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 Incretin Based Therapy Of Type 2 Diabetes Mellitus 1

Incretin Based Therapy Of Type 2 Diabetes Mellitus 1






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

    • 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
      • 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.