Journal Club 亀田メディカルセンター 糖尿病内分泌内科 Diabetes and Endocrine Department, Kameda Medical Center 松田 昌文 Matsuda, Masafumi 2007 年９月６日 8:20-8:50 B 棟８階 カンファレンス室

Steven E. Nissen, M.D., and Kathy Wolski, M.P.H. N Engl J Med Volume 356(24): June 14, 2007 From the Cleveland Clinic, Cleveland. Dr. Nissen at the Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, or at

Study Rosiglitazone Group Control Group Odds Ratio （ 95% Cl ） P Value no. of events / total no. （ % ） Myocardial infarction Small trials combined 44 / 10,280 （ 0.43 ） 22 / 6,105 （ 0.36 ） 1.45 （ ） 0.15 DREAM 15 / 2,635 （ 0.57 ） 9 / 2,634 （ 0.34 ） 1.65 （ ） 0.22 ADOPT 27 / 1,456 （ 1.85 ） 41 / 2,895 （ 1.44 ） 1.33 （ ） 0.27 Overall 1.43 （ ） 0.03 Death from cardiovascular causes Small trials combined 25 / 6,557 （ 0.38 ） 7 / 3,700 （ 0.19 ） 2.40 （ ） 0.02 DREAM 12 / 2,365 （ 0.51 ） 10 / 2,634 （ 0.38 ） 1.20 （ ） 0.67 ADOPT 2 / 1,456 （ 0.14 ） 5 / 2,854 （ 0.18 ） 0.80 （ ） 0.78 Overall 1.64 （ ） 0.06 Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes Nissen SE.:N Engl J Med May 21.Online

FDA the Drug Safety and Risk Management Advisory Committee :00~17:00 （ JST :00 ～ 31 7:00 ）

Rosen C. N Engl J Med 2007; /NEJMp Results of FDA Meta-Analysis of 42 Randomized Trials Comparing Rosiglitazone with Other Drugs or Placebo

Rosen C. N Engl J Med 2007; /NEJMp Risk of Cardiac Events with Rosiglitazone and Pioglitazone as Compared with Other Oral Antidiabetic Agents, According to the WellPoint Observational Study

Center for Drug Evaluation and Research Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee July 30, 2007 Assessment of the cardiovascular risks and health benefits of rosiglitazone David J. Graham, MD, MPH Office of Surveillance and Epidemiology Food and Drug Administration July 30, 2007 David J. Graham, MD, MPH Office of Surveillance and Epidemiology Food and Drug Administration July 30, 2007

Center for Drug Evaluation and Research Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee July 30, 2007 Does CV risk with RSG differ from that with PIO? Yes From DREAM, relatively low-risk population: RSG increased risk by ~40% c/w PBO From PROactive, high risk population: PIO decreased risk by ~15% c/w PBO From RSG meta-analysis: RSG increased risk of serious IHD by ~40% c/w all comparators & by ~70% c/w PBO From PIO meta-analysis: PIO decreased risk by ~25% c/w all comparators From head-to-head GLAI: RSG increased risk 3.5-fold c/w PIO Yes From DREAM, relatively low-risk population: RSG increased risk by ~40% c/w PBO From PROactive, high risk population: PIO decreased risk by ~15% c/w PBO From RSG meta-analysis: RSG increased risk of serious IHD by ~40% c/w all comparators & by ~70% c/w PBO From PIO meta-analysis: PIO decreased risk by ~25% c/w all comparators From head-to-head GLAI: RSG increased risk 3.5-fold c/w PIO

Center for Drug Evaluation and Research Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee July 30, 2007 Summary of meta-analysis of pioglitazone clinical trials including PROactive Source: Takeda’s submission

Center for Drug Evaluation and Research Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee July 30, 2007

Center for Drug Evaluation and Research Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee July 30, 2007

