Pioglitazone appears to lower the risk of death, myocardial infarction, and stroke in diabetes patients, just the opposite of the closely related drug rosiglitazone, according to separate meta-analyses on the two agents.
It is not yet clear why these two thiazolidinediones may have such disparate effects on cardiovascular outcomes, the investigators said.
In one meta-analysis, Dr. A. Michael Lincoff and his associates at the Cleveland Clinic used data provided by Takeda Pharma, manufacturer of Actos, to assess pioglitazone's effect on the incidence of ischemic cardiovascular complications. They pooled data on 19 randomized, double-blinded, controlled clinical trials of the drug in 16,390 diabetes patients.
The investigators found that the composite outcome of death, myocardial infarction, or stroke was 18% lower in patients who took pioglitazone than in those who received placebo or other diabetes medications.
“The magnitude and direction of this protective effect … was homogeneous across trials of different durations ranging from 4 months to 3.5 years, across studies using a variety of control or concomitant diabetic therapies, and among trials of patients with and without established vascular disease,” Dr. Lincoff and his associates said (JAMA 2007;298:1180–8).
Like rosiglitazone, pioglitazone was found to raise the rate of congestive heart failure. However, it did not increase the incidence of heart failure mortality.
“These findings suggest that the net clinical cardiovascular benefit with pioglitazone therapy is favorable, with an important reduction in irreversible ischemic events that is not attenuated by the risk of more frequent heart failure complications,” Dr. Lincoff and his associates said.
In contrast, Dr. Sonal Singh of Wake Forest University, Winston-Salem, N.C., and his associates found in their meta-analysis that rosiglitazone significantly raised the risk of both myocardial infarction and heart failure.
This led them to conclude that “regulatory agencies ought to reevaluate whether rosiglitazone should be allowed to remain on the market.”
The researchers pooled the results of four randomized clinical trials of at least 1 year's duration (14,291 patients) and three systematic reviews to assess rosiglitazone's effect on MI, heart failure, and cardiovascular mortality.
The drug approximately doubled the risk of heart failure, and increased the risk of MI by 42%. However, it did not affect the risk of cardiovascular death.
“We estimate that there may be more than 3.5 million current users of rosiglitazone in the United States alone,” which may account for 4,000 excess MIs and 9,000 excess heart failure events among Americans each year, the researchers wrote (JAMA 2007;298:1189–95).
In August, the U.S. Food and Drug Administration announced that the labels of all thiazolidinediones will now carry a black box warning about the risk of heart failure.
“Health plans and physicians should not wait for regulatory actions. They should avoid using rosiglitazone in patients with diabetes who are at risk of cardiovascular events, especially since safer treatment alternatives are available,” Dr. Singh and his associates said.