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Up Date of Sulfonylureas and Meglitinides in CLINICAL DIABETES

Explore the efficacy and side effects of sulfonylureas and meglitinides in the treatment of type 2 diabetes, based on the latest clinical findings and treatment algorithms. Learn about the mechanism of action, selectivity, and outcomes associated with these oral hypoglycemic drugs.

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Up Date of Sulfonylureas and Meglitinides in CLINICAL DIABETES

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  1. Up Date of Sulfonylureas and Meglitinidesin CLINICAL DIABETES F. Hadaegh Jan. 2017

  2. AGENDA • Available treatment algorithms for T2DM • Basic and clinical points • Review on available literatures • Efficacy • Side effects • outcomes • Take home message

  3. Available Treatment Algorithms for T2DM

  4. ADA/EASD position statement 2015 ADA/EASD position statement 2015 Inzucchiet al. Diabetes Care 2015;38:140-149

  5. Treatment of Type 2 Diabetes: IDF guidelines IDF Lifestyle measures Then, at each step, if not to target (generally HbA1c <7.0%) Consider first line Metformin Sulfonylurea or α-glucosidase inhibitor Consider second line Sulpholynurea Metformin[if not first line] α-glucosidase inhibitor or DPP-4 inhibitor or thiazolidinedione or Consider third line Basal insulin orpremix insulin α-glucosidase inhibitor or DPP-4 inhibitor or thiazolidinedione GLP-1 agonist or or Consider fourth line = usual approach Basal +meal-time insulin Basal insulin orPremix insulin [later basal + meal-time] = alternative approach ← IDF, International Diabetes Federation; DPP-4i, dipeptidyl peptidase-4 inhibitor; GLP-1, glucagon-like peptide-1 IDF Global Guideline for Type 2 Diabetes. http://www.idf.org/global-guideline-type-2-diabetes-2012

  6. Mechanism of Action • Two classes of oral hypoglycemic drugs directly stimulate release of insulin from pancreatic beta cells: the sulfonylureas and meglitinides.  • They work by stimulating insulin secretion so are useful only in patients with some beta cell function.

  7. GLICLAZIDE • Formula: C15H21N3O3S • Pancreatic cells-specific SU. J Clin Endo Metab. 2010; 95(11): 4993-5002.

  8. Mechanism Of Action • Gliclazide selectively binds to sulfonylurea receptors (SUR-1) on the surface of the pancreatic β-cells. • It was shown to provide cardiovascular protection as it does not bind to sulfonylurea receptors (SUR-2A) in the heart. Diabetologia.2001; 44(8): 1019–25.

  9. Meglitinides (Mechanism of action) •  Exert their effects via different pancreatic beta cell receptors, but they act similarly by regulating adenosine triphosphate (ATP)-sensitive potassium channels (K-ATP channels) in pancreatic beta cells, thereby increasing insulin secretion . • Meglitinideshave a rapid onset and short duration of action .They are administered with meals to reduce postprandial hyperglycemia.

  10. Which SU Should Be Used? • Individual SUs express a different selectivity for pancreatic and myocardial SU receptors. • Gliclazide seems the most selective with respect to pancreatic receptor stimulation. • Amongst other SUs, specifically advising Gliclazide is based on evidence from observational studies showing cardiovascular benefits of Gliclazide over other SUs.

  11. Up To Date

  12. Glycemic efficacy of SUF

  13. IF :16.59

  14. Annals internal medicine ,2016, IF :16,59

  15. April 2016

  16. Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007;  • SELECTION CRITERIA: We included randomised controlled, parallel or cross-over trials comparing at least 10 weeks of treatment with meglitinide analogues to placebo, head-to-head, metformin or in combination with insulin. • MAIN RESULTS: Fifteen trials involving 3781 participants were included. No studies reported the effect of meglitinides on mortality or morbidity. In the eleven studies comparing meglitinides to placebo, both repaglinide and nateglinide resulted in a reductions in glycosylated haemoglobin (0.1% to 2.1% reduction in HbA1c for repaglinide; 0.2% to 0.6% for nateglinide).

  17. Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007;  • Only two trials compared repaglinide to nateglinide (342 participants), with greater reduction in glycosylated haemoglobin in those receiving repaglinide. Repaglinide (248 participants in three trials) had a similar degree of effect in reducing glycosylated haemoglobin as metformin. • Weight gain was generally greater in those treated with meglitinides compared with metformin (up to 3 kg in three months). Diarrhoea occurred less frequently and hypoglycaemia occurred more frequently but rarely severely enough as to require assistance. • CONCLUSIONS:Meglitinides may offer an alternative oral hypoglycaemic agent of similar potency to metformin, and may be indicated where side effects of metformin are intolerable or where metformin is contraindicated. However, there is no evidence available to indicate what effect meglitinides will have on important long-term outcomes, particularly mortality.

