Comparative trials show that there are important differences between and among the GLP-1 receptor agonists and DPP-4 inhibitors with respect to glycemic lowering, weight effects, and effects on systolic blood pressure and the lipid profile. •Nausea, diarrhea, headaches, and dizziness are common with the available GLP-1 receptor agonists. •Upper respiratory tract infections, nasopharyngitis, and headaches are common with the DPP-4 inhibitors. •Ongoing safety evaluations should provide a clear picture regarding long-term safety.

1. Prospects of Incretin
Mimetics in Therapeutics
Dr. Sukanta Sen
MD, DNB, MNAMS
Department Clinical & Experimental Pharmacology,
Calcutta School of Tropical Medicine

2. Introduction
• Type 2 diabetes is a metabolic disease characterized by high
blood glucose caused by an insufficiency of the pancreas to
produce insulin, hyperglucagonemia and impaired insulin
sensitivity.
• The typical symptoms include thirst, polyuria, recurrent
infections and weight loss.

3. THE HISTORY OF INCRETINS
• In 1902, Bayliss and Starling proposed that intestinal mucosa contains a
hormone, which stimulates the exocrine secretion of the pancreas ("Secretin").
However, oral administration of extracts of intestinal mucosa failed to help
several patients with type 1 diabetes.
• In 1932 La Barre proposed the name ‘incretin’ for a hormone extracted from
the upper gut mucosa, which caused hypoglycaemia and proposed a possible
therapeutic role in diabetes.
• In 1939–1940, based on their studies, Leow et al. concluded the existence of
incretins was “questionable.” No further research in this area was performed
for about thirty years until 1970. However, as molecular biology advanced this
hypothesis was re-visited with the subsequent development of a therapeutic
strategy that would revolutionise the treatment of type 2 diabetes.

4. • In 2000 the global mortality due to diabetes was estimated to be 5.2% or 2.9
million deaths. The increased mortality is mainly due to cardiovascular events.
• Recent estimates indicate that 171 million people worldwide had diabetes in
2000 and this number is projected to increase to 366 million by 2030.
• As a consequence, diabetes-related deaths are likely to increase by more than
50% in the next 10 years.
• In developed countries most people with diabetes are above 64 years of age
while most people with diabetes in the developing countries are younger (45 to
64 years). The disease is equally distributed among sexes.
• The global economic impact of diabetes, due to premature death and
complications from the disease, is considerable. At least $232 billion were
spent on treatment and prevention of diabetes worldwide in 2007, with three
quarters of that amount spent in industrialized countries on the treatment of
long-term complications and on general care, such as efforts to prevent micro-
and macrovascular complications.
[International Diabetes Federation Diabetes atlas, third edition. Brussels, Belgium: International
Diabetes Federation, 2006:237, 241.]

5. • Type2 DM is a progressive disease warranting intensification
of treatment, as beta-cell function declines over time.
• Current treatment algorithms recommend metformin as the
first-line agent, while advocating the addition of either basal-
bolus or premixed insulin as the final level of intervention.
• Incretin therapy, including incretin mimetics or enhancers, are
the latest group of drugs available for treatment of T2DM.

6. • The optimal goal for glycemic control is a HbA1c below 7%. In order to reach
this target an intensified regimen with combinations of antidiabetes agents
is often needed.
• Oral agents in monotherapy (thiazolidinediones [TZDs], metformin,
repaglinide, α-glucosidase inhibitors and sulfonylurea [SU] compounds)
improve glycemic control to almost the same degree (decrease in HbA1c of
approximately 1%).
• Type 2 diabetes is a progressive disease with an almost linear decline in
beta-cell function (probably combined with a decrease in beta-cell mass)
over time. None of the mentioned antidiabetes drugs have been shown to
preserve pancreatic beta-cell function over time and, notably, SUs have been
shown to accelerate the apoptosis of human beta-cells.

