Incretin Based Therapy of Type 2 Diabetes Mellitus

BY

Prof. ADEL A EL-SAYED MDProf. of Internal Medicine

Sohag Faculty of Medicine

SOHAG

EGYPT

Pathophysiology of Type 2 Diabetes

• Insulin resistance.

• Beta cell dysfunction.

Pathophysiology of Type 2 Diabetes

Insulin Resistance

• Insulin Resistance starts very early in the course of the disease.

• insulin resistance alone will not produce diabetes. If beta-cell function is normal, one can compensate for insulin resistance by increasing insulin secretion.

Pathophysiology of Type 2 Diabetes

Beta cell defect• all type 2 patients have at least a relative defect in both

beta-cell function and mass. • Function: in the (UKPDS), newly diagnosed people with

diabetes had, on average, only about 50% of normal beta-cell function.[Diabetes. 1995;44:1249-1258 , Diab Res Clin Pract. 1998;40(suppl):S21-S25.]

• Mass: Autopsy studies comparing the volume of beta

cells in nondiabetic individuals with that of people with diabetes found a 41% decrease in beta-cell mass among people with type 2 diabetes

Pathophysiology of Type 2 Diabetes

Beta cell defect

IV glucose infusion to a nondiabetic individual results in a biphasic insulin response:

- Immediate first-phase insulin response in the first few minutes.

- Second-phase response, more prolonged.

Pathophysiology of Type 2 Diabetes

Beta cell defect

• This first-phase insulin response is absent in type 2 diabetic patients contributing to the excessive and prolonged glucose rise after a meal in those with diabetes Diabetologia. 2004;47(suppl 1):A279.

• Infusing insulin can only partially improve this condition.

Pathophysiology of Type 2 Diabetes

Other Factors

• Historically, hyperglycemia in diabetes has been viewed as a failure of insulin-mediated glucose disposal into muscle and adipose tissue.

• This looks to be an over simplification of a more complicated issue.

Pathophysiology of Type 2 Diabetes

Other Factors

• Two other factors:

- Glucagon.

- Gastric emptying.

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.

• 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”.

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

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

One last 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 o 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.

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).

What are incretins?

Gastric Inhibitory Polypeptide (GIP)

• Secreted by the K cells of the proximal gut. However, type 2 diabetes patients are resistant to its action (high blood level), making it a less attractive therapeutic target.

What are incretins? Glucagon-like peptide-1 (GLP-1)

• a 30-amino acid peptide secreted in response to the oral ingestion of nutrients by L cells, primarily in the ileum and colon.

• There are GLP-1 receptors in islet cells and in the central nervous system, among other places.

• GLP-1 is metabolized by the enzyme dipeptidyl peptidase-IV (DPP-IV) .

Actions of GLP-1

• It enhances glucose-dependent insulin secretion.

• Inhibits glucagon secretion and therefore hepatic glucose production.

• Slows gastric emptying. • Increases satiety resulting in less food

intake. • Appears to stimulate insulin gene

transcription and insulin synthesis.

Actions of GLP-1

• In animal studies it increases beta-cell mass by:

- Decreasing beta cell apoptosis. - Stimulating the growth of new beta

cells. Diabetes Care. 2003;26:2929-2940.

???... Long term benefit in reversing the progressive insulin deficiency.

Actions of GLP-1

• Important, as glucose levels approach the normal range, the GLP-1 effects on insulin stimulation and glucagon inhibition declined (glucose dependence - reduction of hypoglycemia. - therapeutic advantage) Diabetologia. 1993;36:741-744

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.

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 mimetics

Exenatide

• 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.

Clinical Trials of Exenatide

• Three pivotal randomized, double-blind, placebo-controlled, multicenter clinical trials were conducted to support the approval of exenatide (the AMIGO studies).

• patients with type 2 diabetes who had not achieved adequate glycemic control despite treatment with metformin, a sulfonylurea, or the combination of metformin and a sulfonylurea.

• Patients were randomized to two well matched groups to receive either placebo or exenatide (5 and 10 (mcg) twice daily by subcutaneous injection).

Weight Loss With Exenatide

After adding exenatide:• the group that was on metformin alone lost about 3 kg of

body weight at 30 weeks, • while the sulfonylurea group experienced a 1.5- to 2-kg

weight reduction. • Patients receiving metformin and a sulfonylurea in

combination along with exenatide lost an average of 2 kg.

• Weight loss of up to 10 kg has been documented, but it varies from person to person.

• recently published findings have shown progressive weight loss continuing for 82 weeks. Patients convenience

Diabetes Care. 2004;27:2628-2635, 2005;28:1092-1100, 2005;28:1083-1091. Diabetes, Obesity and Metabolism. 2006;

8(4):436; ISSN: 4.

Nausea With Exenatide

• was seen uniformly across the clinical trials, although most episodes were mild-to-moderate in intensity and generally intermittent.

• more frequent at the initiation of treatment and decreased over the course of several weeks.

Incretin mimetics Recent Advances

• Liraglutide: Another GLP-1 analog with longer half-life, similar to exenatide with once-daily injection. Diabetes Care. 2007;30:1608-1610

• Long acting exenatide: Highly effective with once weekly injection. Diabetes Care. 2007;30:1487-1493

Dipeptidyl Peptidase-IV Antagonists

• The concept is to allow the endogenous GLP-1 to remain in circulation for a longer period.

• DPP-IV inhibitors are oral, rather than injectable. • Weight neutral. • associated with a low incidence of hypoglycemia

or gastrointestinal side effects. Diabetes Care. 2004;27:2874-2880.

• Preliminary long-term studies suggest a durable effect on glycemia and improvement in some parameters of beta-cell function. (www.glucagon.com).

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.

Dipeptidyl Peptidase-IV Antagonists Recent Advances

• During the last ADA meeting in Chicago, Illiois, 22-26 June 2007, fifty-five presentations addressed 12 different DPP-IV inhibitors and “… more will be seen during the coming months…”

• Some members seem particularly interesting as saxagliptin (? potent) and alogliptin (long acting… ? Better affecting fasting glucose).

Summary

• Insulin resistance and relative insulin secretory defect are key elements of the pathogenesis of type 2 diabetes.

• GLP-1 deficiency is another key component in diabetic pathophysiology contributing to:

- insulin secretory deficit. - excess of plasma glucagon. - postprandial hyperglycemia.

Summary

• Incretin mimetics offer a new approach in the management of type 2 diabetes.

• Exenatide is the first agent in this class and is administered via injection twice a day.

• In addition to improving glycemic control, exenatide has the unique benefit of causing weight loss that appears to be prolonged based on initial studies.

Summary

• DPP-IV inhibitors raise GLP-1 levels 2- to 3-fold. • They appear to be weight neutral and have a

remarkable low incidence of adverse reactions. • Sitagliptin ad vildagliptin are the first of the DPP-

IV inhibitors to receive FDA approval. • these promising new therapies should be

undertaken in combination not only with existing oral antidiabetes medications as indicated, but also with other proven cardiovascular risk-reduction strategies, including lifestyle reduction and pharmacologic therapy, as needed.

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