Dr.Rosen also calls for approval of antidiabetic drugs based on long-term clinical outcomes, not on the surrogate of glycated hemoglobin, a measure of glycemic control. Although he does not describe a specific study, we assume he is suggesting that approval should require evidence that cardiovascular events, a major long-term complication of diabetes mellitus, are reduced. This change could have major implications for the availability of treatments for type 2 diabetes. From FDA

For new antidiabetic drugs, a reasonable approach might be to approve new entities on the basis of improved glycemic control and to ensure that well-designed, long-term studies comparing the new treatment with established therapy, with cardiovascular outcomes as end points of interest, are conducted in a timely manner after approval. From FDA

I disagree that this would delay the availability of new drugs for the treatment of type 2 diabetes. In fact, as noted in my article, larger phase 3 outcome trials for safety are critical before approval. I agree and have noted previously that it has yet to be demonstrated that any antidiabetic agent reduces macrovascular risk; furthermore, Joffe and colleagues are correct in stating that establishing the efficacy of any single drug for the treatment of type 2 diabetes by long-term comparison with multiple drugs is a formidable task.

Copyright restrictions may apply. Brophy, J. M. JAMA 2005;0: jed Incidence of Cardiovascular Event Rates*

Adv. Committee Q1 ． Rosiglitazone increases cardiac risk in patients with type 2 diabetes ？ Q2 ． Rosiglitazone should remain available to physicians and patients ？ ○For 20 ×Against 3 23 members voted ○For 22 ×Against 1 （ weak ） ・ label warnings ・ extensive educational efforts

Although the advisory committee voted 20 to 3 that rosiglitazone increases cardiac risk in patients with type 2 diabetes, many members of the committee made statements accompanying their votes that drew a distinction between the risk as compared with placebo and the risk as compared with other antidiabetic drugs. From GlaxoSmithKline

After carefully considering the evidence, the committee recommended by a vote of 22 to 1 that rosiglitazone should remain available to physicians and patients and that, as Dr. Rosen points out, physicians and patients should be educated and there should be additions to the label. GlaxoSmithKline has embraced these recommendations and is actively discussing with the FDA additional language for the label along with educational efforts to clarify the potential for myocardial ischemic events. From GlaxoSmithKline

What is missing from the end of that voting statement, however, is the question. Krall notes but does not elaborate on the greater ischemic risk consistently reported when the analyses were confined to trials comparing rosiglitazone with placebo only. Finally, Krall reports that epidemiologic studies found no statistical differences in the rates of myocardial infarction for rosiglitazone as compared with those for metformin or sulfonylureas; however, observational studies, whether from independent sources or from pharmaceutical sponsors, have notable limitations, particularly in terms of adjudication, when reporting very common events (e.g., angina) in large cohorts.

Labeling Issue Boxed Worning August 14, 2007

AIM to investigate the incidence of diabetes and IFG in a large cohort of patients who had had a myocardial infarction within the previous 3 months. and to assess the independent demographic, clinical, and lifestyle risk factors related to an increased risk.

METHODS Subjects: from GISSI-Prevenzione study, a randomised trial of fish oil and vitamin E in patients who had had a myocardial infarction. The baseline assessment was done on average 3·5 weeks (mean 25 days [SD 21]; <5 days in 14 people) after myocardial infarction. Participants were followed-up at regular clinic visits at 0.5, 1.0, 1.5, 2.5, and 3.5 years.

Baseline characteristics of non-diabetic patients with recent myocardial infarction

Time to development of new-onset diabetes or impaired fasting glucose D.Mozaffarian et al.: 12% developed diabetes in 3.2 years 33% developed either diabetes or IFG Recruited → 2139 diabetes

Risk factors for incident diabetes patients with recent myocardial infarction

Multivariable-adjusted relative risk of death associated with development of diabetes or IFG

Patients’ characteristics categorised by baseline consumption of a Mediterranean- type diet in patients with recent myocardial infarction

Incidence of IFG and diabetes is high in the years after myocardial infarction, suggesting that acute myocardial infarction could be a prediabetes risk- equivalent. & Mediterranean foods could substantially lower this risk. CONCLUSION