Thiazolidinediones cause metabolic changes that might reduce risk for macrovascular complications in patients with type 2 diabetes. In this international study, funded and partially conducted by the manufacturer of the thiazolidinedione pioglitazone, researchers randomized 5238 patients (mean age, 62; 99% white) with type 2 diabetes (hemoglobin A1c >6.5% despite treatment) and advanced macrovascular disease to receive placebo or pioglitazone (maximum, 45 mg daily). All patients received other oral hypoglycemic agents and insulin as needed to reduce HbA1c below 6.5%, as well as optimal antihypertensive, antiplatelet, and antihyperlipidemic therapies.
During a mean follow-up of 35 months, the median decrease in HbA1c was significantly greater with pioglitazone than with placebo (–0.8% vs. –0.3%), and significantly fewer pioglitazone patients started chronic insulin therapy. At the final visit, the pioglitazone group had a significantly lower median triglyceride level and LDL/HDL ratio than did the placebo group, although the median LDL level had risen significantly more with pioglitazone. The incidence of the composite endpoint of death, nonfatal myocardial infarction, or stroke was significantly lower with pioglitazone than with placebo (12% vs. 14%). The incidence of heart failure was significantly higher with pioglitazone (11% vs. 8%), but heart failure–related mortality did not differ between the groups.
In these patients with type 2 diabetes and advanced macrovascular disease, pioglitazone appeared to reduce risk for new cardiovascular events; whether this effect was mediated by better glycemic control or other metabolic changes is unclear. Heart failure remains a worrisome side effect with pioglitazone and other thiazolidinediones.
Reference:
Dormandy JA et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): A randomised controlled trial. Lancet 2005 Oct 8; 366:1279-89.