Incretin Based Therapy Of Type 2 Diabetes Mellitus 1
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Incretin Based Therapy Of Type 2 Diabetes Mellitus 1 Presentation Transcript

  • 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. Pathophysiology of Type 2 Diabetes
    • Insulin resistance.
    • Beta cell dysfunction.
  • 3. 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.
  • 4. 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
  • 5. 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.
  • 6. 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.
  • 7. 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.
  • 8. Pathophysiology of Type 2 Diabetes Other Factors
    • Two other factors:
    • - Glucagon.
    • - Gastric emptying.
  • 9. 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.
  • 10. 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.
  • 11.  
  • 12. 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.
  • 13. 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.
  • 14. 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).
  • 15. 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.
  • 16. 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) .
  • 17. 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.
  • 18. 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.
  • 19. 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
  • 20.  
  • 21. 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).
  • 22. 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.
  • 23. 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.
  • 24.  
  • 25. 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.
  • 26.  
  • 27. 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).
  • 28.  
  • 29. 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.
  • 30. 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.
  • 31. 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
  • 32. 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).
  • 33.  
  • 34. 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.
  • 35. 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).
  • 36. 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.
  • 37. 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.
  • 38. 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.
  • 39.  
  • 40. THANK YOU