Role of Incretin in the management of diabetes

Outline

Core defect in Type 2 DM What is Incretin? Evidences Safety DPP4 Inhibitor GLP 1

Defect in Type 2 DM

Three Hormone Theory

Insulin Deficiency,Glucagon Excess Decreased Incretin effect

Two Hormone TheoryInsulin Deficiency Glucagon Excess

One Hormone TheoryInsulin Deficiency

Multiple Defects Underlie the Pathophysiology of Type 2 Diabetes

ImpairedIncretin Effect

ImpairedIncretin Effect

Relative InsulinDeficiency

Relative InsulinDeficiency

InsulinResistance

InsulinResistance

Prediabetes and Type 2 Diabetes

Prediabetes and Type 2 Diabetes

Kendall DM, Cuddihy, RM, Bergenstal RM. Provided by David M. Kendall. MD.

Pathophysiology of Type 2 Diabetes The Glucagon Factor• In response to a carbohydrate-containing meal,

individuals without diabetes not only increase insulin secretion but also simultaneously decrease pancreatic alpha-cell glucagon secretion.

• The decrease in glucagon is associated with a decrease in hepatic glucose production, and along with the insulin response, results in a very modest increase in postprandial glucose.

N Engl J Med. 1971;285:443-449.

Pathophysiology of Type 2 Diabetes The Glucagon Factor• In contrast, the glucagon secretion in type 2 diabetics is

not decreased, and may even be paradoxically increased.

• These insulin and glucagon abnormalities produce an excessive postprandial glucose excursion.

N Engl J Med. 1971;285:443-449.

• More than 35 years ago, Roger Unger presciently stated,

"One wonders if the development of a pharmacologic means of suppressing glucagon to appropriate levels would increase the effectiveness of available treatments for diabetes”.

Hepatic glucoseoutput

Insulin resistance

Glucose uptake

Glucagon(alpha cell)

Insulin(beta cell)

Pancreas

Liver

Hyperglycemia

Islet-cell dysfunction

Major Pathophysiologic Defects in Type 2 Diabetes1,2

Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.1. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781. 2. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.

MuscleAdipose tissue

Pathophysiology of Type 2 Diabetes The Gastric Emptying Factor

• Many factors can affect the rate of gastric emptying.

• Studies suggest that all other factors being equal, most people with type 1 and type 2 diabetes have accelerated gastric emptying compared to those without diabetes.

Gastroenterology. 1990;98:A378.

Pathophysiology of Type 2 Diabetes

Another observation

• In 1930 La Barre described a greater effect of oral rather parenteral glucose in increasing insulin secretion.

• In 1986 Nauck demonstrated that a glucose infusion graded to achieve plasma glucose levels identical of those achieved with oral glucose led to a insulin response that was only one quarter as great.

J Clin Endocrinol Metab. 1986;63:492-498.

• Incretin hormones were discovered during researchers trials to find out interpretation to this phenomenon which has been called the incretin effect.

Oral glucose load (50 g) IV glucose infusion

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The incretin hormones play a crucial role in a healthy insulin response

• Insulin response is greater following oral glucose than IV glucose, despite similar plasma glucose concentration

Insulin response

Insu

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/L)

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Incretineffect

Nauck et al. Diabetologia 1986;29:46–52, healthy volunteers (n=8)

History of Incretins• Concept proposed in 1906 by Moore; secretin proposed as

gut hormone that enhanced postprandial insulin release• Term incretin introduced 1932 by LaBerre• Berson and Yalow developed RIA for insulin in 1960s, after

which several groups found plasma insulin levels were higher after PO than IV glucose when BG was the same

• Term entero-insular axis coined by Unger (1969)• GIP isolated by Brown in 1969 (Gastric Inhibitory Peptide)• GLP-1 (7-36) discovered in 1988 (Göke)• Term incretins (glucoincretins, insulinotrophic hormones)

today refer to hormones/peptides that reduce glucose excursions into blood after a meal via various mechanisms

What are incretins?

• Hormones produced by the gastrointestinal tract in response to incoming nutrients, and have important actions that contribute to glucose homeostasis.

• Two hormones: Gastric inhibitory polypeptide (GIP) Glucagon-like peptide-1 (GLP-1).

INCRETIN= INtestinal+seCRETion of INsulin

GLP-1 and GIP Are Incretin Hormones

GLP-1 GIP Is released from L cells in ileum and

colon1,2

Is released from K cells in duodenum1,2

Stimulates insulin response from beta cells in a glucose-dependent manner1

Stimulates insulin response from beta cells in a glucose-dependent manner1

Inhibits gastric emptying1,2 Has minimal effects on gastric emptying2

Reduces food intake and body weight2

Has no significant effects on satiety or body weight2

Inhibits glucagon secretion from alpha cells in a glucose-dependent manner1

Does not appear to inhibit glucagon secretion from alpha cells1,2

1. Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606. 2. Drucker DJ. Diabetes Care. 2003;26:2929–2940.

