Metformin
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metformin old drug new benefits

metformin old drug new benefits

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Metformin Presentation Transcript

  • 1. Metformin Old Molecule…. New Benefits Dr.T.V.Narayan Rao, M. D. E.S.I.Hospital, Andhra Hospitals
  • 2. Galega Officinalis, Goat’s rue, French Lilac, Italian Fitch, professor -weed
  • 3. History of metformin  Galega officinalis – known to reduce symptoms of DM in middle ages  Found to contain Guanidine in late 1800’s  Georges Tanret identified Galegine in 1920  Synthalin A & B – less Toxic – 1920’s  Advent of Insulin in 1930’s  Flumamine ( Dimethyl Biguanide ) – used for Influenza in Philippines
  • 4. History of Metformin  Jean Sterne – Aron Labs & Hopital Laennec in Paris – studied several Biguanides in 1956  Selected Metformin (DI methyl Biguanide)  Published  Ungar in 1957, named “Glucophage” – Phenformin in 1957  Mehnert - Buformin
  • 5. Jean Sterne (1909–1997)- the Hôpital Laennec in Paris
  • 6. Metformin History  Aron Labs acquired by Lipha Pharmaceuticals, now Merck  Metformin brought to US in 1995 under franchise to BMS  Introduced  US in UK in 1958, Canada in 1972 FDA approval in 1994!
  • 7. TYPE 2 DIABETES  On the verge of becoming a pandemic in India.  According to WHO reports    presently India has 32 million diabetic subjects projected to increase to 100 million i.e. a rise by 250 % by the year 2035. Life expectancy of people with diabetes is reduced by nearly eight years due to increased mortality. J Diabetes Sci Technol 2010;4(1):158–170, Medicine Update 2005,
  • 8. MANAGEMENT OF T2DM  The drug armamentarium has grown in recent years and now provides the physician with treatment regimens that can be tailored to the individual patient's needs AGENTS AVAILABLE CURRENTLY FOR MANAGEMENT OF T2DM Biguanides Sulfonylureas Meglitinide derivatives Alpha-glucosidase inhibitors Thiazolidinediones (TZDs) Glucagonlike peptide–1 (GLP-1) agonists Dipeptidyl peptidase IV (DPP-4) inhibitors Selective sodiumglucose transporter-2 (SGLT-2) inhibitors Amylinomimetics Insulins Bile acid sequestrants Dopamine agonists Lilian Rojas and Gomes Diabetology & Metabolic Syndrome 2013, 5:6, http://emedicine.medscape.com/article/117853-treatment#aw2aab6b6b2
  • 9. METFORMIN- FIRST LINE AGENT  50 year old molecule  Current guidelines from the ADA/EASD and the AACE/ACE recommend early initiation of metformin as a first-line drug for monotherapy and combination therapy for patients with T2DM  Lowers FPG 70 mg/dl  Decreases HbA1c level by 27.5% after 16 Weeks* by upto * Metformin & lifestyle interventions, ADA- EASDAmerican Diabetes Association/ European Association for the Study of Diabetes , AACE/ACE American Association of Clinical Endocrinologists/American College of Endocrinology, Arrigo F.G. Cicero et al. Arch Med Sci 2012 Oct; 907917, Clinical Diabetes April 2012 vol. 30 no. 2 72-75, J. Med. Invest. 59 : 166-173, February, 2012
  • 10. Mechanism of Action of Metformin Bailey CJ, Turner RC. N Engl J Med 1996;334:574-579.
  • 11. Contraindications for Metformin Bailey CJ, Turner RC. N Engl J Med 1996;334:574-579.
  • 12. CMAJ • AUG. 30, 2005; 173 (5)
  • 13. CMAJ • AUG. 30, 2005; 173 (5)
  • 14. Metformin – clinical usage • • • • • • Monotherapy or in combination with others Maximum daily dose is 2550 mgs Side effects are predominantly GI related Start with small dose and uptitrate Use sustained release preparations Size of the tablet ?
