPG
as well as a significant improvement in the proinsulin/insulin ratio vs. placebo. There
was no increased risk of hypoglycemia in the sitagliptin-treated patients compared with
One potential and hoped for advantage of the DPP-4 inhibitors is that they may be able
to modify the progression of type 2 diabetes by maintenance or improvement of beta-
cell function. A failing beta-cell is unable to process proinsulin to insulin and C-peptide
appropriately. Consequently, the beta-cell secretes an abnormal amount of proinsulin
and the ratio of proinsulin/insulin is increased. Another measure of beta-cell function is
HOMA-B, a measurement of beta-cell homeostasis. In the study by Aschner and
colleagues, sitagliptin improved both indices of beta-cell function when administered
to T2DM patients. At a dose of 100 mg daily, sitagliptin significantly reduced the
proinsulin/insulin ratio and increased the HOMA-B from baseline compared to placebo.
Although sitagliptin reduced FPG, the incidence of hypoglycemia was similar between
the 2 groups. These results were confirmed in the study by Raz and co-workers,
referred to above, who again demonstrated that sitagliptin reduced HbA1c and
improved beta-cell function in patients with T2DM.
Vildagliptin (Galvus, Novartis) is a potent, competitive, and reversible inhibitor of
human DPP-4 in vitro and is highly specific relative to other peptidases. It is currently
under consideration but it has not yet been approved for marketing by the FDA. In
healthy humans, vildagliptin is rapidly and almost completely absorbed (approximately
85% of administered dose) after oral administration with a Tmax of 1-2 hours post-dose
and a plasma half-life that ranges from 1.5 to 4.5 hours with doses from 25 to 200 mg.
Slide 6. Vildagliptin Studies: Summary
In a study of vildagliptin (50 mg twice daily) versus metformin (1000 mg twice daily) in
T2DM patients who were drug naive, dosing for 52 weeks showed both drugs to rapidly
decrease HbA1c and that the effect was sustained for 52 weeks. The between-group
difference did not establish non-inferiority of vildagliptin in drug naive patients, and the
incidence of side-effects was similar between the groups, although there were fewer
gastrointestinal-related side effects with vildagliptin.
The addition of vildagliptin to metformin was studied for 24 weeks in T2DM patients.
When compared to placebo+metformin, vildagliptin (50 mg every day)+metformin
significantly reduced HbA1c (P < .001), with a corresponding reduction in FPG. To
ascertain the mechanism for this reduction in FPG, Balas and colleagues conducted
a meal tolerance test (MTT) and demonstrated that vildagliptin augments insulin
secretion and inhibits glucagon release, leading to enhanced suppression of
endogenous glucose production.
Rosenstock and colleagues compared vildagliptin to rosiglitazone when each was
given as monotherapy and showed them to be equally effective in reducing HbA1c.
Body weight increased with rosiglitazone treatment and was unchanged with
D'Alessio and colleagues compared vildagliptin and placebo for 12 weeks and
demonstrated an improvement of beta-cell function in those patients treated with
vildagliptin as well as a concomitant attenuation of insulin resistance independent of
acute increases in GLP-1. Furthermore, this improvement was sustained for 2-4 weeks
after the completion of study therapy, leading to the hypothesis that vildagliptin may
exert some disease-modifying effect. Overall, studies with the DPP-4 inhibitors have
demonstrated that, when administered to patients with T2DM, either as monotherapy or
in addition to other available treatments for the disease, there is an improvement in
glycemic control and beta-cell function.
Inhibiting the breakdown of GLP-1 using DPP-4 inhibitors is 1 way to leverage the
therapeutic potential of GLP-1 in T2DM. An alternative approach is to find a substrate
that has the same or similar properties to GLP-1 at the receptor site but is resistant to
degradation by DPP-4. Several compounds are available or in development that have
this capability and have been termed incretin mimetics. Although the incretin mimetics
may exhibit glucoregulatory effects similar to GLP-1, their actions may not be mediated
solely through the pancreatic GLP-1 receptor. Therefore, the class incretin mimetic is
intended to emphasize the glucoregulatory and metabolic effects of these agents,
rather than their specific mechanism of action.