7. Besides, the current available drugs are associated with a number of
shortcomings: body weight increase (TZDs, Sus and insulin),
hypoglycemia (SUs, repaglinides and insulin) and gastrointestinal side
effects (metformin and α-glucosidase
inhibitors).
The limitations of the pre-existing antidiabetes treatments, make new
medical therapies that offer improved efficacy and/or durability, better
convenience, and an improves safety and tolerability profile an
absolutely imperative in order to get more patients to glycemic goal initially
and to avoid or delay the need for additional treatment.

9. Incretin hormones
• The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-
dependent insulinotropic polypeptide (GIP) are intestinal peptide hormones
released in response to ingestion of meals.
• The most important effect of GLP-1 and GIP is their ability to potentiate
glucose-induced insulin secretion from the pancreas – the so-called
incretin effect.
• In healthy subjects the incretin effect accounts for up to 70% of the insulin
secreted in response to glucose ingestion.
• GLP-1 is a 30-amino acid polypeptide processed from proglucagon in the
endocrine L-cells distributed primarily in the mucosa of the distal part of
the small intestine and colon.
• GIP is a 42-amino acid polypeptide released from endocrine K-cells found
in the mucosa of the duodenum and upper jejunum.

15. • While GLP-1 is rapidly degraded (by the ubiquitous enzyme dipeptidyl
peptidase-4 (DPP-4)) in the circulation with an apparent half-life of 1 to 1.5
minutes,
• GIP is degraded more slowly, with a half-life for the intact hormone of 7 minutes.
• The hormones enhance insulin secretion from the beginning of a meal, but has no
insulinotropic activity at lower glucose concentrations (less than 4 mM); thereby
not promoting hypoglycemia.
• GLP-1 also enhances insulin biosynthesis and insulin gene expression.
• In addition, it exerts trophic and protective actions on the beta-cells and
strongly inhibits pancreatic glucagon secretion in a glucose-dependent manner.

16. • In contrast, GIP has been shown to stimulate glucagon secretion. The
hormones exhibit their insulinotropic effect via G-protein coupled receptors on
the pancreatic beta-cells.
• GLP-1 receptors are found in various regions of the brain and when activated
these are believed to promote feeling of satiety which in combination with
GLP-1-induced inhibition of gastrointestinal motility (mediated through the
vagus nerve) reduces food intake and body weight.
• GLP-1 has also been found to reduce the postprandial rise in triglycerides and
lower the concentration of free fatty acids in humans.
• Finally, animal as well as human studies indicate that GLP-1 has natriuretic
and diuretic properties by modulation of renal Na+/H+ exchange – a
mechanism that might serve to reduce blood pressure.

24. Incretin mimetics
•Exenatide, the first in this new class of drugs, was introduced to the
market in the United States in 2005 and in Europe in 2007 under the
trade name Byetta® (Amylin Pharmaceuticals/Eli Lilly). Was approved
India in July 2007.
•Liraglutide has been introduced to the market in Europe July 2009 and
in the United States and Japan in January 2010 under the trade name
Victoza® (Novo Nordisk). The FDA approval for Bydureon® Pen
(exenatide extended-release for injectable suspension) for once-
weekly treatment of adults with type 2 diabetes was received in
2012. BYDUREON is currently available in 42 countries worldwide,
including European Union countries.

25. • More recently, Liraglutide was approved by the FDA on
December 23, 2014 for treatment for obesity in adults with
some related comorbidity.
• In 2015, Novo Nordisk began marketing it in the U.S. under the
brand name Saxenda as a treatment for obesity in adults with at
least one weight-related comorbid condition.
• Liraglutide is marketed under the brand name Victoza in the
U.S., India, Canada, Europe and Japan. It has been launched in
Germany, Denmark, the Netherlands, the United Kingdom,
Ireland, Sweden, Japan, Canada, the United States, France,
Malaysia and Singapore.

