Research finds drugs cut cardiac risk for diabetics

Insulin sensitizers are poised to become standard medications to reduce the risk of coronary events in patients with Type 2 diabetes, said researchers at the American Heart Association's Scientific Sessions 2005, held recently in Dallas.

In a secondary analysis of PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events), a trial conducted at 321 medical centers throughout Europe, the insulin-sensitizing agent pioglitazone (Actos, Takeda) significantly reduced the risk of a second coronary event in patients with Type 2 diabetes.

"This is the first drug in diabetes which has been shown ... to decrease mortality, myocardial infarction [MI]), and acute coronary syndrome [ACS]," said Erland Erdmann, M.D., lead investigator of the study and a professor of medicine at the University of Cologne in Germany. "I think it is of utmost importance that this drug lowers cardiovascular risks, especially in those patients who have the most serious prognosis."

The PROactive study included 2,445 patients with Type 2 diabetes and a previous MI who were randomized to pioglitazone or placebo in addition to optimal standard therapy with antidiabetic, lipid-modifying, and antihypertensive medications. Fifty-five percent of the study group were on statin therapy at baseline, which increased to 63% by study's end, said Erdmann.

Patients were followed for a mean of 2.85 years, at which time pioglitazone was associated with a 28% reduction (p = 0.045) in the incidence of a second MI and a 37% reduction (p = 0.035) in occurrence of ACS. There was also a 19% reduction (p = 0.034) in the risk of the cardiac composite endpoint composed of nonfatal MI, coronary revascularization, ACS, and cardiac death.

It should be noted that the larger PROactive study population included 5,238 high-risk patients. In the larger trial, the results of which were announced at the 41st annual meeting of the European Association for the Study of Diabetes in Athens, pioglitazone was associated with a 10% reduction in the primary endpoint of seven different macrovascular events, but it failed to reach statistical significance (p = 0.095), whereas the combined risk of death, MI, and stroke, a secondary endpoint, was reduced by a significant 16% (p = 0.027) with pioglitazone.

In another study comparing rosiglitazone and metformin in 92 patients with suboptimally controlled Type 2 diabetes, rosiglitazone (Avandia, GlaxoSmithKline) was associated with a reduction in carotid atherosclerosis of 0.037 mm, as measured by carotid intima-media thickness (CIMT), whereas CIMT progressed in the metformin group by 0.084 mm; p = 0.02 for the between-group comparison. The difference occurred despite similarly significant improvements in glycemic control, said Allen J. Taylor, M.D., director of cardiovascular research at Walter Reed Army Medical Center in Washington, D.C.

The fibric acid derivative fenofibrate (Tricor, Abbott) failed to significantly reduce the incidence of total coronary events in patients with Type 2 diabetes but significantly reduced the risk of total cardiovascular events, said Anthony Keech, M.D., lead investigator of the FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study. FIELD included 9,795 Type 2 diabetes patients who have well-controlled glucose levels who were treated once daily with micronized fenofibrate, 200 mg, or placebo for five to seven years. None of the patients enrolled had a clear indication for lipid-modifying therapy, and more than three fourths (78%) had no history of cardiovascular disease.

Although fenofibrate reduced the risk of total coronary events by 11% compared with placebo, the difference failed to achieve statistical significance (p = 0.16). Twice as many patients randomized to placebo had statin therapy initiated during the trial. When adjusting for this difference in drop-in statin use, fenofibrate was associated with a significant 19% reduction in coronary events (p = 0.01), noted Keech, professor of medicine at the University of Sydney, Australia.