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The Rosiglitazone storm

The Rosiglitazone storm. Nabil Isseh, MD Damascus medical school. THANKS. What is the Most Common Cause of Death in People with Diabetes?. Mortality in People with Diabetes Causes of Death. % of Deaths. Ischemic heart disease. Other heart disease. Diabetes. Cancer. Stroke. Infection.

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The Rosiglitazone storm

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  1. The Rosiglitazone storm Nabil Isseh, MD Damascus medical school

  2. THANKS

  3. What is the Most Common Cause of Death in People with Diabetes?

  4. Mortality in People with DiabetesCauses of Death % of Deaths Ischemicheartdisease Otherheartdisease Diabetes Cancer Stroke Infection Other Geiss LS et al. In: Diabetes in America. 2nd ed. 1995; chap 11.

  5. Why new recommendations ? 2006 consensus IDF EASD ADA

  6. The Story of Rosiglitazone Money Medicine Politics

  7. The Origin of the RSG storm

  8. Glitazone in Diabetes Therapy May preserve B-cell function Protective CVD Effects The Impact on Clinical CVD endpoints!!

  9. Can any of the available treatments change the course of the disease?(i.e. preserve β cell function)

  10. Can the Glitazones Reduce CVD in diabetes?

  11. The insulin resistance syndrome and its components Central/abdominal obesity Hypertension Type 2 diabetes Insulin resistance syndrome Coronary heart disease Hyperinsulinemia Dyslipidemia Microalbuminuria Groop et al. Front Horm Res 1997; 22:131–156.

  12. Glitazones: potential Impact on CVD Risk Hyperglycemia BP TZD IR HDL and sdLDL Microalbuminuria PAI-1 CRP Vascular reactivity Atherosclerosis, CVD?

  13. WHEN ALL HELL BROKE LOOSE!

  14. N Engl J Med Effect Of Rosiglitazone on the risk Of Myocardial Infraction and Death From Cardiovascular Causes 23/5/2007

  15. A correction has been published: N Engl J Med 2007;357(1):100. Institution: Syrian Arab Republic | Sign In as Individual| Contact Subscription Administrator at Your Institution | FAQ Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes Steven E. Nissen, M.D., and Kathy Wolski, M.P.H

  16. Nissen Meta-Analysis 42 Studies Increased odds ratio of 1.43 for Acute MI risk And 1.64 for the risk of cardiac death NEJM May 21, 2007

  17. Nissen Analysis Weakness • No access of original source data: unable to perform time – to – end analysis. • The trials were not designed to explore CVD outcomes. • The number of adverse events were small. • Confidence intervals were very wide.

  18. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes Conclusions • Rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderlinesignificance Nissen, S.E. and Wolski, K., N Engl J Med 2007;356.

  19. …AND HELL BROKE LOOSE!

  20. Heart Attack Risk Seen in Drug for Diabetes May 22 2007

  21. Money Aspect of RSG Storm Deutsche Bank June 26, 2007 World wide sales $ 3.2 billion RSG prescriptin down 42% sales down 22% share price down

  22. The USA Congress Consistent concern about the possibility of increased CVD risk with RSG

  23. ADA Panel debate

  24. Perspectives - Rosiglitazone and CVD Science and Public Health

  25. Rosiglitazon The scientific and regulatory issues underlying the current controversy Steve E. Nissen MD ADA June Meeting 2007

  26. Rosiglitazon Registratione (May 1999) Major concerns had emerged about hepatic toxicity of troglitazone. FDA was eager to approve a “safer” alternative and rosiglitazone and pioglitazone appeared free of this life-threatening side effect. The registration “package” for rosiglitazone consisted of 5 trials (2902 patients), mostly short-term (24 weeks) glycemic control studies. The drug was presented to an FDA Advisory Panel on May 22, 1999. ADA June Meeting 2007

  27. Rosiglitazone Advisory Panel: CV Events Ischemic Heart Disease Events FED Reviewer “A post-marketing study to evaluate long” Term safety RSG should be required for approval. ADA June Meeting 2007

  28. Rosiglitazone Approval Issues In the initial studies submitted for approval, rosiglitazone increased LDL-cholesterol by 18.6% obviously a major concern in diabetic patients. The numerical excess of cardiovascular ischemic events and increase in atherogenic lipoproteins received little attention after initial approval. However, one individual, incoming ADA President John Buse, expressed concern at scientific meeting and wrote to the company and FDA. ADA June Meeting 2007

  29. Post-Registration Studies • No major cardiovascular outcome trial, but many small, generally short-term, efficacy studies conducted. • Three larger, longer term studies. • Dream: A three year 5000 patient, placebo-controlled, “diabetes prevention” trial (Lancent September 2006). • ADOPT: A four year, 4400 patient metforin and glyburide controlled study of glycemic durability, but no adjudication of cardiovascular events (NEJM December 2006). • RECORD: An open label, six year, 4400 patient, European regulatory cardiovascular outcome study (comparison with metformin/sulfonylurea) due in 2009. ADA June Meeting 2007

  30. DREAM: Major Cardiovascular Outcomes ADA June Meeting 2007

  31. ADOPT : Major Cardiovascular Outcomes ADA June Meeting 2007

  32. Rosiglitazone Staus: December 2006 Pooled “registration” trials showed a 1.8 fold higher rate of ischemic CV events with rosiglitazone compared with placebo or other agents. The DREAM Trial showed a 1.66 fold higher rate of MI with rosigltazone compared with placebo. The ADOPT Trial showed a 1.33 fold higher rate of MI with rosiglitazone compared with other agents. Although none of the individual studies reached statistical significance, the consistent pattern of excess myocardial infractions was very worrisome. ADA June Meeting 2007

  33. Meta-analysis NEJM-May 2007 With published data showing trends towards cardiovascular harm, further analysis warranted. Since available trials were too small to provide adequate power to answer this scientific question, a meta-analysis was the next logical step. Fortunately, as a result of a lawsuit by NY Attorney General Elliott Spitzer, GSK was required to publicly disclose all clinical trial results. This disclosure include 42 randomized studies (mostly unpublished) comparing rosiglitazone with other agents or placebo (> 24 weeks duration)> ADA June Meeting 2007

  34. Meta - analysis :Myocardial Infarction ADA June Meeting 2007

  35. Meta - analysis : Cardiovascular Death ADA June Meeting 2007

  36. Glaxo Smith Kline and FDA Analysis Near completion of our meta-analysis, we learned that GSK had performed a similar study (never published), initially in September 2005, updates in October 2006. Not including DERAM and ADOPT, the company’s own analysis showed a statistically significant 31 percent greater rate of “myocardial ischemic events”. The GSK analysis used the more powerful patient-level data not available in our meta-analysis. Recently, FDA announced that they had conducted their own independent meta-analysis, which showed “approximately 40%” greater rate of ischemic events. ADA June Meeting 2007

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