  18. Sulfonylureas ,Weight and Hypo

  19. Sulfonylureas & weight

  20. Sulfonylureas & Hypoglycemia

  21. Administration in patients with low eGFR

  22. Review on The Evidences For CVD Safety

  23. J Clin Endo Metab 2010; 95:4993-5002

  24. Hypothesis • Poorer outcomes in the setting of MI are due to sulfonylurea toxicity, it may be related to the effect of sulfonylureas on K-ATP channels on cardiac cells and coronary vessels. • It is possible that the presence of sulfonylureas at the time of a myocardial infarction prevents adequate coronary vasodilation and thus may result in a larger area of myocardial damage.

  25. Hypothesis • Other hypotheses for the effect of SUF medications on cardiovascular events and mortality are interference with ischemic preconditioning or possible arrhythmogenic effects. • Newer sulfonylureas, such asgliclazide and glimepiride, are selective for the pancreatic sulfonylurea receptors over the cardiac receptors and do not appear to be associated with increased cardiovascular mortality compared with metformin or other diabetes medications, although direct controlled clinical trials have not been performed

  26. Zeller et al., J ClinEndocrinolMetab. 2010; 95(11):4993–5002

  27. In-hospital Complications in Diabetic Patients with Acute MI in patients on previous sulfonylurea therapy Lower risk in patients receiving Gliclazidevs. Glibenclamide persisted after multivariate adjustment Zeller et al., J ClinEndocrinolMetab. 2010; 95(11):4993–5002

  28. Cardiovascular Diabetology, 2010; 9:54.

  29. Diabetes medications and Cardiovascular outcomes after MI Jørgensen et al. Cardiovascular Diabetology2010; 9:54.

  30. Kaplan-Meier Composite EndpointCardiovascular Mortality & Non-fatal MI Treatment groups were baseline glucose-lowering drug monotherapy < 180 days prior to MI Jørgensen et al. Cardiovascular Diabetology2010; 9:54.

  31. Risk of Outcomes in CohortMetformin vs. SUs vs. Insulin • Gliclazide was the only sulfonylurea not associated with increased risk compared with metformin (HR 1.03 [0.88-1.22]). Jørgensen et al. Cardiovascular Diabetology2010; 9:54.

  32. Mortality and cardiovascular risk associated with all available ISs have been compared with metformin in a nation-wide study • A total of 107806subjects were included, of whom 9607 had previous MI • Patients were followed for up to 9 years (median 3.3 years) EHJ ,2011:IF :15

  33. ALL-cause Mortality

  34. Lancet Diabetes Endocrinol 2015; 3:43-51.

  35. Mortality Risk Among Sulfonylureas:a systematic review and network meta-analysis Cardiovascular-related mortality All-cause mortality Lancet Diabetes Endocrinol2015; 3:43-51.

  36. Ann Intern Med. 2016;164:740-751. doi:10.7326/M15-2650 www.annals.org

  37. 2016,IF:13.58

  38. Fig 3. Forest plots for all-cause mortality of sulfonylureas according to comparator (placebo/diet or active comparators). Rados DV, Pinto LC, Remonti LR, Leitão CB, Gross JL (2016) The Association between Sulfonylurea Use and All-Cause and Cardiovascular Mortality: A Meta-Analysis with Trial Sequential Analysis of Randomized Clinical Trials. PLOS Medicine 13(4): e1001992. doi:10.1371/journal.pmed.1001992 http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001992

  39. Fig 4. Forest plots for cardiovascular mortality of sulfonylureas according to comparator (placebo/diet or active comparators). Rados DV, Pinto LC, Remonti LR, Leitão CB, Gross JL (2016) The Association between Sulfonylurea Use and All-Cause and Cardiovascular Mortality: A Meta-Analysis with Trial Sequential Analysis of Randomized Clinical Trials. PLOS Medicine 13(4): e1001992. doi:10.1371/journal.pmed.1001992 http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001992

  40. Fig 5. Forest plots for all-cause and cardiovascular mortality of sulfonylureas as an add-on to metformin. Rados DV, Pinto LC, Remonti LR, Leitão CB, Gross JL (2016) The Association between Sulfonylurea Use and All-Cause and Cardiovascular Mortality: A Meta-Analysis with Trial Sequential Analysis of Randomized Clinical Trials. PLOS Medicine 13(4): e1001992. doi:10.1371/journal.pmed.1001992 http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1001992

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