The two primary incretin hormones are Glucagon-like Polypeptide -1 (GLP-1) and Gastric Inhibitory Polypeptide (GIP)

• Circulating GIP and GLP-1 levels are regulated by multiple factors2

– Low in the basal fasting state; they rise rapidly following a meal from neuronal, neuroendocrine, and direct nutrient stimulation of intestinal cells

1Wei Y, et al. FEBS Lett 1995;358:219–224; 2Drucker DJ. Diabetes Care 2003;26:2929–2940.

GLP-1 GIP30 amino acid peptide1 42 amino acid peptide2

Synthesised and released by L cells of ileum and colon2

Synthesised and released from K cells of jejunum and duodenum2

Sites of action1:Pancreatic β-cells and α-cellsGI tractCNSLungsHeart

Sites of action2:Pancreatic β-cellsAdipocytes

Incretin Physiology in Type 2 Diabetes Mellitus

GLP-1 & GIP Secretion inType 2 Diabetes Mellitus

0

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Time after start of meal, minutes

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P-1

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Type 2 diabetes, n=54

IGT, n=15

NGT, n=33

Decreased Postprandial Levels of the Incretin Hormone GLP-1 in Patients With Type 2 Diabetes

* * * * ** *

*P<0.05, Type 2 diabetes vs NGT. Reprinted with permission from Toft-Nielsen MB et al. J Clin Endocrinol Metab. 2001;86:3717–3723. Copyright © 2001, The Endocrine Society.

Meal Started

Meal Finished

(10-15)

Glucose-Dependent Insulinotropic Polypeptide (GIP) Response During OGTT

Gastric Inhibitory Polypeptide (GIP) Insulinotrophic polypeptide

• Type 2 diabetes patients are resistant to its action (high blood level), making it a less attractive therapeutic target.

• In contrast to GLP-1 levels, plasma GIP is increased in patients with T2DM during an OGTT, while the plasma insulin response is diminished. This suggests resistance to the stimulator effect of GIP on insulin secretion and, in fact, this has been demon-strated by Holst et al.

• Jones IR, Owens DR, Luzio S, et al. The glucose dependent insulinotropic polypeptide response to oral glucose and mixed meals is increased in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1989;32(9):668-677.

• Holst JJ, et al. Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans. Am J Physiol Endocrinol Metab 2004;287:199-206.

Insulin Secretion

β-Cell Neogenesis

β-Cell Apoptosis

Glucagon Secretion

Glucose Production

Heart

GI TractLiver

MuscleDrucker DJ. Cell Metab. 2006;3:153-165.

BrainAppetite

Cardioprotection

Cardiac Output GLP-1

Stomach

Gastric Emptying

Neuroprotection

Glucose Uptake

_

+

Summary of Pharmacologic Incretin Actions on Different Target Tissues

GLP-1 modes of action in humans

GLP-1 is secretedfrom the L-cellsin the intestine

This in turn…

• Stimulates glucose-dependent insulin secretion

• Suppresses glucagon secretion

• Slows gastric emptying

Long term effectsdemonstrated in animals…

• Increases beta-cell mass and maintains beta-cell efficiency

• Improves insulin sensitivity

• Reduces food intake

Upon ingestion of food…

Drucker DJ. Curr Pharm Des 2001; 7:1399-1412Drucker DJ. Mol Endocrinol 2003; 17:161-171

EVIDENCE?

GLP-1 effects are glucose-dependent in type 2 diabetes

Mean (SE); N = 10; *P < 0.05.Nauck MA, et al. Diabetologia 1993;36:741–744.

Glu

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PBOGLP-1

PBOGLP-1

PBOGLP-1

Placebo (PBO)GLP-1

Effect of GLP-1 (7-36)amide SC on Gastric Emptying

Subcutaneous injection of GLP-1 reduces the postmeal plasma glucose concentration, stimulates insulin secretion, and delays gastric emptying of a liquid meal.

Exenatide Increases Gastric Half-Emptying Time (T50) for Solid Meal (Tc-Labeled Eggs)

Exenatide causes a dose-response inhibition of gastric emptying of a solid meal.

GLP-1 Regulates Central Feeding Behavior

Intracerebroventricular injection of GLP-1 causes a dose-response decrease in food intake in rats. As shown in the insert in the upper right, GLP-1 receptors are abundant in the paraventricuar nucleus of the hypothalamus and the central nucleus of the amygdala.