26. Lixisenatide is approved in Europe for the treatment of adults with
type 2 diabetes mellitus to achieve glycemic control in
combination with oral glucose-lowering medicinal products
and/or basal insulin when these, together with diet and exercise,
do not provide adequate glycemic control.
Lixisenatide is also approved in Mexico, Australia and Japan for
the treatment of adults with type 2 diabetes.
Sanofi's Lyxumia® (Lixisenatide) showed more pronounced after-
test-meal blood sugar lowering than liraglutide when both were
added to insulin glargine.

28. Incretin hormones and type 2 diabetes pathophysiology
•In patients with type 2 diabetes the incretin effect is severely reduced.
•This pathophysiological trait is likely to play a central role in the
inability of these patients to secrete sufficient amount of insulin to
prevent hyperglycemia following oral glucose.
•Attenuated postprandial secretion and decreased insulinotropic potency of
GLP-1 in combination with abolished insulinotropic effect of GIP seem to
be responsible for the reduced incretin effect in patients with type 2
diabetes

29. These incretin-based agents were included in the 2009 recommendations of an
American Association of Clinical Endocrinologists–American College of
Endocrinology consensus panel, which suggested that patients with A1C levels of
7.6–9.0% be treated with dual therapy with metformin (unless contraindicated) plus, in
order of preference, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl
peptidase-4 (DPP-4) inhibitors, glinides, or sulfonylureas.
The panel emphasized the lower risk of hypoglycemia with GLP-1 receptor agonists and
DPP-4 inhibitors compared with glinides and sulfonylureas, but preferred GLP-1
receptor agonists over DPP-4 inhibitors because of their greater potential for lower
PPG level and substantial weight loss.
For patients requiring triple therapy, metformin, a GLP-1 receptor agonist, and a third oral
antidiabetic drug—a thiazolidinedione, a sulfonylurea, or a glinide—are recommended.
[Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American
College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract
2009;15:540–59.]

30. Pharmacology
Exenatide
• Exenatide was isolated from the saliva of the lizard
Heloderma suspectum in a search for biologically active
peptides.
• It shares 53% homology with native GLP-1 and binds to and
activates GLP-1 receptors on pancreatic beta-cells following
which insulin secretion and synthesis is initiated.
• Following sc administration, exenatide is rapidly absorbed
reaching peak concentrations in approximately 2 hours.
• The half-life of exenatide is approximately 2 hours.

32. • Exenatide is, unlike native GLP-1, not substantially degraded by
DPP-4 but is cleared primarily in the kidneys by glomerular
filtration resulting in a plasma half-life for the peptide of
approximately 30 minutes after iv administration.
• Exenatide is indicated for therapy of patients with type 2 DM
inadequately controlled on metformin, sulfonylurea,
thiazolidinedione or combination of the two.
• Studies of combination treatment with metformin and exenatide
have shown little risk of hypoglycemia.
• People on exenatide eat about 20% less and often lose weight.
With prolonged use, weight loss has been associated with
improvements in blood pressure and lipids.
• The recommended dose of exenatide is 5-10 μg twice daily.
Exenatide therapy reduces HbA1c levels by approximately 1%
and body weight by 2-3 kg.

33. • The most common adverse effect is nausea.
• US FDA has received reports of pancreatitis in patients
taking exenatide, two of whom died because of hemorrhagic or
necrotizing.
• GLP-1 may prove to have a therapeutic role in heart disease,
with small-scale human trials showing that it improves left
ventricular function, both after primary angioplasty for
acute myocardial infarction and in patients with New York
Heart Association Class III/IV heart failure.

34. Liraglutide
• Liraglutide is an acylated analogue of human GLP-1 and has
97% sequence homology to native GLP-1 analogue is produced
using the recombinant DNA technology in yeast.
• A high degree of PPB causes decreased susceptibility to
metabolism by DPP-4 and the half-life following sc
administration of liraglutide is approximately 13 hours.
• This protracted action profile makes liraglutide suitable for
once-daily administration.