  • 15. Metformin in Diabetes/IGT 1.Metformin is documented to reduce CV events and mortality in Diabetes.
  • 16. REACH for metformin to reduce deaths in patients with diabetes and Atherothrombosis In patients with diabetes and documented Atherothrombosis, the use of metformin was associated with a significant 24% reduction in all-cause mortality after two years of follow-up, according to a subgroup analysis from a large registry study presented at the American Diabetes Association (ADA) 2010 Scientific Sessions.    Metformin showed - 24% reduced mortality These are very interesting results from an observational study. I think it's fascinating. Certainly, metformin appears to be very favorable with an impact on mortality.
  • 17. The Final Endorsement for Metformin in Vascular Protection…  Intensive metformin seems to reduce the risk for any clinical endpoint related to diabetes, death related to diabetes, all cause mortality & myocardial infarction.  Patients assigned to receiving metformin monotherapy showed a significant reduction from baseline for HbA1c, BMI/weight, cholesterol, LDL-c, TGs, insulin, DBP & increasing HDL-c.
  • 18. Improved CV outcomes with Metformin in T2DM: Plethora of Evidence STUDY MAIN FINDINGS Randomized Trials UKPDS 34 Reduced risk of macrovascular diabetic complications Kooy et al Reduced risk of composite of macrovascular events Observational Studies PRESTO Reduced risk of any clinical outcome, MI, Death Johnson et al 40% reduction in risk of death Reduced risk of mortality, hospitalization, cardiovascular death Eurich et al 30% reduction in risk of death, 17% reduction in risk of death or hospitalization Evans et al 3.7 fold lower risk of cardiovascular mortality REACH Registry 24% risk reduction in mortality in patients with atherothrombosis Clifford J Bailey, Ian W Campbell, Metformin: The gold standard
  • 19. METFORMIN - CARDIOPROTECTIVE EFFECTS Improves Decreases diastolic function  hyperglycemia  HDL-C  TC, VLDL, LDL-C  vascular relaxation  oxidative stress  tPA activity  PAI-1 levels  von Willebrand factor levels  platelet aggregation and adhesion Ann Intern Med 2002;137:25-33.
  • 20. METFORMIN – PROVIDES CARDIOVASCULAR PROTECTION  Reduces incidence of macro vascular events Rojas and Gomes Diabetology & Metabolic Syndrome 2013, 5:6
  • 21. Metformin in Diabetes/IGT 1.Metformin is documented to reduce CV events and mortality in Diabetes. 2.Metformin is known to prevent CV events in diabetic patients with cardiac disease undergoing intervention
  • 22. Survival Benefits of Metformin in ACS Patients Undergoing Coronary Intervention PRESTO Study a Retrospective analysis Diabetics with cardiac disease b requiring revascularisation Multiple Therapies (-) Metformin N=1110 Multiple Therapies (+) Metformin N=887 9 Month Follow-Up a Prevention of re-stenosis with tranilast and its outcomes trial b Previous MI (40%), previous PCI (55%), unstable angina (64%), CHF (11%) Coronary Intervention CABG, Angioplasty Final Visit Re-stenosis MI, Death Kao et al. Am J Cardiol 2004; 93: 1347-50
  • 23. Metformin Effect on Clinical Outcomes After Coronary Intervention 1.0 Proportion event-free a Metformin therapy n = 887 0.9 Other therapy n =1110 0.8 0.7 0.6 Kaplan - Meier analysis, p = 0.005 0.5 0 50 100 150 200 250 Days of Follow-up a From either revascularisation, MI or death Kao et al. Am J Cardiol 2004; 93: 1347-50
  • 24. Br J Diabetes Vasc Dis. 2007;7:204-210
  • 25. Metformin in Diabetes/IGT 1. Metformin is documented to reduce CV events and mortality in Diabetes. 1. Metformin is known to prevent CV events in diabetic patients with cardiac disease undergoing intervention 2. Metformin is known to prevent onset of diabetes in patients with IGT
  • 26. Diabetes Prevention Program: Benefit of Metformin in reducing progression to Type 2 Diabetes Cases/100 person-years Average follow-up of 2.8 years 12 Metformin reduced the incidence of developing diabetes by 31% as compared with placebo. 10  31%* 8 DPP Study showed that treatment with metformin was one 6  58%* of the highly effective means of delaying or preventing type 4 2 diabetes. 2 0 Placebo Metformin Intensive lifestyle *All pairwise comparisons significantly different by group; sequential log-rank test. The Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393.
