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Newer Therapies For Diabetes

Newer Therapies For Diabetes. By Dr. Ganapathi. B Prof & head Dept. of Endocrinology St. johns Medical college, Bangalore. INTRODUCTION :. Discovery of insulin - Banting and Best in 1922 The last decade has witnessed an explosion in newer therapeutics. Inhaled/oral Insulin,

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Newer Therapies For Diabetes

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  1. Newer Therapies For Diabetes By Dr. Ganapathi. B Prof & head Dept. of Endocrinology St. johns Medical college, Bangalore

  2. INTRODUCTION : • Discovery of insulin - Banting and Best in 1922 • The last decade has witnessed an explosion in newer therapeutics

  3. Inhaled/oral Insulin, Gut Peptides Detemir -2004 Aspart - 2002 Where Are We Now ? Glargines - 2000 Glinides - 2001 Glitazones - 1998 Lispro - 1996 Metformin - 1995 Human Insulin - 1981 Sulfonylureas -1956 Animal insulin- 1922

  4. Need for Newer drugs : • Current therapies for T 2 DM • Associated with • Inadequate control of PP glucose • weight gain • In the case of oral agents, loss of efficacy over time.

  5. Newer Drugs : • Incretins : • 1) Amylin analogs - Pramlintide • 2) Glucagons-like petide-1 & it’s analogs-exenatide, Liraglutide • 3) Dipeptidyl peptidase IV inhibitors- sitagliptin, saxagliptin • B) Glitazars : Muraglitazar, Tesaglitazar & Ragaglitazar • C)SGLT2 inhibitors-TI095 • D) Insulin Analogs : • 1) Inhaled Insulins -Exubra, • 2) Oral Insulins- Hexyl insulin , Oralin

  6. Newer Drugs : • INGAP (Islet Neogenesis Gene-Associated Protein) : • Bromocriptine • Salicylates- studies have described both inhibitory effects on hepatic glucose production and improved insulin action from inhibition of the kinases IKK-B (inhibitor of B) and IKK-A (inhibitor of A) involved in tissue inflammation.

  7. Newer Drugs : • Colesevelam Hydrochloride-Potential explanations include the following: 1) bile acid sequestrants act in the gastrointestinal tract, reducing the amount of glucose absorbed and/or altering the time course of glucose absorption and/or 2) bile acid sequestrants bind bile acids, thus disrupting the enterohepatic pathway of bile metabolism, which has indirect effects on glucose metabolism 3)bile acids are endogenous ligands of the farnesoid X receptor (FXR), a member of the nuclear receptor superfamily of ligand-activated transcription factors that play an important role in bile acid, cholesterol, and glucose metabolism. Diabetes is associated with a dysregulation of FXR expression.

  8. INCRETINS :

  9. Increntins are gut derived hormones • Enhance insulin secretion after oral glucose ingestion • Inhibit GI motility, induce satiety • Promote insulin mediated glucose uptake • GLP-1 accounts to 70 to 80 % incretin secretion • It maintains normoglycemia in non diabetic individuals • Has potential use in diabetics

  10. GLP 1 AGONISTS :

  11. GLP 1 AGONISTS :

  12. Plasma GLP-1 cons in T2DM patients, NGT and IGT during a 240-min meal test NGT T2DM (J Clin Endocrinol Metab 86: 3717–3723, 2001) IGT

  13. GLP 1 AGONISTS :…… • Enhances insulin secretion •  upper GI motility • Induces satiety • Promotes insulin mediated glucose uptake

  14. GLP 1 AGONISTS : • Inhibits glucagon secretion • Possibly stimulates islet cell growth • GLP-1 has short half life : 4- 11 mins • Clearance rate 13ml/kg/min • Exendin – 4 & Liraglutide are GLP-1 Analogs • Exendin-4 (FDA approved in April 2005) & Liraglutide (FDA approved in 2009) are GLP 1 analogs

  15. GLP 1 AGONISTS :…….. • Effectively controls postprandial glucose • Associated with weight loss • Subcutaneous injections – major drawback • Anti-apoptotic effects and - cell neogenesis • Clinically significant hypoglycemia - rare • Mainly GI Side effects

  16. GILA MONSTER

  17. Exenatide : • 39 aas , derived from Gila monster • Whole spectrum of action of GLP-1 • 5 – 10 mcg OD or BID • Effective in Post Prandial glucose than Fasting • Has completed exentive Phase 3 trials • Can be used to adjunct to oral agents • Side effects similar to GLP-1

  18. U.S. Clinical Trials of Exenatide: Summary of Selected Outcomes

  19. Liraglutide :

  20. Liraglutide : • Replicates all metabolic activities of GLP-1 • Half – life : 12 to 14 hrs • Reduces FPG and PPPG • Can be used with OHA • No side effects beyond GLP-1 • Low risk of hypoglycemia and weight gain

  21. Nauck & colleage • 144 subjects • Liraglutide monotherapy or add on to metformin • Dose titrated from 0.5 to 2mg/day – 5 wks • HbA1c reduced by 1.1% • 2.4 % wt loss

  22. Improved Glycemic Control in T 2 DM With Liraglutide (NN2211) STEN MADSBAD, et all .DIABETES CARE, VOLUME 27, NUMBER 6, JUNE 2004

