Incretin Based Therapy Of Type 2 Diabetes Mellitus 1


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Incretin Based Therapy Of Type 2 Diabetes Mellitus 1

  1. 1. 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
  2. 2. Pathophysiology of Type 2 Diabetes <ul><li>Insulin resistance. </li></ul><ul><li>Beta cell dysfunction. </li></ul>
  3. 3. Pathophysiology of Type 2 Diabetes Insulin Resistance <ul><li>Insulin Resistance starts very early in the course of the disease. </li></ul><ul><li>insulin resistance alone will not produce diabetes. If beta-cell function is normal, one can compensate for insulin resistance by increasing insulin secretion. </li></ul>
  4. 4. Pathophysiology of Type 2 Diabetes Beta cell defect <ul><li>all type 2 patients have at least a relative defect in both beta-cell function and mass. </li></ul><ul><li>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.] </li></ul><ul><li>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 </li></ul>
  5. 5. Pathophysiology of Type 2 Diabetes Beta cell defect <ul><li>IV glucose infusion to a nondiabetic individual results in a biphasic insulin response: </li></ul><ul><li>- Immediate first-phase insulin response in the first few minutes. </li></ul><ul><li>- Second-phase response, more prolonged. </li></ul>
  6. 6. Pathophysiology of Type 2 Diabetes Beta cell defect <ul><li>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. </li></ul><ul><li>Infusing insulin can only partially improve this condition. </li></ul>
  7. 7. Pathophysiology of Type 2 Diabetes Other Factors <ul><li>Historically, hyperglycemia in diabetes has been viewed as a failure of insulin-mediated glucose disposal into muscle and adipose tissue. </li></ul><ul><li>This looks to be an over simplification of a more complicated issue. </li></ul>
  8. 8. Pathophysiology of Type 2 Diabetes Other Factors <ul><li>Two other factors: </li></ul><ul><li>- Glucagon. </li></ul><ul><li>- Gastric emptying. </li></ul>
  9. 9. Pathophysiology of Type 2 Diabetes The Glucagon Factor <ul><li>In response to a carbohydrate-containing meal, individuals without diabetes not only increase insulin secretion but also simultaneously decrease pancreatic alpha-cell glucagon secretion. </li></ul><ul><li>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. </li></ul><ul><li>N Engl J Med. 1971;285:443-449. </li></ul>
  10. 10. Pathophysiology of Type 2 Diabetes The Glucagon Factor <ul><li>In contrast, the glucagon secretion in type 2 diabetics is not decreased, and may even be paradoxically increased. </li></ul><ul><li>These insulin and glucagon abnormalities produce an excessive postprandial glucose excursion. </li></ul><ul><li>more than 35 years ago, Roger Unger presciently stated, &quot;One wonders if the development of a pharmacologic means of suppressing glucagon to appropriate levels would increase the effectiveness of available treatments for diabetes”. </li></ul><ul><li>N Engl J Med. 1971;285:443-449. </li></ul>
  11. 12. Pathophysiology of Type 2 Diabetes The Gastric Emptying Factor <ul><li>Many factors can affect the rate of gastric emptying. </li></ul><ul><li>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. </li></ul><ul><li>Gastroenterology. 1990;98:A378. </li></ul>
  12. 13. Pathophysiology of Type 2 Diabetes One last observation <ul><li>In 1930 La Barre described a greater effect of oral rather parenteral glucose in increasing insulin secretion. </li></ul><ul><li>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. </li></ul><ul><li>J Clin Endocrinol Metab. 1986;63:492-498. </li></ul><ul><li>Incretin hormones were discovered during researchers trials to find out interpretation to this phenomenon which has been called the incretin effect. </li></ul>
  13. 14. What are incretins? <ul><li>Hormones produced by the gastrointestinal tract in response to incoming nutrients, and have important actions that contribute to glucose homeostasis. </li></ul><ul><li>Two hormones: </li></ul><ul><li>- Gastric inhibitory polypeptide (GIP) . - Glucagon-like peptide-1 (GLP-1). </li></ul>
  14. 15. What are incretins? Gastric Inhibitory Polypeptide (GIP) <ul><li>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. </li></ul>
  15. 16. What are incretins? Glucagon-like peptide-1 (GLP-1) <ul><li>a 30-amino acid peptide secreted in response to the oral ingestion of nutrients by L cells, primarily in the ileum and colon. </li></ul><ul><li>There are GLP-1 receptors in islet cells and in the central nervous system, among other places. </li></ul><ul><li>GLP-1 is metabolized by the enzyme dipeptidyl peptidase-IV (DPP-IV) . </li></ul>
  16. 17. Actions of GLP-1 <ul><li>It enhances glucose-dependent insulin secretion. </li></ul><ul><li>Inhibits glucagon secretion and therefore hepatic glucose production. </li></ul><ul><li>Slows gastric emptying. </li></ul><ul><li>Increases satiety resulting in less food intake. </li></ul><ul><li>Appears to stimulate insulin gene transcription and insulin synthesis. </li></ul>
  17. 18. Actions of GLP-1 <ul><li>In animal studies it increases beta-cell mass by: </li></ul><ul><li>- Decreasing beta cell apoptosis. </li></ul><ul><li>- Stimulating the growth of new beta cells. Diabetes Care. 2003;26:2929-2940. </li></ul><ul><li>???... Long term benefit in reversing the progressive insulin deficiency. </li></ul>
  18. 19. Actions of GLP-1 <ul><li>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 </li></ul>