Change in Body Weight Over 24 Weeks:Sitagliptin Monotherapy Studies

In a 24-week study, sitagliptin was shown to have no effect on body weight in patients with

T2DM.

Sitagliptin + Pioglitazone Are Weight Neutral Compared to Pioglitazone Alone in T2DM

Actions of GLP-1 The Problem

• Unfortunately, GLP-1 is rapidly broken down by the DPP-IV enzyme (very short half-life in plasma - requires continuous IV infusion).

The solution

Two options:

• Incretin mimetics are glucagon-like peptide-1 (GLP-1) agonists.

• Dipeptidyl peptidase-IV (DPP-IV) antagonists inhibit the breakdown of GLP-1.

What Is DPP-4?• A serine protease widely distributed throughout the body• Cleaves N-terminal amino acids of a number of biologically

active peptides, including the incretins GLP-1 and gastric inhibitory peptide (GIP), resulting in inactivation

• Its effects on GLP-1 and GIP have been shown to affect incretin activity

• Inactivates GLP-1 >50% in ~1 to 2 minutes

Ahrën B. Curr Enzyme Inhib. 2005;1:65-73.

DPP-4

Inhibition of DPP-4 Increases Active GLP-1

GLP-1 and GIP Are Degraded by the DPP-4 Enzyme

Meal

Intestinal GIP and GLP-1 release

GIP and GLP-1 Actions

DPP-4Enzyme

GIP-(1–42)GLP-1(7–36)

Intact

GIP-(3–42)GLP-1(9–36)Metabolites

Rapid Inactivation

Half-life*GLP-1 ~ 2 minutes

GIP ~ 5 minutes

Deacon CF et al. Diabetes. 1995;44:1126–1131.*Meier JJ et al. Diabetes. 2004;53:654–662.

Native GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4)

Human ileum, GLP-1 producingL-cells

Capillaries, DPP-4 (Di-Peptidyl Peptidase-4)

Double immunohistochemical staining for DPP-4 (red) and GLP-1 (green) in the human ileum

Adapted from: Hansen et al. Endocrinology 1999;140:5356–63

Food intake

Stomach

GI tract

Intestine

Increases and prolongs GLP-1 effect on alpha-cells:

Alpha-cells

Pancreas

Insulin release

Net effect: Blood glucose

Beta-cells

Increases and prolongs GLP-1 and GIP effects on beta-cells:

DPP-4 inhibitor

Glucagon secretion

Incretins

DPP-4

DPP-4 Inhibitors Enhance Incretin and Insulin Secretion

Adapted from: Barnett A. Int J Clin Pract 2006;60:1454-70 Drucker DJ, Nauck MA. Nature 2006;368:1696-705Idris I, Donnelly R. Diabetes Obes Metab 2007;9:153-65

Dipeptidyl Peptidase-IV Antagonists Sitagliptin and Vildagliptin

• Sitagliptin and vildagliptin are the first agents in this class to have received FDA approval.

• Incidence of adverse reactions was reported to be very low in a pooled safety data from 5141 patients. ADA meeting, Chicago, June 2007.

• They are indicated as monotherapy and in combination with metformin, thiazolidinediones and insulin.

• They look to be at least weight neutral.

Plasma Levels of Bioactive Intact GLP-1 (9-36)amide After Sitagliptin Administration in T2DM

Sitagliptin Reduces Glucose AUC After a Glucose Load

Sitagliptin Once Daily Improves Both Fasting and Postmeal Glucose Concentration

Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29(12):2632-2637. Aschner P, Kipnes MS, Lunceford JK, et al; Sitagliptin Study 021 Group

Part 3

Sitagliptin Monotherapy and Coadministration With Metformin

Sitagliptin monotherapy and metformin monotherapy produce similar reductions in A1C in patients with T2DM and, when given in combination, provide an additive effect to reduce A1C.

Sitagliptin: Proportion of Patients Achieving A1C Goals

Sitagliptin monotherapy and metformin monotherapy allow a similar percentage of participants with T2DM to achieve an A1C <7.0% and have an additive effect to reduce A1C to <7.0%. 

Sitagliptin: Active-Comparator (Glipizide) Add-on to Metformin

The addition of sitagliptin to metformin produces a similar decrease in A1C as the addition of glipizide to metformin over a 1-year period. 

Sitagliptin: Effect on Baseline A1C

The addition of sitagliptin to metformin produces a similar decrease in A1C, irrespective of the starting baseline A1C, as does the addition of glipizide to metformin over a 1-year period.

