SOURCE: Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016;374:1321-1331.

In addition to traditional risk factors for cardiovascular (CV) events (e.g., hyperlipidemia, hypertension, cigarette smoking), it has not gone unnoticed that insulin resistance, even in the absence of frank diabetes, also is associated with stroke and myocardial infarction (MI). Might a pharmacologic agent that improves insulin resistance be effective in secondary prevention of CV events?

Kernan et al performed a randomized, double-blind, placebo-controlled trial of adults who had sustained a stroke or transient ischemic attack (n = 3,876) to compare pioglitazone, an agent that improves insulin sensitivity, to placebo. Diabetic patients were excluded; rather, inclusion criteria required that patients demonstrate insulin resistance (as measured by the HOMA-IR metric), but did not meet criteria for diabetes. The primary outcome was fatal or nonfatal stroke or MI.

At 4.8 years, subjects who had been treated with pioglitazone experienced a 24% relative risk reduction in the primary endpoint (9% vs. 11.8%). Additionally, pioglitazone served well as a tool to prevent progression to diabetes by reducing incident diabetes more than 50% (3.8% vs. 7.7%). There was a trend toward lower mortality in the pioglitazone group that did not achieve statistical significance.

Before making an abrupt practice change based on this study, it is important to note that the incidence of fracture requiring surgery or hospitalization statistically significantly increased in the pioglitazone treatment arm (5.1% vs. 3.2%). Hence, the absolute reduction in CV events (almost 3%) is nearly offset by the increase in fractures (nearly 2%). Arguably, elimination of a major CV event substantially outweighs a new bone event, but clinicians should consider such adverse events in their therapeutic decision process, especially in patients acknowledged to be at high risk for fracture.