Liraglutide is a long-acting acylated GLP-1 analogue, currently in phase 3 studies.
Studies in healthy subjects and in T2DM after single and multiple dosing[27,28] have
reported a half-life of approximately 12 hours. Juhl and colleagues compared the
effect of a single subcutaneous dose of liraglutide to placebo when administered at
bedtime to 11 T2DM patients. The patients were given a standard mixed meal 12.5
hours later. Profiles of circulating insulin, C-peptide, glucose, and glucagon were then
monitored after study treatment was administered. Fasting plasma glucose was
significantly reduced by 1.2 mmol/L compared to placebo (P < .01). The hypoglycemic
effect in the fasting condition was associated with an increase in insulin secretion, but
there was no change in plasma glucagon concentration in the fasting state. This group
of investigators then studied the effects of liraglutide when administered for 1 week.
This study was a randomized, placebo-controlled, double-blind comparison of
liraglutide and placebo when given to T2DM subjects. The study treatment was
administered by subcutaneous injection each morning for 9 days. On days 8 and 9, the
subjects were admitted to a clinical research unit to allow detailed measurements of
pancreatic and metabolic function. Data from 24-hour substrate and hormonal profiles
demonstrated a markedly reduced circadian plasma glucose level during liraglutide
treatment exhibited by fasting, prandial, and nocturnal concentrations. Basal and
prandial insulin secretion rates were unchanged, despite the substantial reduction in
glycemia, indicating improved beta-cell function.
A double-blind, randomized, parallel group, placebo-controlled trial with an open-label
comparator was conducted in 190 T2DM patients by Madsbad and colleagues. The
study examined the effect of 5 doses of liraglutide, placebo, or open-label sulfonylurea
on HbA1c after 12 weeks of treatment. HbA1c was decreased in all the liraglutide
treatment groups except the lowest dose (0.045 mg). The highest dose of liraglutide
(0.75 mg) resulted in a significant decrease of 0.75% in HbA1c (P < .0001), and FPG
was also significantly decreased. Body weight was not increased in the liraglutide
treatment groups and was observed to decrease in the 0.45-mg liraglutide treatment
group. Conversely, although patients treated with glimepiride had a decreased HbA1c
and FPG, it was at the cost of a slight increase in body weight. Of 135 patients
exposed to liraglutide, 7 experienced hypoglycemia compared to 26 in the glimepiride
group. The number of patients with adverse events was comparable across the
liraglutide and placebo groups. This study was the first to demonstrate a sustained
improvement in glycemic control after long-term treatment with liraglutide. More than
half the patients in the 2 higher liraglutide dosage groups (0.60 mg and 0.75 mg) had
HbA1c ≤ 7.0% after 12 weeks of treatment.
The clinical effectiveness of liraglutide is being evaluated in a series of clinical trials as
part of the Liraglutide Effect and Action in Diabetes, or LEAD program, which consists
of 5 randomized, double-blind controlled studies. These trials will assess the clinical
effectiveness of liraglutide in some 3800 patients with T2DM patients whose blood
glucose is inadequately controlled with standard oral therapies. The release of data
from 3 of the 5 major phase 3 studies suggests that the addition of liraglutide to
ongoing oral antidiabetic drugs can significantly improve glycemic control in previously
uncontrolled T2DM patients. In LEAD 1, a trial in which 1026 patients receiving
maximal dose glimepiride were subsequently randomized to treatment with liraglutide,
rosiglitazone. or placebo, liraglutide achieved statistically significantly better glucose
control (HbA1c < 7%) than rosiglitazone. In LEAD 2, in which 1026 patients receiving
the maximal dose of metformin were subsequently randomized to treatment with
liraglutide, glimepiride, or placebo, the improvement in HbA1c was similar in the
liraglutide and glimepiride treatment arms. In LEAD 5, a 581-patient study, the addition
of liraglutide to metformin and glimepiride saw over 50% of patients achieving good
glycemic control (HbA1c < 7%) with over 35% achieving an HbA1c of < 6.5%. The
reduction in HbA1c achieved with liraglutide was >0.2% better than that achieved in the
active comparator arm (insulin glargine), a statistically significant difference.