35. • The clinical effects of liraglutide treatment have been
investigated in the LEAD (Liraglutide Effect and Action in
Diabetes) series of phase III studies including more than 4000
patients with type 2 diabetes.
• In average liraglutide reduced HbA1c by 1.2% from a baseline
of 8.2% to 8.5%.
• A direct comparison between liraglutide (1.8 mg once daily)
and exenatide (10 μg twice daily) was reported from the open-
labeled LEAD 6 study. Mean HbA1c reduction was
significantly greater with liraglutide treatment than with
exenatide (1.1% vs 0.8%).

36. • Liraglutide reduced mean body weight or was weight neutral as
monotherapy and in combination with one or two oral antidiabetes agents
compared to placebo or active comparators.
• The LEAD 6 study examined the lipid profile on exenatide and liraglutide.
• Significant greater reductions in triglycerides (−0.4 vs −0.2 mM) and
free fatty acids (−0.17 vs −0.10 mM) in the liraglutide group were
observed.
• Both compounds caused a significant decrease in blood pressure (systolic
blood pressure −2.2 mmHg and diastolic pressure −1.5 mmHg) with no
significant differences between the two compounds.
[Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day
for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label
trial (LEAD-6). Lancet. 2009;374:39–47.]

37. • Liraglutide should be initiated in a dose of 0.6 mg daily.
• After at least 1 week, the dose should be increased to 1.2 mg.
• The dose can be increased to 1.8 mg to further improve glycemic
control.
• Daily doses higher than 1.8 mg are not recommended because
of side effects.

38. Safety and tolerability
• The major side-effects of all compounds are mild to moderate and transient
nausea and vomiting. These side effects are dose dependent and decline
over time.
• Other frequently reported side effects are headache and upper respiratory
infection.
• The incidence of treatment-associated hypoglycemia is reported to be low –
apparently due to the glucose-dependent insulinotropic and glucagonostatic
effects of GLP-1.
• In the exenatide/insulin glargine study 1.5% of patients experienced severe
hypoglycemia.
• Neither exenatide nor liraglutide is recommended during pregnancy or
lactation due to lack of sufficient data.

39. • In the LEAD studies a total of 9 reports of pancreatitis were
observed, with reports of pancreatitis in both in liraglutide-,
placebo- and active comparator-treated patients.
• it is recommended to discontinue incretin mimetic treatment if
pancreatitis is suspected.
• In carcinogenicity studies with liraglutide, C-cell tumors were
observed in thyroid tissue of mice and rats. It has been suggested
that the findings in rodents are caused by a non-genotoxic, specific
GLP-1 receptor-mediated mechanism to which rodents are
particularly sensitive.

40. Lixisenatide
• The selective once-daily prandial glucagon-like peptide-1 (GLP-1)
receptor agonist lixisenatide (Lyxumia(®)) marketed by Sanofi for the
treatment of type 2 diabetes mellitus.
• Lixisenatide belongs to a class of GLP-1 compounds designed to mimic
the endogenous hormone GLP-1.
• Native GLP-1 stimulates insulin secretion in a glucose-dependent manner,
as well as suppressing glucagon production and slowing gastric emptying. A
once-daily subcutaneous formulation of lixisenatide has been approved in
the EU, Iceland, Liechtenstein, Norway and Mexico for the treatment of
type 2 diabetes, and is under regulatory review in the USA, Switzerland,
Brazil, Canada, Ukraine, South Africa, Japan and Australia.
• It is given as an injection under the skin in the abdominal wall (at the front
of the waist), upper arm or thigh. Lyxumia is started at a dose of 10
micrograms once a day which is increased to 20 micrograms once a day
after 14 days.