  • 27. The cumulative incidence of Diabetes in Metformin group was 40.5% as compared to 55% in control group. The absolute & relative risk reduction with Metformin was 26.4% Control LSM Metformin LSM + Metformin Diabetologica. 2006;49:289-297
  • 28. Metformin in the IDPP Study  Metformin was effective to reduce the progression rate of IGT to diabetes in the Asian Indian population at a much smaller dose (500 mg/day) as compared to DPP (1700 mg/day).  Lower number of people needed to be treated with metformin to prevent 1 case of diabetes (6.9) as compared to the DPP (13.9). There was no additional benefit of combining metformin with LSM as compared to Metformin alone. The IDPP showed that Metformin used at lower doses was equally effective as LSM to prevent diabetes in Asian Indians at high risk. Diabetologia. 2006;49:289-297
  • 29.   3 RCTs varied in ethnicity of the population studied, in the rates of conversion to diabetes from prediabetes, and in the dose of metformin used Metformin significantly reduced the conversion from prediabetes to diabetes   NNT was between 7 and 14 for treatment over a 3-year period This was true at higher dosage (850 mg twice daily) and even lower dosage (250 mg 3 times daily). Can Fam Physician 2009;55:363-9
  • 30. Metformin in Prediabetes: ADA 2013 Endorsement  Role of Metformin in prevention or delay in progression of IGT to diabetes is well known & evidence based. Diabetes Care. 2013;36(Suppl 1):S11-S66
  • 31. Metformin in Prediabetes: AACE 2013 Endorsement AGI Endocrine Practice April, 2013; Vol 19(2)
  • 32. BMJ VOLUME 327 25 OCTOBER 2003 bmj.com
  • 33. Conclusions Metformin is an effective treatment for anovulation in women with polycystic ovary syndrome. Its choice as a first line agent seems justified, and there is some evidence of benefit on variables of the metabolic syndrome. No data are available regarding the safety of metformin in long term use in young women and only limited data on its safety in early pregnancy. It should be used as an adjuvant to general lifestyle improvements and not as a replacement for increased exercise and improved diet. BMJ VOLUME 327 25 OCTOBER 2003 bmj.com
  • 34. TAKE HOME MESSAGE Metformin  An old and widely accepted first line agent  Stands out not only for its antihyperglycemic properties but also for its effects beyond glycemic control such as improvements in endothelial dysfunction, hemostasis and oxidative stress, insulin resistance, lipid profiles, and fat redistribution.  High safety profile due to  Negligible risk of hypoglycemia in monotherapy  Few drug interactions of clinical relevance Lilian Beatriz Aguayo Rojas and Marilia Brito Gomes, Diabetology & Metabolic Syndrome 2013, 5:6
  • 35. TAKE HOME MESSAGE Metformin  The only oral antidiabetic agent to show a significant effect on CV risk  Has benefits beyond glucose lowering – reduces weight and improves lipid profile  Thus, Metformin is OLD but GOLD  Small tablet size is preferred by both patients and doctors & helps improve adherence to therapy  Technologically advanced Metformin XR may the ideal choice, when you need to prescribe Metformin
  • 36. “The right dose differentiates a poison from a useful medicine” Theopharastus Bombastus von Hohenhein Better Known as Paracelsus (1493 – 1541) Swiss Physician
  • 37. “I wish to say what I think and feel today with the proviso that tomorrow probably I shall contradict it all” – Ralph Waldo Emerson Thank you