Slide 7. Once-Daily Injection Covers 24 Hours in Type 2 Diabetes
Exenatide (Byetta, Amylin Pharmaceuticals, Inc), a GLP-1 receptor agonist, is the first
drug in this class to be approved by the FDA and marketed in the United States. It has
been approved as an adjunctive therapy for use in patients with T2DM who take
metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a
sulfonylurea or a combination of metformin and a thiazolidinedione. In contrast to
sitagliptin and vildagliptin, which are administered orally, exenatide is given by twice
daily subcutaneous injection.
Exenatide is the synthetic version of exendin-4, originally isolated from the salivary
secretions of the lizard Heloderma suspectum, otherwise known as the Gila monster.
The venom contains a number of highly bioactive peptides including the peptides
exendin-3 and exendin-4. These peptides were named exendins by Eng and Raufman
in that they were isolated from an exocrine gland and were subsequently shown to
have endocrine actions. This animal is 1 of the 2 most venomous lizards in the world,
and its venom is secreted as it bites down on its prey (ingestion of a meal) thus
representing the first example of an endocrine hormone secreted from the salivary
glands. Exendin-4 is a naturally occurring 39-amino acid peptide. Exenatide has 53%
homology overlap with exendin-4. As an agonist at the GLP-1 receptor, it has a longer
duration of action than GLP-1 largely due to its resistance to DDP-4-mediated
Data from animal models demonstrate a number of acute and longer term actions with
administration of exenatide. The primary acute actions are enhancement of glucose-
dependent insulin secretion, glucose-dependent suppression of inappropriately high
postprandial glucagon secretion, and slowing of gastric emptying. The longer term
actions include reduction of food intake with subsequent weight reduction, enhanced
insulin sensitivity, and an increase in beta-cell mass. To determine whether these
actions are also seen in humans, Koltermann and colleagues reported the results
from 2 studies designed to explore the postprandial and fasting glucose-lowering effect
of exenatide in subjects with T2DM. The plasma glucose response to a Sustacal meal
was significantly reduced by the administration of exenatide. In addition, exenatide
caused reductions in postprandial insulin concentrations and attenuation of the
glucagon response. These effects were shown to be a result of delayed gastric
emptying. In the second part of the study, the investigators evaluated the effects of 3
doses of exenatide on fasting glucose concentrations. All 3 doses markedly reduced
plasma glucose concentrations compared to the fasting state during an 8-hour
observation period. Exenatide also impacted serum insulin concentrations within the
first 3 hours post-dose compared to placebo. There was a statistically significant dose-
dependent increase in fasting insulin for AUC0-3h (P < .0001). In contrast, there was a
relatively stable response to placebo administration. The rise and peak serum insulin
concentrations coincided with the rapid decline of fasting glucose concentrations. The
most frequent study-related adverse events for subjects administered exenatide were
headache, vomiting, and nausea. The findings of these 2 studies would suggest that
exenatide can acutely reduce both fasting and postprandial glucose concentrations in
patients with T2DM. The overall acute effect is mediated by several mechanisms. In
the fasting state, both glucose-dependent enhancement of insulin secretion and
suppression of glucagon secretion are predominant, whereas in the postprandial
period, slowing of gastric emptying also plays a significant role.
Treatment with exenatide was then evaluated in 3 phase 3 trials when it was
administered to patients with T2DM. The studies have been labeled the
AC2993:Diabetes Management for Improving Glucose Outcome (AMIGO) development
program. The 3 studies were very similar in design; all were randomized, double-blind,
placebo-controlled, add-on therapy, multicenter studies with change in HbA1c as the
primary outcome variable. Following a 4-week placebo run-in period, subjects were
randomized to receive either exenatide 5 mcg twice daily, exenatide 10 mcg twice
daily, or placebo to match both exenatide treatment arms. The 10-mcg group and the
matched placebo group were initiated at the 5-mcg dose and volume, with a forced
titration to the higher dose and volume after 4 weeks. All subjects were then followed
for a subsequent 26 weeks.
