RECORD Confirms Climb in HF Risk With Rosiglitazone

February 11, 2010

February 11, 2010 (Sophia Antipolis, France) — A secondary analysis of a high-profile randomized trial concluded that the risk of heart-failure events in diabetics goes up when rosiglitazone (Avandia, GlaxoSmithKline) is added to standard glucose-lowering monotherapy, either metformin or a sulfonylurea [1].

It's well recognized that the insulin-sensitizing thiazolidinediones (TZDs), primarily rosiglitazone and pioglitazone (Actos, Takeda Pharmaceuticals), promote water retention, and there are abundant data suggesting they can induce new or aggravate existing heart failure.

So a twofold increase in risk of heart-failure death or hospitalization observed in the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial comes as not a surprise but as further support for treatment guidelines that already recommend against using rosiglitazone in diabetics with heart failure, according to Dr Michel Komajda (Université Pierre et Marie Curie, Paris, France) and colleagues in a study published online January 29, 2010 in the European Heart Journal.

On the other hand, the results can also be seen as validating cautions against rosiglitazone as add-on therapy even in diabetics without heart failure. A 2007 interim analysis of the trial also pointed to a doubling of heart-failure risk associated with the TZD.

RECORD randomized 4447 type 2 diabetics to receive either rosiglitazone (on top of either metformin or sulfonylurea) or a metformin/sulfonylurea combination.

The rate of cardiovascular (CV) hospitalization or death from cardiovascular causes, the primary end point, reached 14.5% in both groups over an average of 5.5 years [2], as previously reported by heartwire . There were no significant differences in individual rates of CV death, myocardial infarction (MI), or stroke.

The nonsignificant 14% increased risk of MI in the TZD group was noteworthy to some observers, given published evidence that rosiglitazone might increase MI risk [3], also as covered by heartwire .

The RECORD authors have pointed out that their trial wasn't powered to show significant differences in the rate of MI on its own.

In their current analysis, by intention-to-treat, the hazard ratio (HR) for fatal or nonfatal heart-failure events in the rosiglitazone group compared with controls was 2.10 (95% CI 1.35–3.27; p=0.001). The estimated excess heart-failure event rate was 2.6 per 1000 person-years. There was no rosiglitazone-related significant increase in risk of cardiovascular mortality or hospitalization or of CV death, the group reported.

Significant independent baseline predictors of heart-failure events included age, increased body-mass index, urinary-albumin-to-creatinine ratio, rosiglitazone treatment (p<0.001 for all), and increased systolic blood pressure (p=0.002), but not a history of cardiovascular disease.

Funding to pay the open-access publication charges for the paper was provided by GlaxoSmithKline. Two coauthors are employees of and hold stock in the company. All other coauthors "receive funding for research, educational, and/or advisory activities from pharmaceutical companies including GlaxoSmithKline, the manufacturers of rosiglitazone, and in some cases from the manufacturers of sulfonylurea and metformin preparations and other competing products."