A. Michael Lincoff, Kathy
Wolski, Stephen J. Nicholls and Steven E. Nissen
ABSTRACT
THIAZOLIDINEDIONES
ARE AGOnists of the peroxisome proliferation–activated receptor _(PPAR-_),
which regulate transcription of a variety of genes encoding proteins involved
in glucose homeostasis and lipid metabolism.1,2 By virtue of their efficacy in
achieving glycemic control, the thiazolidinediones pioglitazone and
rosiglitazone are both widely used to treat patients with type 2 diabetes
mellitus. Although these agents can cause peripheral edema and congestive heart
failure,3,4 their beneficial effects on glucose metabolism and insulin
sensitivity have stimulated interest that thiazolidinediones might reduce
ischemic cardiovascular complications of diabetes mellitus.
However,
a recent meta-analysis of 42 trials comparing rosiglitazone with placebo or
active comparators in more than 27 000 patients with diabetes suggested that
treatment with rosiglitazone was associated with an increased risk of
myocardial infarction and cardiovascular death.5 Furthermore, a previous
analysis had demonstrated that muraglitazar, an investigational dual agonist of
both _- and _-isoforms of
Context
Pioglitazone is widely used for glycemic control in patients
with type 2 diabetes mellitus, but evidence is mixed regarding the influence of
medications of this class on cardiovascular outcomes.
Objective
To systematically evaluate the effect of pioglitazone on
ischemic cardiovascular events.
Data
Sources and Study Selection A database containing
individual patientlevel time-to-event data collected during pioglitazone clinical
trials was transferred from the drug’s manufacturer for independent analysis.
Trials were included if they were randomized, double-blinded, and controlled
with placebo or active comparator.
Data
Extraction The primary outcome was a composite of death, myocardial
infarction, or stroke. Secondary outcome measures included the incidence of
serious heart failure. A fixed-effects approach was used to combine the
estimates across the duration strata and statistical heterogeneity across all
the trials was tested with the I2 statistic.
Data
Synthesis A total of 19 trials enrolling 16 390 patients were analyzed. Study
drug treatment duration ranged from 4 months to 3.5 years. Death, myocardial infarction,
or stroke occurred in 375 of 8554 patients (4.4%) receiving pioglitazone and
450 of 7836 patients (5.7%) receiving control therapy (hazard ratio [HR], 0.82;
95% confidence interval [CI], 0.72-0.94; P=.005). Progressive separation
of time-to-event curves became apparent after approximately 1 year of therapy. Individual
components of the primary end point were all reduced by a similar magnitude
with pioglitazone treatment, with HRs ranging from 0.80 to 0.92. Serious heart
failure was reported in 200 (2.3%) of the pioglitazone-treated patients and 139
(1.8%) of the control patients (HR, 1.41; 95% CI, 1.14-1.76; P=.002).
The magnitude and direction of the favorable effect of pioglitazone on ischemic
events and unfavorable effect on heart failure was homogeneous across trials of
different durations, for different comparators, and for patients with or
without established vascular disease. There was no evidence of heterogeneity
across the trials for either end point (I2=0%; P=.87 for the
composite end point and I2=0%; P=.97 for heart failure).
Conclusions
Pioglitazone is associated with a significantly lower risk of
death, myocardial infarction, or stroke among a diverse population of patients
with diabetes. Serious heart failure is increased by pioglitazone, although
without an associated increase in mortality.
Keywords : Pioglitazone, ower risk of death, myocardial infarction, stroke, patients with diabetes, Risk of Cardiovascular Events, ischemic cardiovascular events, pioglitazone clinical trials, serious heart failure
Sumber : JAMA,
September 12, 2007—Vol 298, No. 10
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