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AHA: More Evidence Against Broad Cardiovascular Risk with Pioglitazone

Nov 13, 2007

Pioglitazone (Actos) appeared, at worst, neutral for cardiovascular risk, except heart failure, in yet another meta-analysis examining thiazolidinedione safety.

Pioglitazone did not increase risk of MI, stroke, revascularization, death, or various combinations thereof, according to the five-trial meta-analysis reported here at the American Heart Association meeting.
Nagapradeep Nagajothi, M.D., of the Rosalind Franklin University of Medicine and Science in North Chicago, Ill., reports that neither did it significantly reduce risk aside from unstable coronary syndromes (P=0.039) and stroke and MI combined (P=0.024).

Nevertheless, they concluded that their findings supported those of a much larger but less specific meta-analysis that appeared in the September issue of the Journal of the American Medical Association.

The JAMA analysis suggested an 18% reduction in risk of MI, stroke, or death with the drug (P=0.02). (See: Ups and Downs of Thiazolidinediones for Diabetes Assessed by Dueling Meta-Analyses)

"These are two comparable studies that show similar results," Dr. Nagajothi said.
But despite the researchers’ enthusiasm, the results were suggestive rather than confirmatory.
The meta-analysis included five randomized controlled trials with a total of 9,965 patients in which MI outcomes were reported for pioglitazone monotherapy.

The comparison drug was metformin or gliclazide in one trial, glyburide in another, and glimepiride (Amaryl) in a third. Two trials used placebo as the comparator arm. Study duration ranged from six to 34.5 months.

Comparing pioglitazone with controls, the findings included:  MI risk was 14% lower, though not significantly.  Stroke risk was 21% lower with a trend for significance.  Revascularization risk was 60% lower but still not significant. All-cause mortality was similar between treatment groups.  The combined endpoint of stroke, MI, revascularization, and death was 37% lower.  MI and unstable angina together were significantly reduced and that sroke and MI together were significantly reduced as well .

The flurry of cardiovascular risk studies sparked by a meta-analysis in the New England Journal of Medicine that suggested rosiglitazone (Avandia) increased MI risk by 43% have consistently found an increased risk of heart failure, so the researchers did not look at that outcome.

However, the heart failure risk for pioglitazone may be related to fluid retention rather than damage to the heart muscle itself, other researchers have suggested. (See: This Time It’s A Draw for Rosiglitazone (Avandia) and Pioglitazone (Actos))
The differences seen in cardiovascular risk between the drugs suggest that there is not a class effect, which might be explained by pioglitazone’s relatively more favorable effects on lipids, Dr. Nagajothi said.
"Thiazolidinediones turn on or off more than 100 genes each, which are not identical," he added.
Practice Pearl:

Explain to interested patients that the thiazolidinediones pioglitazone and rosiglitazone do appear to carry a risk of heart failure, but this study supports that other cardiovascular risks may be different between the two.

Nagajothi N, et al "Pioglitazone and cardiovascular outcomes" AHA meeting 2007; Abstract 3732.


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