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Journal Club
2007年９月６日 8:20-8:50
B棟８階 カンファレンス室
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
Steven E. Nissen, M.D., and Kathy Wolski, M.P.H.
From the Cleveland Clinic, Cleveland. Dr. Nissen at the Department of Cardiovascular
Medicine, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44195, or at
[email protected].
N Engl J Med
Volume 356(24):2457-2471
June 14, 2007
Effect of Rosiglitazone on the Risk of Myocardial Infarction
and Death from Cardiovascular Causes
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（0.88-2.39）
0.15
DREAM
15 / 2,635（0.57）
9 / 2,634（0.34）
1.65（0.74-3.68）
0.22
ADOPT
27 / 1,456（1.85）
41 / 2,895（1.44）
1.33（0.80-2.21）
0.27
1.43（1.03-1.98）
0.03
Overall
Death from cardiovascular causes
Small trials
combined
25 / 6,557（0.38）
7 / 3,700（0.19）
2.40（1.17-4.91）
0.02
DREAM
12 / 2,365（0.51）
10 / 2,634（0.38）
1.20（0.52-2.78）
0.67
ADOPT
2 / 1,456（0.14）
5 / 2,854（0.18）
0.80（0.17-3.86）
0.78
1.64（0.98-2.74）
0.06
Overall
Nissen SE.:N Engl J Med.356.2007.May 21.Online
FDA
the Drug Safety and Risk
Management Advisory Committee
2007.7.30 8:00~17:00（JST 7.30 21:00～31 7:00）
Results of FDA Meta-Analysis of 42 Randomized Trials
Comparing Rosiglitazone with Other Drugs or Placebo
Rosen C. N Engl J Med 2007;10.1056/NEJMp078167
Risk of Cardiac Events with Rosiglitazone and Pioglitazone
as Compared with Other Oral Antidiabetic Agents,
According to the WellPoint Observational Study
Rosen C. N Engl J Med 2007;10.1056/NEJMp078167
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
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
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
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
From FDA
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.
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.
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.
Incidence of Cardiovascular Event Rates*
Brophy, J. M. JAMA 2005;0:294.20.jed50074-3.
Copyright restrictions may apply.
Adv. Committee
23 members voted
Q1．Rosiglitazone increases cardiac risk in
patients with type 2 diabetes？
○For 20
×Against 3
Q2．Rosiglitazone should remain available to
physicians and patients？
○For 22
×Against 1 （weak）
・ label warnings ・ extensive educational efforts
From GlaxoSmithKline
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.
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
12% developed diabetes in 3.2 years
33% developed either diabetes or IFG
Recruited 11323 → 2139 diabetes
D.Mozaffarian et al.:
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 Mediterraneantype diet in patients with recent myocardial
infarction
CONCLUSION
Incidence of IFG and diabetes is
high in the years after
myocardial infarction, suggesting
that acute myocardial infarction
could be a prediabetes riskequivalent.
&
Mediterranean foods could
substantially lower this risk.