The 3 studies are distinguished by the entry criteria of the individual study. The first
study, AMIGO I, examined exenatide treatment in T2DM patients inadequately
controlled on metformin monotherapy. The second study, AMIGO II, enrolled subjects
inadequately controlled on sulfonylurea monotherapy; the third study, AMIGO III,
enrolled subjects inadequately controlled on the combination of metformin and
sulfonylurea. In all 3 studies, the patients continued their concurrent medication.
However, in AMIGO III, to explore the risk of hypoglycemia, all patients continued their
current dose of metformin but were randomized to either a maximally effective or
minimum recommended dose of their sulfonylurea. No dietary intervention was
included in the studies, and subjects were instructed to maintain their previously
prescribed dietary regimens. Data were reported for the 3 individual studies.[33,34,35]
Slide 8. Exenatide: Effects on Glycemic Control in Combination With Current Oral
AMIGO I recruited 336 patients with an average HbA1c of 8.2 =/- 1.1% and a mean
disease duration of 6 years. Amigo II recruited 377 patients with an average HbA1c of
8.6 ± 1.2% and a mean duration of disease of 6 years. Amigo III recruited 734 patients
with a mean HbA1c of 8.5 ± 1.0% HbA1c and a mean duration of disease of 9 years.
Minorities were well represented throughout all study cohorts.
In all 3 studies, the addition of exenatide to the patient's concurrent therapy resulted in
a significantly greater proportion achieving an HbA1c ≤ 7%. In addition, each
respective group of patients treated with exenatide had significant reductions in mean
HbA1c when compared to placebo (P < .001). Because of the identical study design
between the 3 studies, it is acceptable to pool the data and make comparisons of
exenatide versus placebo. In the measurement of HbA1c, pooled data show an
increase of 0.1% for those subjects randomized to placebo, whereas 5 mcg of
exenatide twice daily led to a mean reduction of 0.6% and 10 mcg twice daily exenatide
led to a mean reduction of 0.9%, and both decreases were statistically significant when
compared to placebo twice daily .
Pooled data from the AMIGO studies also demonstrated a beneficial effect of exenatide
on FPG and postprandial glucose levels. Both were significantly reduced by exenatide
after 30 weeks of treatment.
Slide 9. Exenatide Reduced Weight: Large Phase 3 Clinical Studies
Allied with the reduction of FPG and the improved control of postprandial glucose
levels was a progressive weight loss, predefined in the protocols as a secondary
outcome, for those subjects treated with exenatide. Pooling the data showed that
subjects treated with exenatide 10 mcg twice daily had an end of study loss of 1.8 kg
from baseline; subjects randomized to the lower dose of exenatide had a weight loss of
1.4 kg, whereas the placebo group showed a 0.1-kg weight loss from baseline.
In general, across the 3 studies, exenatide was well tolerated and the adverse event
profile was also similar with the exception of hypoglycemia risk. A modest increase in
hypoglycemia risk was seen with the addition of exenatide to sulfonylurea or the
combination of metformin plus sulfonylurea. Combination of exenatide with metformin
did not demonstrate any appreciable increase in the incidence of hypoglycemia, which
would suggest that, in the absence of an insulin secretogogue or exogenous insulin,
exenatide does not cause hypoglycemia. The most commonly reported adverse event
was mild-moderate nausea, which more often than not occurred early after the initiation
of exenatide treatment. In AMIGO I, 45% of patients in the group receiving exenatide
10 mcg twice daily reported nausea compared to 23% in the placebo group. There was
a 3% dropout for the exenatide group and 0% for the placebo group. In the AMIGO III
study, 49% of patients taking 10 mcg of exenatide twice daily reported nausea
compared with 21% for placebo. However, the nausea seemed to be minimized by
gradual dose titration. A partial coefficient and subgroup analysis indicate that nausea
had a negligible effect on HbA1c or the reduction in body weight seen with exenatide
On completion of the treatment period in their respective study, patients were given the
opportunity to continue with open-label exenatide treatment at a dose of 10 mcg twice
daily. Results reported by Webb and co-workers from 314 overweight patients that
used exenatide twice daily for 82 continuous weeks demonstrated that patients
continued to lose weight, with a mean loss of 4.4 kg. Ratner and colleagues reported
the data from the patients also taking metformin and in addition to the continued loss of
body weight, there was a durable and continued decrease in HbA1c of 1.3% from
baseline compared to a decrease of 1.0% after 30 weeks dosing. Another benefit from
long-term dosing with exenatide was an improvement in cardiovascular risk factors
when compared to baseline. A variety of risk factors were measured, and the data are
presented in Table 1.
