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Incretin Based Therapy of Type 2 Diabetes Mellitus. BY Prof. ADEL A EL-SAYED MD Prof. 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.
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Incretin Based Therapy of Type 2 Diabetes Mellitus BY Prof. ADEL A EL-SAYED MD Prof. of Internal Medicine Sohag Faculty of Medicine SOHAG EGYPT
Pathophysiology of Type 2 Diabetes • Insulin resistance. • Beta cell dysfunction.
Pathophysiology of Type 2 DiabetesInsulin 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 DiabetesBeta 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 DiabetesBeta 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 DiabetesBeta 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 DiabetesOther 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 DiabetesOther Factors • Two other factors: - Glucagon. - Gastric emptying.
Pathophysiology of Type 2 DiabetesThe 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 DiabetesThe 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 DiabetesThe 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 DiabetesOne 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-1The 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 mimeticsExenatide • 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.
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 mimeticsRecent 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 AntagonistsSitagliptin 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 AntagonistsRecent 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.