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New Treatments for T2DM

New Treatments for T2DM. By:Dina Palmer Advisor: Robert Hadley Ph.D., PA-C . The doom of T2DM. 20.8 million Americans with diabetes 54 million with pre-diabetes Rise in all age groups due to aging of our population, increased obesity, and sedentary lifestyles

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New Treatments for T2DM

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  1. New Treatments for T2DM By:Dina Palmer Advisor: Robert Hadley Ph.D., PA-C

  2. The doom of T2DM • 20.8 million Americans with diabetes • 54 million with pre-diabetes • Rise in all age groups due to aging of our population, increased obesity, and sedentary lifestyles • Glycemic control of 7% A1C or less • These are our patients !

  3. Old and new drugs… • Combination therapy • Favorites: metformin, sulfonylureas, thiazolidinediones • New classes… • -DPP4 inhibitors: Sitagliptin (Januvia) and Vildagliptin (Galvus) • -GLP-1 agonists: Exenatide (Byetta) and Liraglutide • -Glitazars: Muraglitazar (Pargluva)

  4. DPP4 inhibitors • Sitagliptin (Januvia) and Vildagliptin (Galvus) • Incretins are hormones released by the GI tract in response to nutrient ingestion that stimulate beta cells to secrete insulin—these effects are diminished in T2DM • DPP4 is a protease that breaks down the endogenous incretin glucagon-like peptide (GLP)-1 • This class prevents the degradation of GLP-1 by competitively and reversibly inhibiting the protease DPP4, and leads to longer presence and actions of GLP-1 • SE: No weight gain! rare hypoglycemia. • Both to be used as a combination, both oral. Sitagliptin approved Fall 2006, Vildagliptin awaiting approval.

  5. GLP-1 agonists • Exenatide (Byetta) and Liraglutide • Exogenous GLP-1 products that are resistant to DPP4 degradation, same actions as the endogenous incretin. • Also known as incretin mimetics. • Exenatide a 2xd inj. approved 2005 for use with metformin and/or a sulfonylurea. SE: n/v/diar, hypoglyc (esp with sulfas), w. loss. Contra: GI dz, renal Cr <30mL/min. Current trials for once weekly injection. • Liraglutide is awaiting approval. Has longer half life than Byetta thus only requiring once daily injections. Same SE, no contraindications identified yet.

  6. Glitazars • Muraglitazar (Pargluva) • Approved by FDA, then withdrawn in Spring 2006. Other trials in this category are in progress. • Glitazars activate two subtypes of receptors called peroxisome proliferator–activated receptors (PPARs). • PPARgamma activation reduces insulin resistance and improves glycemic control, while activation of PPARalpha reduces triglycerides and increases HDL concentration by increasing fatty acid oxidation. • Oral dose. SE: w. gain, edema, low incidence of coronary and cerebral vascular events, possible congestive heart failure-FDA decided it was of enough significance.

  7. To sum up… • T2DM is growing. • Glycemic control is essential for preventing the microvascular complications of this disease including retinal, glomerular, and nerve changes, and for preventing diabetes progression. • Current treatments don’t always maintain glycemic control and some have unfavorable side effects (esp weight gain).