Parameter Mean Baseline Mean ∆ From Baseline 95% CI
Total cholesterol (mg/dL) 188.2 -2.4 -6.3 to +1.5
LDL-C (mg/dL) 116.7 -1.6 -5.2 to +1.9
HDL-C (mg/dL) 38.6 +4.6 +3.7 to +5.4
Apo B (mg/dL) 92.6 -1.1 -3.5 to +1.3
Triglycerides (mg/dL) 243.1 -38.6 -55.5 to -21.6
Systolic BP (mm Hg) 129.0 -1.3 -3.1 to +0.5
Diastolic BP (mm Hg) 78.8 -2.7 -3.8 to -1.7
Table 1: Exenatide Improved Cardiovascular Risk Factors at Week 82
For 82-week completers, N = 314. Data from Blonde et al. Diabetes Obes Metab.
CI, confidence interval; LDL-C, low density lipoprotein cholesterol; HDL-C, high density
lipoprotein cholesterol; Apo B, apolipoprotein B; BP, blood pressure.
Another beneficial feature of long-term treatment with exenatide was an observed
improvement in hepatic injury biomarkers when followed over 2 years. Buse and
colleagues reported that patients with normal levels of alanine transferase (ALT) at
baseline had no significant change after 2 years of treatment with exenatide. However,
patients with elevated ALT at baseline (38 ± 1 IU/L, N = 151) had a mean reduction of
11 ± 1 IU/L (P < .05), and 39% of these subjects achieved a normal ALT by the end of
2 years treatment. Aspartate amino transferase was also improved over the same
period. The same authors also reported an improvement in HOMA-B with an almost
50% increase from baseline.
The AMIGO studies clearly demonstrated a benefit of adding exenatide to ongoing
metformin or sulfonylurea therapy in the treatment of T2DM, and for most patients the
effect persisted during long-term therapy. Zinman and colleagues reported the results
of a randomized, placebo-controlled, double-blind study where the objective was to
examine the effect of adding exenatide to thiazolidinediones (TZD), another class of
drug also used in the treatment of T2DM. Patients considered for the study were
suboptimally controlled on their current therapy and were to have been on a stable
dose of either rosiglitazone (≥ 4 mg/day) or pioglitazone (≥ 30 mg/day) for at least 30
days. The primary outcome was the change in HbA1c from baseline; secondary
outcomes included FSG, body weight, and self-monitored blood glucose levels.
Slide 10. Seven-Point Self-monitored Blood Glucose Profiles
The addition of exenatide for 16 weeks reduced mean HbA1c by 0.98% (P < .001),
whereas there was a marginal increase in HbA1c with placebo treatment. Within the
exenatide treatment population, 62% of patients were able to achieve the ADA target of
an HbA1c ≤ 7% compared to only 16% in the placebo group (P < .001). Also of note is
the finding that 30% of exenatide patients achieved an HbA1c level of ≤6.5% compared
to 8% in the placebo group (P < .001). Exenatide also improved FPG level with a mean
reduction of 1.69 mmol/L compared to the reduction of 1.17 mmol/L observed with
placebo (confidence interval, -2.22 to -1.17 mmol/L). The administration of exenatide
also reduced body weight by an average of 1.51 kg.
