GLIPTINS – CURRENT STATUS AND FUTURE PRO

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Information about GLIPTINS – CURRENT STATUS AND FUTURE PRO
Science-Technology

Published on July 7, 2009

Author: drapande

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GLIPTINS – CURRENT STATUS AND FUTURE PROSPECTS : GLIPTINS – CURRENT STATUS AND FUTURE PROSPECTS ARINDAM PANDE PGT, DEPT. OF MEDICINE MEDICAL COLLEGE, KOLKATA BASICS REVISITED--HYPERGLYCEMIA IN T2DM : BASICS REVISITED--HYPERGLYCEMIA IN T2DM Insulin resistance in peripheral tissues. Insufficient pancreatic ß-cell function. Increased hepatic glucose output due to ? insulin and ? glucagon – primarily contributing to fasting hyperglycemia. Major Pathophysiologic Defects in Type 2 Diabetes : Major Pathophysiologic Defects in Type 2 Diabetes Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168; Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781; Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254. Hepatic glucose output Insulin resistance Glucose uptake Glucagon (a cell) Insulin (ß cell) Hyperglycemia Islet-cell Dysfunction Pancreas Control of insulin responsiveness : Control of insulin responsiveness HISTORY.. : HISTORY.. Publication by Moore, Edie and Abram, entitled “On the treatment of diabetes mellitus by acid extract of duodenal mucous membrane” in 1906. Bajaj and Chhina proposed in 1976 the existence of ‘Entero-hypothalamo-insular’ axis. THE INCRETINS : THE INCRETINS Incretin effect, demonstrated in 1964. Glucose dependent insulinotropic polypeptide (GIP, previously named gastro inhibitory polypeptide), a 42 amino acid peptide, isolated in1970. Glucagon-like peptide1(GLP-1) and its truncated form GLP-1(7-36), a 30 amino acid peptide hormone, discovered in 1985. GLP-1 receptors demonstrated in the stomach, intestine and CNS, in addition to their presence in kidney, heart and lungs. Glucose-dependent release in gut tissue : Glucose-dependent release in gut tissue Biological effects of incretins : Biological effects of incretins Gastric inhibitory peptide, also glucose- dependent insulinotropic peptide Slide 10: Dipeptidyl peptidase 4 PHYSIOLOGICAL ACTIONS OF GLP-1 : PHYSIOLOGICAL ACTIONS OF GLP-1 ? glucose dependent insulin secretion. ? glucagon secretion. Enhances insulin gene transcription and ? insulin biosynthesis. Enhances cellular transformation from pancreatic ductal tissues to ß-cell tissue. ? ß-cell mass by cellular neogenesis and proliferation. Inhibits ß-cell apoptosis. Stimulates somatostatin secretion. Induce satiety through entero-hypothalamo-insular axis. THERAPEUTIC OPTIONS : THERAPEUTIC OPTIONS Circulating GIP levels normal or high in T2DM, indicating possible GIP resistance. Circulating GLP-1 levels significantly reduced in T2DM. Why there a defect in the incretin effect in T2DM remains to be fully resolved. GIP does not affect pancreatic a-cells secretion of glucagon, nor does it delay gastric emptying. Slide 13: To circumvent the problem of rapid inactivation of GLP-1, two strategies successfully explored— --Use of DPP-4 resistant GLP-1 receptor agonists (GLP-1 mimetics). e.g.- Exenatide, Liraglutide, ExenatideLAR. --Use of DPP4 inhibitors, thus prolonging the action of endogenously released incretin hormones. DPP4 INHIBITORS : DPP4 INHIBITORS In human, they ? PP as well as fasting level of circulating active GLP-1, with preserved circadian rhythm. Also ? levels of active GIP. Sitagliptin approved by the FDA in October’2006 and in the UK in April’2007. Several other inhibitors in various phases of development. --Collectively these are often termed gliptins and categorized as incretin enhancers. Status Of DPP4 Inhibitors : Status Of DPP4 Inhibitors Mechanism of Action of Sitagliptin : Mechanism of Action of Sitagliptin Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels increase in response to a meal. Release of active incretins GLP-1 and GIP ? Blood glucose in fasting and postprandial states Ingestion of food ? Glucagon (GLP-1) ? Hepatic glucose production GI tract DPP-4 enzyme Inactive GLP-1 X Sitagliptin (DPP-4 inhibitor) ? Insulin (GLP-1 andGIP) Glucose- dependent Glucose dependent Pancreas Inactive