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

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

5. Ischemic heart disease % of Deaths Geiss LS et al. In: Diabetes in America. 2 nd ed. 1995; chap 11. Mortality in People with Diabetes Causes of Death Other heart disease DiabetesCancerStrokeInfectionOther

6. Why new recommendations ? 2006 consensus EASD ADA IDF

8. Money Medicine Politics The Story of Rosiglitazone

9. The Origin of the RSG storm

11. Glitazone in Diabetes Therapy 1.May preserve B-cell function 2.Protective CVD Effects 3.The Impact on Clinical CVD endpoints!!

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

15. Can the Glitazones Reduce CVD in diabetes?

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

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

20. WHEN ALL HELL BROKE LOOSE!

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

22. HOMEHOME | SUBSCRIBE | CURRENT ISSUE | PAST ISSUES | COLLECTIONS | HELP | Search Term Advanced SearchSUBSCRIBECURRENT ISSUEPAST ISSUESCOLLECTIONSHELPAdvanced Search Institution: Syrian Arab Republic | Sign In as Individual | Contact Subscription Administrator at Your Institution | FAQSign In as IndividualContact Subscription Administrator at Your InstitutionFAQ A correction has been published: N Engl J Med 2007;357(1):100. 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 Number 24 June 14, 2007 Volume 356:2457-2471

23. 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

24. Nissen Analysis Weakness 1.No access of original source data: unable to perform time – to – end analysis. 2.The trials were not designed to explore CVD outcomes. 3. The number of adverse events were small. 4.Confidence intervals were very wide.

25. 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 borderline significance Nissen, S.E. and Wolski, K., N Engl J Med 2007;356.

26. …AND HELL BROKE LOOSE!

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

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

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

34. ADA Panel debate

35. Rosiglitazone: The scientific and regulatory issues underlying the current controversy Steven Nissen, MD Rosiglitazone Panel John Buse, MD, PhD; Barry Goldstein, MD; Philip Home, MD; Richard Kahn, PhD; David Nathan, MD; Steven Nissen, MD Rosiglitazone and CV disease: does the RECORD study help? Philip Home, MD Perspectives - Rosiglitazone and CVD Science and Public Health

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

39. 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

40. Rosiglitazone Advisory Panel: CV Events Ischemic Heart Disease Events Relative RiskComparatorsRosiglitazone 1.8010/1452 (0.69%)36/2902 (1.24%) FED Reviewer “A post-marketing study to evaluate long” Term safety RSG should be required for approval. ADA June Meeting 2007

41. 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

42. 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

43. DREAM: Major Cardiovascular Outcomes P value HR (95% CI) Placebo N=2634 RSG n=2635 0.21.66(0.73-3.80)915MI 0.61.39(0.44-4.40)57Stroke 0.71.20(0.52-2.77)1012CV Death 0.017.03(1.6-30.9)214Adj CHF 0.51.2(0.66-2.17)2024New Angine 0.31.29(0.78-2.14)2735Revasc 0.081.37(0.97-1.94)5575Composite ADA June Meeting 2007

44. ADOPT : Major Cardiovascular Outcomes Myocardial Infarction P valueOdds Ratio Comparators Rosiglitazone 0.27 1.33 (0.80-2.21) 41/2895 (1.42%) 27/1456 (1.85%) ADA June Meeting 2007

45. 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

46. 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

47. Meta - analysis :Myocardial Infarction P valueOdds Ratio Control Group RSG 0.15 1.45 (0.88-2.39) 22/610644/10285 Small Trials 0.22 1.65 (0.74-3.68) 9/263415/2635DREAM 0.27 1.33 (0.80-2.21) 41/289527/1456ADOPT 0.03 1.43 (1.03-1.98) Overall ADA June Meeting 2007

48. Meta - analysis : Cardiovascular Death P valueOdds Ratio Control Group RSG 0.15 2.40 (1.17-4.91) 7/398025/6845 Small Trials 0.67 1.20 (0.52-2.78) 10/263412/2635DREAM 0.78 0.80 (0.17-3.86) 5/28952/1456ADOPT 0.06 1.64 (0.98-2.74) Overall ADA June Meeting 2007