Patients were encouraged to self-monitor their blood glucose at 7 specified daily events
to allow blood glucose profiles to be built. The profiles at baseline and post-treatment
were almost identical and superimposable upon the placebo group profiles. In the
exenatide treatment group, there were clear reductions in blood glucose throughout the
day and the postprandial excursions were also attenuated. Overall, it can be concluded
that the addition of exenatide to TZD improved glycemic control and reduced body
weight, with a slight increase in the reporting of gastrointestinal side effects, primarily
nausea, when compared to placebo.
Recently, data from 217 subjects who have received exenatide 10 mcg twice daily for 3
years were presented. There was a sustained reduction in HbA1c and FPG. A total of
46% of the study participants achieved the ADA goal of an HbA1c below 7%, and 36%
achieved an HbA1c of 6.5% or less. Weight loss was progressive with study subjects
losing a mean 5.3 ± 0.4 kg at 3 years. In a subset of 92 subjects, 3 years of treatment
with exenatide resulted in a 17% improvement from baseline in beta-cell function as
determined by HOMA-B.
Pharmacokinetic studies with exenatide show its half-life to be 2.4 hours with effects
lasting up to 8 hours. This is 20-30 times longer than GLP-1 when compared in
preclinical studies. However, as exenatide is administered in the morning and evening,
the possibility exists that it may not provide complete coverage after midday meals or
overnight. Therefore, an extended release formulation was developed with the
objective of providing once weekly subcutaneous administration of exenatide. This new
formulation, referred to as exenatide LAR (long-acting release), was compared at 2
dose levels to placebo in a 15-week double-blind, randomized study in T2DM patients.
The dose levels of exenatide were 0.8 mg and 2.0 mg, which were targeted to result
in blood levels previously found to be therapeutic with twice daily exenatide. Plasma
concentrations of exenatide rose steadily and reached steady state levels by weeks
6-7. After about 6 weeks of treatment with 2.0 mg of exenatide LAR, plasma exenatide
concentrations were maintained at levels similar to the maximum concentration
achieved with a single injection of 10 mcg of exenatide.
Slide 11. Exenatide LAR Reduced FPG
Exenatide LAR reduced HbA1c by week 3 in both active treatment groups, and HbA1c
decreased progressively throughout the remainder of the treatment period. Fasting
plasma glucose was rapidly and significantly reduced in both exenatide groups. All 3
groups had similar self-monitored glucose profiles at baseline. After 15 weeks of study
treatment, the average daily blood glucose concentration decreased for both LAR
treatment groups and increased for the placebo treatment group. Exenatide LAR also
decreased preprandial and postprandial glucose excursions. Body weight decreased
progressively in the 2.0-mg exenatide LAR group (P < .05 vs placebo). Body weight
was unchanged for the 0.8-mg exenatide LAR and the placebo groups.
Slide 12. Exenatide LAR Reduced Overall Daily Glucose
As in studies with conventional exenatide, the most frequently reported adverse event
was nausea (exenatide LAR 0.8 mg 19%, exenatide LAR 2 mg 13% vs placebo LAR
15%) followed by gastroenteritis and hypoglycemia. Most treatment emergent adverse
events were reported as mild or moderate.
In summary, the incretin mimetics have been shown to be effective in sustaining
glycemic control together with gradual but continuous reductions in body weight and
improvements in beta-cell function. In the case of exenatide, data are now available,
showing that the efficacy persists for up to 3 years. Side effects are generally mild to
moderate in severity. With exenatide, there is a noticeable increase in the number of
reports of nausea, although these reports do seem to decrease over time.
Although the ADA treatment algorithm was published only recently, the availability,
safety, and proven effects of these newer agents, the DPP-4 inhibitors and the incretin
mimetics, would suggest that they should be incorporated into a revised treatment
algorithm in the near future. Both classes represent a novel strategy for improving the
imbalance of glucose homeostasis that occurs in T2DM and for restoring normal
physiology. The introduction of these new agents may have a dramatic impact and
unprecedented impact on T2DM as true disease-modifying agents, perhaps improving
or preventing complications and ultimately improving mortality as the progression of the
disease is delayed or potentially reversed.
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