  23. Amylin Analog :

  24. Amylin & It’s Analogs :…. • Amylin (37 aa peptide) is a pancreatic -cell hormone • Co-packed and co-secreted with insulin • Secretion delayed or diminished in T2 DM • Absent in T1 DM

  25. Metabolic effects : • Endogenous glucagon esp postprandial • Post prandial HGO • Delays gastric emptying • Induces centrally mediated satiety •  Postprandial glucose levels

  26. Amylin Analog :…….. • Naturally available Amylin, Unstable, tends to aggregate • Difficult to formulate, manufacture & store • Hence it’s analog Pramlintide which has better physical properties & similar efficacy • Pramlintide is an analog of human amylin • 30-120 g S.C. thrice daily at or just before meals

  27. Amylin Analog :…….. • Shown modest effect on glycemic control in both T1 & T2 DM • Used as an adjunct to Insulin • Produces wt loss • Reduces postprandial TGL and Glucagon • Phase 2 & 3 trials • Currently approved as an adjunct therapy by US FDA • Has role in predominantly postprandial hyperglycemia

  28. Pramlintide as an Adjunct to Insulin Therapy improves Long-Term Glycemic and Weight Control in Patients With Type 2 Diabetes. PRISCILLA A. HOLLANDER, MD.et.all .Diabetes Care 26:784–790, 2003

  29. Pramlintide as an Adjunct to Insulin Therapy improves Long-Term Glycemic and Weight Control in Patients With Type 2 Diabetes. PRISCILLA A. HOLLANDER, MD.et.all .Diabetes Care 26:784–790, 2003

  30. Amylin Analog :…….. concerns are: • Nausea, anorexia, rarely vomiting • Early satiety • Hypoglycemia • Additional injections • Can’t be mixed with insulins

  31. DPP- IV INHIBITORS :

  32. DPP- IV INHIBITORS :…. • DPP-IV is an endopeptidase, which rapidly degrades GLP-1 • DPP-IV Inhibitors block GLP-1 degradation • Increases incretin effect • Preserves 1st & 2nd phase of insulin secretion • Controls both fasting & postprandial glucose levels

  33. Most of the DPP-4 inhibitors are structurally distinct. • Alogliptin is a quinazolinone-based compound, • linagliptin is a xanthine derivative, • saxagliptin is a hydroxyadamantyl compound, • sitagliptin is a triazolepyrazine compound, and vildagliptin • and saxagliptin are pyrrolidine-carbonitrile compounds. • Dutogliptin and linagliptin are in phase 3 studies

  34. DPP- IV INHIBITORS :……. • Promising oral agents • Can be used as monotherapy or as adjunctive • Has weight neutrality • Long term consequences – unclear • Short term trials have shown good tolerability • Incidence of hypoglycemia -rare

  35. GLITAZARS :….. • Seems to be promising agent for type 2 D.M as adjuncts • They ameliorate Insulin Resistance, Potent hypolipidemic agents • Possibly weight neutrality • Useful in Metabolic syndrome • Prevention of Type 2 D.M • Muraglitazar is in Phase III trial and may become available widely in future.

  36. GLITAZARS :

  37. GLITAZARS :….. • Combined  and  peroxisome proliferator activator receptor agonists • Muraglitazar, Tesaglitazar & Ragaglitazar • Superior to currently available Glitazones • Controls hyperglycemia and hyper triglyceridemia • It up regulates LPL activity • Has antiproliferative property, Corrects endothelial dysfunction &  blood pressure • May retard atherosclerotic vascular process

  38. SGLT 2 Inhibitors • SGLTs cotransport sodium and glucose into cells using the sodium gradient produced by sodium/potassium ATPase pumps at the basolateral cell membranes. • They belong to the SLC5 gene family, which has nine members with known functions. • Of these, six are plasmamembrane sodium/substrate cotransporters for solutes such as glucose, myoinositol, and iodide (SGLT 1-6). • SGLT1 is primarily expressed in the small intestine but is also found in the trachea, kidney, and heart, and its predominant substrates are glucose and galactose.

  39. SGLT2 is expressed in the S1 and S2 segments of the proximal convoluted tubules and is responsible for renal reabsorption of glucose.

  40. SGLT1 gene mutations lead to glucose-galactose malabsorption, which causes potentially fatal diarrhea. • The oral rehydration therapy that saves millions of lives from infectious diarrhea works via SGLT1 transporters in the enterocytes. • evidence for SGLT2 being a major pathway for renal glucose reabsorption comes from genetic studies of individuals with familial renal glucosuria

  41. Mutations in the SLC5A2 gene encoding SGLT2 lead to familial renal glucosuria, • autosomal recessive trait • normal blood glucose levels, • normal oral glucose tolerance test results, and isolated persistent glucosuria. • Individuals who were found to be carriers of two mutated alleles showed severe glucosuria, defined by a urinary glucose of more than 10 g/1.73 m2 per 24 h (55 mmol/1.73 m2 per 24 h).

  42. homozygous group had plasma renin and serum aldosterone concentration raised to an average of 4.6- and 3.1-fold, respectively, suggesting activation of compensatory mechanisms

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