49. 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

51. Risk of MI with RSG Nissen analysis 43% FDA 40% Glaxo 31% RECORD 11% ADA June Meeting 2007

52. Some final thoughts Nissen With the limitations of RECORD, in the year 2009, 10 years after the launch of rosiglitazone, We may still not know whether this agent benefits or harms patients with Type 2 diabetes. Accordingly, the three meta-analysis (GSK, FDA and NEJM) of all 42 rosiglitazone trials is the best data we are likely to have for the foreseeable future. Therefore, each physician must decide for themselves how to integrate these findings into their treatment decisions for individual patients. ADA June Meeting 2007

53. Professor Philip Home New Castle University, UK ADA June Meeting 2007

54. Rosiglitazone and CVD Science and Public Policy Rosiglitazone and CV disease Does the RECORD study help? Professor philip Home Newcastle Diabetes Centre Newcastle University UK

55. HOMEHOME | SUBSCRIBE | CURRENT ISSUE | PAST ISSUES | COLLECTIONS | HELP | Search Term Advanced SearchSUBSCRIBECURRENT ISSUEPAST ISSUESCOLLECTIONSHELPAdvanced Search Institution: Syrian Arab Republic | Sign In as Individual | Contact Subscription Administrator at Your Institution | FAQSign In as IndividualContact Subscription Administrator at Your InstitutionFAQ Rosiglitazone Evaluated for Cardiovascular Outcomes — An Interim Analysis Philip D. Home, D.M., D.Phil., Stuart J. Pocock, Ph.D., Henning Beck-Nielsen, D.M.S.C., Ramón Gomis, M.D., Ph.D., Markolf Hanefeld, M.D., Ph.D., Nigel P. Jones, M.A., Michel Komajda, M.D., John J.V. McMurray, M.D., for the RECORD Study Group Volume 357:28-38 July 5, 2007 Number 1

56. Nissen and Wolski Results OR rosiglitazone vs placebo or active comparator MI 1.43 (95% CI 1.03 to 1.98) P:0.03 CV death 1.64 (95% CI, 0.98 to 2.74), P:0.06 Problems: 42 studies – some excluded Many studies only zero or 1 report Events not endpoints, just investigator reports No time- to – events analysis Hypothesis generating not testing ADA June Meeting 2007

57. The RECOCRD Study Interim Analysis Why?? Not normally appropriate However:  Safety analysis prepared for the regulators were leaking into the press  Acute reaction to the Nissen/Wolski study began to lead to withdrawals 23 May – Steering Committee decision that publication of interim analysis lesser of the evils 05 June – Publication on line of revised paper after 8 reviewer report ADA June Meeting 2007

58. The RECORD Study Primarily a cardiovascular safety study People with Type 2 diabetes in 2001 – 2003 Primarily endpoints  A composite of cardiac and vascular outcomes  Active comparator study  Assessed for non-inferiority of rosiglitazone Add-on oral agents – combination therapy study Planned 6 years follow-up ADA June Meeting 2007

59. The RECORD Study interim analysis Adjudicated endpoints PHR(95%CI) Metf/SU (n) Rosi (n) NS1.08(0.89-1.31)202217Primary endpoint Death NS0.83(0.51-1.36)3529Cardiovascular causes NS0.93(0.67-1.27)8074Any cause NS0.97(0.73-1.29)9693CV death/MI/stroke NS1.16(0.75-1.81)3743Acute myocardial infarction 0.0062.24(1.27-3.97)1738Congestive heart failure ADA June Meeting 2007

61. RECORDE Study and Interim Analysis: Some Conclusions By comparison with other medications believed to improve cardiovascular outcome, rosiglitazone appears to behave similarly for CV-death, all cause death, and CV composite This suggests that rosiglitazone should still have a role in the glucose-lowering armoury A clinically significant increase in MI not causing death cannot be ruled out from the RECORD data The known problem of CHF is again confirmed RECORD should continue to its planned end ADA June Meeting 2007