GIP ß cells a cells ? Glucose uptake by peripheral tissues SITAGLIPTIN : SITAGLIPTIN Successfully investigated both as monotherapy as well as in combination with either metformin or thiazolidinedione or insulin. If used in combination with sulphonylurea(SU), the dose of SU should be lowered to ? the risk of SU-induced hypoglycemia. Effectiveness of treatment not affected by the age of the patient or the degree of obesity. SITAGLIPTIN : SITAGLIPTIN Can be taken with or without food. C/I– in ketoacidosis, pregnancy and breast feeding. Dose-- 100mg once daily. If creatinine clearance <50ml/min—50mg OD If creatinine clearance <30ml/min—25mg OD S/E-- Upper RTI, peripheral edema, osteoarthritis, anorexia, headache, dizziness. VILDAGLIPTIN : VILDAGLIPTIN Equally encouraging result both as monotherapy, or in combination. Improves ß-cell function without increase in absolute plasma insulin level (Garber et al). Dose– 100mg (in two equally divided doses). When used in combination with sulphonylurea, the dose should be 50mg. u : u Slide 22: The Combination of Sitagliptin and Metformin Addresses the 3 Core Defects of Type 2 Diabetes in a Complementary Manner HGO=hepatic glucose overproduction. Aschner P et al. Diabetes Care. 2006;29:2632–2637; Abbasi F et al. Diabetes Care. 1998;21:1301–1305; Inzucchi SE. JAMA 2002;287:360–372; Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33; Zhou G et al. J Clin Invest. 2001;108:1167–1174. 22 CONCERNS : CONCERNS DPP4 also cleaves other bioactive peptides with alanin or proline as the second amino acid from amino-terminal end. Possibility of the side effects due to accumulation of physiologically important peptides such as NPY (neuropeptide Y), gastrin releasing peptide and substance P among others. However, till date no such adverse effects reported in experimental animal studies or in the clinical studies in human. CONCERNS : CONCERNS DPP4 also an immune T-cell activating antigen CD26. Whether long term administration result in any organ-specific immune mediated pathological alterations? Long-term follow-up and chronic toxicology studies in appropriate animal models required. COST FACTOR : COST FACTOR In India and other developing countries, cost factor needs to be seriously considered. Present cost of 100mg of Sitagliptin approximates Rs. 42/- per day (Merck US price:$185.25 per 30 tablets). Vildagliptin 100mg- Rs. 70/- per day. FUTURE PROSPECTS : FUTURE PROSPECTS Clinically, the most pertinent and relevant question in a newly diagnosed patient with T2DM– How best we can preserve ß-cell mass & function and prevent progressive ß-cell failure? What is the clinical relevance of the experimental studies which show an enhanced ß-cell mass with the use of incretins? Whether the early introduction of gliptins will preserve and protect ß-cell function? FUTURE PROSPECTS : FUTURE PROSPECTS Related corollary is the possible role of incretins in impaired fasting glycemia (IFG) & impaired glucose tolerance (IGT). Will early use prevent or delay the progression of early stages to overt T2DM? Considering the safety & cost effectiveness, will such therapeutic interventions be superior to life-style modification alone or with metformin? Slide 28: “---There seems to be light at the end of the tunnel, albeit the tunnel is undoubtedly very long…” FUTURE PROSPECTS : FUTURE PROSPECTS Only the long-term studies with incretin may provide realistic answer to these basic questions. Indian data regarding gliptins also required. CONCLUSION : CONCLUSION Gliptins are still now not an automatic choice in the management of T2DM. They can only be used in a selective group of uncontrolled T2DM patients as add-on drugs. There is no suggestion of their use in T1DM. CONCLUSION : CONCLUSION But, in spite of very limited experience with the use of these drugs, the future potential seems to be convincing. The possibilities that one of the gliptins may emerge as a first-line treatment in combination with metformin in newly diagnosed patients with T2DM remains distinctly plausible and may materialize into recommended future guidelines. Slide 32: Any questions?

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