Prospects of Incretin Mimetics in Therapeutics

Dr. Sukanta Sen

MD, DNB, MNAMS Department Clinical & Experimental Pharmacology,

Calcutta School of Tropical Medicine

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.

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.

• 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.]

• 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.

• 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.

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.

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.

• 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.

• 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.

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.

• 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.

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.

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

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.]

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.

• 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.

• 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.

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.

• 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%).

• 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.]

• 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.

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.

• 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.

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.

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.]

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.

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

• 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.

Choosing GLP-1 Receptor Agonists or DPP-4

Inhibitors: Weighing the Clinical Trial Evidence

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.

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.

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

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

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.

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.

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.

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.

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.