62. CVD adverse events following percuteneous coronary revescularization Rosiglitazone Placebo n 102 98 Death/MI/stroke or recurrent ischaemia 30.4 31.4 Death/MI/stroke 6.4 11.9 Death 1.2 2.3 MI 5.2 8.4 Stroke 1.2 2.3 PPAR Study Bhatt et al Am Heart J 2007 Ischaemic events over 12 months (% patients) ADA June Meeting 2007

65. Rosiglitazone and Cardiotoxicity — Weighing the Evidence David M. Nathan, M.D Number 1 July 5, 2007 Volume 357:64-66 Next Previous Institution: Syrian Arab Republic | Sign In as Individual | Contact Subscription Administrator at Your Institution | FAQSign In as IndividualContact Subscription Administrator at Your InstitutionFAQ HOMEHOME | SUBSCRIBE | CURRENT ISSUE | PAST ISSUES | COLLECTIONS | HELP | Search Term Advanced SearchSUBSCRIBECURRENT ISSUEPAST ISSUESCOLLECTIONSHELPAdvanced Search

66. NEJM, June 5, 2007 The Jury David Nathan The Jury may still be out with regard to the cardio toxicity of rosiglitazone. But when it comes to patients safety, first do no harm, should outweigh any presumption of innocent. NEJM June 5, 2007

67. The Jury-David Nathan It is reasonable to ask whether physician should feel comfortable using a drug that might have an excess risk of CVD when other choices available, including Pioglitazone which has limited clinical trial data suggesting a Proactive CVD…. NEJM June 5, 2007

71. A Special FDA Advisory Panel Meeting July 31, 2007

72. 1.RSG increases the Cardiac Ischemic risk in Type II diabetes 2.The drug should stay on the market

73. More Risk – Subset Analysis 1.CHF 2.CHD 3.Taking Insulin 4.Taking Nitrate 5.Taking ACE – I 6.Taking Metformin And RSG

74. CHD CHF Insulin Nitrate

75. CHD CHF Insulin Nitrate

76. What about Pioglitazone?

77. Rosiglitazone vs Pioglitazone Class effect ?? 1.Lipids 2.PROactive 3.CHICAGO 4.FDA data Coke VS Pepsi

78. Risk of MI in Pioglitazone 1.FDA: unpublished data 2.Pioglitazone reduced MI risk by 22% FDA Advisory panel meeting July 31, 2007

80. Have Glitazones lost the throne?

81. Where I stand?

82. My Stand 1.RSG has proven glucose – lowering abilliteis 2.Long – established risks for CHF 3.It poses a small but significant risk of MI 4.Still useful but in very selective cases

83. A correction has been published: N Engl J Med 2007;356(13):1387. Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy Steven E. Kahn, M.B., Ch.B., Steven M. Haffner, M.D., Mark A. Heise, Ph.D., William H. Herman, M.D., M.P.H., Rury R. Holman, F.R.C.P., Nigel P. Jones, M.A., Barbara G. Kravitz, M.S., John M. Lachin, Sc.D., M. Colleen O'Neill, B.Sc., Bernard Zinman, M.D., F.R.C.P.C., Giancarlo Viberti, M.D., F.R.C.P., for the ADOPT Study Group Number 23 December 7, 2006 Volume 355:2427-2443 HOMEHOME | SUBSCRIBE | CURRENT ISSUE | PAST ISSUES | COLLECTIONS | HELP | Search Term Advanced SearchSUBSCRIBECURRENT ISSUEPAST ISSUESCOLLECTIONSHELPAdvanced Search Institution: Syrian Arab Republic | Sign In as Individual | Contact Subscription Administrator at Your Institution | FAQSign In as IndividualContact Subscription Administrator at Your InstitutionFAQ

86. Wonder drug Approved prematurely Caused undue harm to patients Rosen C N EJM – Aug, 2007 Conclusion RSG story