  8. References: • Ahrén B, Gomis R, Standl E, Mills D, Schweizer A.Twelve- and 52-week efficacy of the Dipeptidyl Peptidase IV Inhibitor LAF237 in Metformin-treated patients with type 2 diabetes. Diabetes Care 27(12):2874-2880, 2004. • Ahrén B, Pacini G, Foley JE, Schweizer A. Improved meal-related beta-cell function and insulin sensitivity by the Dipeptidyl Peptidase-IV Inhibitor Vildagliptin in Metformin-treated patients with type 2 diabetes over 1 year. Diabetes Care.  2005;28(8):1936-1940. • ADA. StandardsofMedicalCareinDiabetes–2006. DiabetesCare2006;29:S4-S42. • ADA. Standards of Medical Care in Diabetes-2007. Diabetes Care 2007:30:S4-41S. • ADA Total prevalence of diabetes and pre-diabetes. www.diabetes.org • Baggio LL, Drucker DJ . American Diabetes Association’s 66th Annual Scientific Sessions-Incretin-Based Therapies- Incretin analogs other than Exenatide. Medscape Diabetes & Endocrinology, Jul 25 2006. URL: http://www.medscape.com/viewarticle/540919, Accessed 11/29/06. • Baggio LL, Drucker DJ.Incretin Hormones in the Treatment of Type 2 Diabetes: Therapeutic Applications of DPP-IV Inhibitors.Medscape Diabetes & Endocrinology. Apr 2006. URL: http://www.medscape.com/viewarticle/530215, Accessed 11/20/06. • Brophy JM. Selling safety—lessons from muraglitazar. JAMA. 2005;294:2633-2635. • Cara JF. Type 2 diabetes mellitus in children. 2000 American Academy of Pediatrics Annual Meeting. Nov 2000. Medscape conference coverage. URL: http://www.medscape.com/viewarticle/420203, Accessed 12/2/06. • Craig CR, Stitzel RE. Modern Pharmacology with Clinical Applications. Lippincott Williams and Wilkins, 2004: 763-776. • Conlon D. Goodbye glitazars?. Br J Diabetes Vasc Dis.  2006;6(3):135-137. • Dale DC, Federman DD, Antman K, Atkinson JP, Cassel CK, Feldman M, et al. ACP medicine textbook. WebMD publishing, 2006: 615-649. • FDA approved drug products. www.fda.gov. • Gavin JR, Conner CS, Drucker DJ, Kahn SE. The clinical impact of incretin-based therapies on type 2 diabetes management, one year later. From the American Diabetes Association’s 66th Annual Scientific Sessions. Consensus medical communications. June 9, 2006. • Hansotia T, Drucker DJ. Therapeutic potential of the DPP-IV inhibitors. 65th Scientific Sessions of the American Diabetes Association. Medscape Diabetes & Endocrinology, Jul 2005. URL: http://www.medscape.com/viewarticle/508221, Accessed 11/29/06. • Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, MD, Fineman MS, et al.  Effects of Exenatide on glycemic control over 30 weeks in patients with type 2 diabetes treated with Metformin and a Sulfonylurea. Diabetes Care 2005;28 (5): 1083-1091. • Kendall DM, Rubin CJ, Mohideen P, Ledeine JM, Belder R, Gross J, et al. Improvement of glycemic control, triglycerides, and HDL cholesterol levels with muraglitazar, a dual (α/γ) peroxisome proliferator-activated receptor activator, in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Diabetes Care.  2006;29(5):1016-1023. • Merck & Co. Prescribing information. www.januvia.com. Merck & Co. 2006. • Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005;294:2581-2586. • Peters AL. American Diabetes Association’s 66th Annual Scientific Sessions-Incretin-Based Therapies-Exenatide. Medscape Diabetes & Endocrinology, Jul 25 2006. URL: http://www.medscape.com/viewarticle/540917, Accessed 11/29/06. • Retnakaran R, Drucker DJ. American Diabetes Association’s 66th Annual Scientific Sessions-Incretin-Based Therapies-DPP-IV Inhibitors. Medscape Diabetes & Endocrinology, Jul 25 2006. URL: http://www.medscape.com/viewarticle/540920, Accessed 10/31/06. • Riddle MC, Drucker DJ.Emerging therapies mimicking the effects of Amylin and Glucagon-Like Peptide 1. Diabetes Care.  2006;29(2):435-449. • Triplitt C, Chiquette E.Exenatide: from the Gila Monster to the pharmacy. J Am Pharm Assoc.  2006;46(1):44-55. • Triplitt C, Wright A, Chiquette E. Incretin mimetics and dipeptidyl peptidase-IV inhibitors: potential new therapies for type 2 diabetes mellitus. Pharmacotherapy Publications, 2006;26(3):360-374.

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