Clinical Adverse Events in Active-Comparator Add-on to Metformin Study

Patients With Adverse Events, n (%) Sitagliptin 100 mg

(n=588) Glipizide (n=584)

One or more AEs 419 (71.3) 444 (76.0)

Drug-related AEs 85 (14.5) 177 (30.3)

Serious AEs (SAEs) 43 ( 7.3) 44 ( 7.5)

Serious drug-related AEs 0 ( 0.0) 2 ( 0.3)

Died 1 ( 0.2) 2 ( 0.3)

Discontinued due to AEs 16 ( 2.7) 21 ( 3.6)

Discontinued due to drug-related AEs

8 ( 1.4) 8 ( 1.4)

Discontinued due to SAEs 6 ( 1.0) 7 ( 1.2)

Discontinued due to serious drug-related AEs

0 ( 0.0) 0 ( 0.0)

Stein P. ADA 66th Scientific Sessions; June 9-14, 2006; Washington DC. Late-breaking abstracts.

Sitagliptin has an excellent safety profile and is associated with significantly fewer drug-related adverse events than glipizide.

Sitagliptin and Measures of -Cell Function

Compared to placebo, sitagliptin therapy for 24 weeks reduced the proinsulin/insulin ratio and increased HOMA-beta, suggesting a beneficial effect on beta-cell function

Sitagliptin: B-Cell Response to Glucose

During the frequently sampled meal tolerance test (MTT) performed before and after 18 weeks, sitagliptin significantly augmented insulin secretion compared to the placebo-treated group.

Sitagliptin Studies: Summary1

As monotherapy, sitagliptin was as effective in reducing A1C as metformin and pioglitazone and was completely additive in decreasing A1C

when given to metformin-treated patients with T2DM.

Incretin mimetics

Exenatide

• The first incretin-related therapy available for patients with type 2 diabetes.

• Naturally occurring peptide from the saliva of the Gila Monster.

• Has an approximate 50% amino acid homology with GLP-1.

• Binds to GLP-1 receptors and behaves as GLP-1.

Incretin mimeticsExenatide

• Resistant to DPP-IV inactivation. Following injection, it is measurably present in plasma for up to 10 hours. Suitable for twice a day administration by subcutaneous injection.

Regul Pept. 2004;117:77-88.

Am J Health Syst Pharm. 2005;62:173-181.

ConclusionAs there is no proven link between use of incretin therapies and pancreatic cancer Diabetes UK does not advocate any change in its management. In particular, patients should NOT stop their medication unless advised to by their doctor. At the same time vigilance is required of patients on such therapies for any side effects suggestive of pancreatic disease. It also reminds clinicians and people with diabetes to be aware that incretin therapies are contraindicated in people with previous pancreatitis.

At this time, patients should continue to take their medicine as directed until they talk to their health care professional, and health care professionals should continue to follow the prescribing recommendations in the drug labels.

The mean age of included individuals was 52 years, and 57.45% were male. Cases were significantly more likely than controls to have hypertriglyceridemia (12.92% vs 8.35%), alcohol use (3.23% vs 0.24%), gallstones (9.06% vs 1.34), tobacco abuse (16.39% vs 5.52%), obesity (19.62% vs 9.77%), biliary and pancreatic cancer (2.84% vs 0%), cystic fibrosis (0.79% vs 0%), and any neoplasm (29.94% vs 18.05%). After adjusting for available confounders and metformin hydrochloride use, current use of GLP-1–based therapies within 30 days (adjusted odds ratio, 2.24 [95% CI, 1.36-3.68]) and recent use past 30 days and less than 2 years (2.01 [1.37-3.18]) were associated with significantly increased odds of acute pancreatitis relative to the odds in nonusers.

Considerations for Healthcare Professionals:•Be aware of the possibility for and monitor for the emergence of the signs and symptoms of pancreatitis such as nausea, vomiting, anorexia, and persistent severe abdominal pain, sometimes radiating to the back.•Discontinue sitagliptin or sitagliptin/metformin if pancreatitis is suspected.•Understand that if pancreatitis is suspected in a patient, supportive medical care should be instituted. The patient should be monitored closely with appropriate laboratory studies such as serum and urine amylase, amylase/creatinine clearance ratio, electrolytes, serum calcium, glucose, and lipase.•Inform patients of the signs and symptoms of acute pancreatitis so they are aware of and able to notify their healthcare professional if they experience any unusual signs or symptoms.

Advice:Health care person should honestly discuss with patient about risk of acute pancreatitis

The three organizations firmly believe that people taking these medications, or those who may consider taking them, should be informed of all that is currently known about their potential risks and advantages in order to make the best possible decisions about their treatment and care, in consultation with their health care providers. At this time, there is insufficient information to modify current treatment recommendations.

Old Antidiabetes drugs

Incretin

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