41. Lyxumia reduced Hb1Ac levels by 0.6% more than placebo.
The study comparing Lyxumia with exenatide (added to metformin)
showed reduced HbA1c levels by 0.79% after 24 weeks
treatment with Lyxumia compared to 0.96% with exenatide twice
daily.
The most common side effects are nausea, vomiting, diarrhoea
and headache. These side effects were mostly mild and usually
resolved over time.
[ref: Diabetes Obes Metab. 2014 Jul;16(7):588-601. doi:
10.1111/dom.12253.]

42. Albiglutide
FDA has approved albiglutide in april 2014 (Tanzeum, GlaxoSmithKline), a
once-weekly injectable GLP-1 receptor agonist to treat type 2 diabetes.
Albiglutide is indicated as monotherapy or in combination therapy with
metformin, glimepiride, pioglitazone, or insulin.
Albiglutide should not be used in patients who have a personal or family
history of MTC or have multiple endocrine neoplasia syndrome type 2
(which predisposes them to MTC).
• The most common side effects in clinical trials of albiglutide were
diarrhea, nausea, and injection-site reactions.
• The FDA approved albiglutide with a risk evaluation and mitigation
strategy (REMS), where the company has a communication plan to inform
healthcare providers about the serious risks associated with it.
• An MTC case registry of at least 15 years' duration to identify any
increase in MTC incidence with the drug.
• Albiglutide is approved in the European Union under the name Eperzan.

43. Dulaglutide
• The US FDA has approved dulaglutide (Trulicity, Eli Lilly & Co), as a once-
weekly injection for the treatment of type 2 diabetes.
• Once-weekly dulaglutide was approved based on 6 clinical trials involving a
total of 3342 patients who received the drug.
• In one trial the once-weekly dulaglutide was noninferior to daily liraglutide,
and in another it topped the oral dipeptidyl peptidase-4 (DPP-4) inhibitor
sitagliptin (Januvia, Merck).
• The most common side effects observed were nausea, diarrhea,
vomiting, abdominal pain, and decreased appetite.
• The following serious reactions are also in the label:
 Risk of Thyroid C-cell Tumors [Warnings and Precautions (5.1)]
 Pancreatitis
 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin
 Hypersensitivity reactions
 Renal impairment

47. • Taspoglutide, a GLP-1 agonist, was under investigation for treatment
of type 2 diabetes being codeveloped by Ipsen and Roche.
• Two phase II trials reported it was effective and well tolerated.
• Of the eight planned phase III clinical trials of weekly taspoglutide
(four against exenatide, sitagliptin, insulin glargine, and pioglitazone),
at least five were active in 2009. Preliminary results in early 2010
were favourable.
• In September 2010 Roche halted Phase III clinical trials due to
incidences of serious hypersensitivity reactions and gastrointestinal
side effects.

48. Choosing GLP-1 Receptor Agonists or DPP-4
Inhibitors: Weighing the Clinical Trial Evidence

51. DPP-4 inhibitors:
• Inhibition of DPP-4 by DPP-4 inhibitors enhances the hormone
activity of GLP-1 and other bioactive peptides (GIP, gastrin
releasing peptide), thereby stimulating the release of insulin and
reducing the secretion of glucagons. This effect contributes to the
regulation of elevated blood glucose levels in type 2 DM patients.
• There are more than 20 different DPP-4 inhibitors being
developed for various therapeutic interests-mainly type 2 DM.
• All have limitations relating to potency, stability or toxicity.

52. Sitagliptin and vildagliptin are two DPP-4 inhibitors that have been approved
in India for human use in October 2007 and January 2008, respectively.
The DPP-4 inhibitors improve metabolic control without causing severe
hypoglycemia.
DPP-4 inhibitors tend to be weight neutral.