  19. 21. Actions of GLP-1 The Problem <ul><li>Unfortunately, GLP-1 is rapidly broken down by the DPP-IV enzyme (very short half-life in plasma - requires continuous IV infusion). </li></ul>
  20. 22. The solution <ul><li>Two options: </li></ul><ul><li>Incretin mimetics are glucagon-like peptide-1 (GLP-1) agonists. </li></ul><ul><li>Dipeptidyl peptidase-IV (DPP-IV) antagonists inhibit the breakdown of GLP-1. </li></ul>
  21. 23. Incretin mimetics Exenatide <ul><li>The first incretin-related therapy available for patients with type 2 diabetes. </li></ul><ul><li>Naturally occurring peptide from the saliva of the Gila Monster. </li></ul><ul><li>Has an approximate 50% amino acid homology with GLP-1. </li></ul><ul><li>Binds to GLP-1 receptors and behaves as GLP-1. </li></ul>
  22. 25. Incretin mimetics Exenatide <ul><li>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 . </li></ul><ul><li>Regul Pept. 2004;117:77-88. </li></ul><ul><li>Am J Health Syst Pharm. 2005;62:173-181. </li></ul>
  23. 27. Clinical Trials of Exenatide <ul><li>Three pivotal randomized, double-blind, placebo-controlled, multicenter clinical trials were conducted to support the approval of exenatide (the AMIGO studies). </li></ul><ul><li>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. </li></ul><ul><li>Patients were randomized to two well matched groups to receive either placebo or exenatide (5 and 10 (mcg) twice daily by subcutaneous injection). </li></ul>
  24. 29. Weight Loss With Exenatide <ul><li>After adding exenatide: </li></ul><ul><li>the group that was on metformin alone lost about 3 kg of body weight at 30 weeks, </li></ul><ul><li>while the sulfonylurea group experienced a 1.5- to 2-kg weight reduction. </li></ul><ul><li>Patients receiving metformin and a sulfonylurea in combination along with exenatide lost an average of 2 kg. </li></ul><ul><li>Weight loss of up to 10 kg has been documented, but it varies from person to person. </li></ul><ul><li>recently published findings have shown progressive weight loss continuing for 82 weeks. Patients convenience </li></ul><ul><li>Diabetes Care. 2004;27:2628-2635, 2005;28:1092-1100, 2005;28:1083-1091. Diabetes, Obesity and Metabolism. 2006; 8(4):436; ISSN: 4. </li></ul>
  25. 30. Nausea With Exenatide <ul><li>was seen uniformly across the clinical trials, although most episodes were mild-to-moderate in intensity and generally intermittent. </li></ul><ul><li>more frequent at the initiation of treatment and decreased over the course of several weeks. </li></ul>
  26. 31. Incretin mimetics Recent Advances <ul><li>Liraglutide: Another GLP-1 analog with longer half-life, similar to exenatide with once-daily injection. Diabetes Care. 2007;30:1608-1610 </li></ul><ul><li>Long acting exenatide: Highly effective with once weekly injection. Diabetes Care. 2007;30:1487-1493 </li></ul>
  27. 32. Dipeptidyl Peptidase-IV Antagonists <ul><li>The concept is to allow the endogenous GLP-1 to remain in circulation for a longer period. </li></ul><ul><li>DPP-IV inhibitors are oral, rather than injectable. </li></ul><ul><li>Weight neutral. </li></ul><ul><li>associated with a low incidence of hypoglycemia or gastrointestinal side effects. Diabetes Care. 2004;27:2874-2880. </li></ul><ul><li>Preliminary long-term studies suggest a durable effect on glycemia and improvement in some parameters of beta-cell function. ( </li></ul>
  28. 34. Dipeptidyl Peptidase-IV Antagonists Sitagliptin and Vildagliptin <ul><li>Sitagliptin and vildagliptin are the first agents in this class to have received FDA approval. </li></ul><ul><li>Incidence of adverse reactions was reported to be very low in a pooled safety data from 5141 patients. ADA meeting, Chicago, June 2007 . </li></ul><ul><li>They are indicated as monotherapy and in combination with metformin, thiazolidinediones and insulin. </li></ul><ul><li>They look to be at least weight neutral. </li></ul>
  29. 35. Dipeptidyl Peptidase-IV Antagonists Recent Advances <ul><li>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…” </li></ul><ul><li>Some members seem particularly interesting as saxagliptin (? potent) and alogliptin (long acting… ? Better affecting fasting glucose). </li></ul>
  30. 36. Summary <ul><li>Insulin resistance and relative insulin secretory defect are key elements of the pathogenesis of type 2 diabetes. </li></ul><ul><li>GLP-1 deficiency is another key component in diabetic pathophysiology contributing to: </li></ul><ul><li>- insulin secretory deficit. </li></ul><ul><li>- excess of plasma glucagon. </li></ul><ul><li>- postprandial hyperglycemia. </li></ul>
  31. 37. Summary <ul><li>Incretin mimetics offer a new approach in the management of type 2 diabetes. </li></ul><ul><li>Exenatide is the first agent in this class and is administered via injection twice a day. </li></ul><ul><li>In addition to improving glycemic control, exenatide has the unique benefit of causing weight loss that appears to be prolonged based on initial studies. </li></ul>
  32. 38. Summary <ul><li>DPP-IV inhibitors raise GLP-1 levels 2- to 3-fold. </li></ul><ul><li>They appear to be weight neutral and have a remarkable low incidence of adverse reactions. </li></ul><ul><li>Sitagliptin ad vildagliptin are the first of the DPP-IV inhibitors to receive FDA approval. </li></ul><ul><li>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. </li></ul>
  33. 40. THANK YOU