53. Drug Highest Development Phase Company
Sitagliptin Launched Merck & Co
Sitagliptin+Metformin Launched Merck & Co
Vildagliptin Launched Novartis
Vildagliptin+Metformin Launched Novartis
Saxagliptin Launched Bristol Myers Squibb
Saxagliptin+Metformin Launched Bristol Myers Squibb
Alogliptin In 2013 the FDA approved the drug
in three formulations: As a stand-
alone, combined with metformin, and
when combined with pioglitazone.
Takeda

54. Drug Highest Development Phase Company
Linagliptin Launched in India 2012 Boehringer Ingelheim India
BI 1356 BS Phase 2 Boehringer Ingelheim
Melogliptin Phase 3 Glenmark Pharmaceuticals
Ltd.
PSN 9301 Phase 2 Prosidion
R 1579 Phase 2 Roche
SYR 472 Phase 2 Takeda San Diego
TA 6666 Mitsubishi Tanabe Pharma
Corporation
Denagliptin Phase 3 (Suspended) Glaxo Smithkline

55. Sitagliptin
• Indicated as an adjunct to diet and exercise to improve glycaemic
control in subjects with T2D as monotherapy for whom metformin
is contraindicated, or as combination therapy with metformin
and/or a TZD and/or an SU and/or insulin.
• Sitagliptin 100 mg OD has been shown to be safe and effective in
reducing hyperglycaemia, associated with HbA1c reductions of 0·6–
1·2% (6·6–13·1 mmol/mol) as monotherapy and up to 0·9% (9·8
mmol/mol) as combination therapy.
• Sitagliptin is weight-neutral and has also shown beneficial effects
on proinsulin to insulin ratio and HOMA-B versus placebo,
markers of insulin secretion and β-cell function.

56. Vildagliptin
• Vildagliptin 50 mg is approved for BID use as monotherapy when
metformin is contraindicated or as combination therapy with either
metformin, an SU or a TZD.
• Vildagliptin has been shown to be effective in a range of clinical
trials examining the drug as monotherapy or as combination therapy.
• Analysis of these clinical studies shows that vildagliptin (either 50
mg BID/OD or 100 mg OD) is associated with an HbA1c reduction
of up to 0·8% (8·7 mmol/mol) as monotherapy and 0·6–1·0% (6·6–
10·9 mmol/mol) as combination therapy.
• Vildagliptin is not associated with any significant changes in body
weight, but β-cell function and insulin secretion show significant
improvements from baseline.

57. Saxagliptin
• Saxagliptin is indicated as an add-on therapy in combination
with either metformin, an SU, a TZD or insulin.
• Two doses of saxagliptin (2·5 and 5·0 mg) have been shown to
be effective in a range of clinical trials.
• These studies show saxagliptin is associated with
HbA1c reductions of up to 0·5% (5·5 mmol/mol) as
monotherapy and between 0·5 and 0·9% (5·5–9·8 mmol/mol) as
combination therapy.
• Similarly to other DPP-4Is, saxagliptin treatment improves β-cell
function from baseline and is weight-neutral.

58. Linagliptin
• The most recent DPP-4I to be licensed is linagliptin, which was
approved in Europe and the USA in 2011 for monotherapy use when
metformin is contraindicated and in combination with either
metformin, a SU or a TZD as treatment for T2D.
• Linagliptin 5 mg OD significantly improves glycaemic control in
combination with metformin, a TZD and as monotherapy, with
HbA1c reductions up to 1·1% (12·0 mmol/mol) compared with placebo.
• Linagliptin also enhances parameters of β-cell function from baseline
and is not associated with weight gain.

61. Conclusion:
•Comparative trials show that there are important differences between
and among the GLP-1 receptor agonists and DPP-4 inhibitors with
respect to glycemic lowering, weight effects, and effects on systolic
blood pressure and the lipid profile.
•Nausea, diarrhea, headaches, and dizziness are common with the
available GLP-1 receptor agonists.
•Upper respiratory tract infections, nasopharyngitis, and headaches
are common with the DPP-4 inhibitors.
•Ongoing safety evaluations should provide a clear picture regarding
long-term safety.