The anti-diabetes drug rosiglitazone is associated with an increased risk for new-onset heart failure (HF) but no increase in acute coronary events as compared with traditional glucose-lowering drugs, post hoc analyses of the RECORD trial indicate.

The new data lay to rest one safety concern associated with rosiglitazone therapy, but confirm and solidify another, according to investigators speaking at the European Society of Cardiology annual meeting in Barcelona, Spain.

John McMurray (University of Glasgow, UK), an investigator in the RECORD trial, told MedWire News: “My personal belief is that you should not give [glitazones] to anyone with HF or structural heart disease.

“The big question mark ” the really important thing ” is what do you do in other patients, who don’t have a background of heart injury or dysfunction. Are [glitazones] even safe in them “

The first analysis, a study into the effect of rosiglitazone on HF events in the RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycemia in Diabetes) trial, was presented at a Clinical Trial Update session on Sunday by Michel Komajda (Universite Pierre et Marie Curie, Paris, France). The main study results were published in June 2009.

The post hoc analysis was undertaken in view of previous reports linking thiazolidinediones with an increased risk for HF. In particular, a meta-analysis found that thiazolidinedione therapy conferred a 72% increase in relative risk for HF versus control.

However, some diabetologists questioned the significance of the “HF” observed in the trials included in the meta-analysis, suggesting that it was not “real” HF but fluid retention, which is a known and relatively harmless side-effect of rosiglitazone therapy.

RECORD was a large, long-term, randomized, open-label clinical trial involving 4447 patients aged 40 “75 years who had Type 2 diabetes mellitus and were on metformin or sulfonylurea monotherapy. All participants were free of HF at baseline.

Metformin-treated patients were randomly assigned to receive add-on rosiglitazone or sulfonylurea (and continued metformin), while sulfonylurea-treated patients were randomly assigned to receive add-on rosiglitazone or metformin (and continued sulfonylurea).

The average duration of follow-up was 5.5 years. During this time, there were a total of 29 fatal and nonfatal HF events in the metformin/sulfonylurea treatment groups versus 61 in the rosiglitazone groups. Fatal HF events accounted for two and 10 events in the metformin/sulfonylurea and rosiglitazone groups, respectively.

Komajda revealed that study participants taking rosiglitazone had a more than two-fold greater risk for developing HF than patients in the other treatment groups (hazard ratio [HR]=2.10, p=0.001).

Kaplan-Meier curves showed that the increased HF risk associated with rosiglitazone became apparent early in the trial and continued to increase over time.

Komajda noted that the risk for HF was similar in patients with and without prior ischemic heart disease, although the absolute risk was greater in the former group.

In multivariate analysis, significant baseline predictors of HF were rosiglitazone treatment (HR=2.25); age 60 years (HR=3.81); waist circumference 104 cm (HR=3.52); presence of microalbuminuria or proteinuria (HR=3.35); and use of beta blockers (HR=1.86).

“Overall, these findings support the current recommendation that rosiglitazone should not be used in patients with symptomatic HF or with a history of HF,” Komadja concluded.

In comments to MedWire News, McMurray said that the new data were important because they laid to rest any notion that the fluid retention observed in rosiglitazone-treated patients was harmless.

“It is a legitimate concern and shouldn’t be diminished as something unimportant or benign,” he said. “The conclusion is that glitazones do cause HF, it is real HF, in other words, it is the syndrome that we know carries a very poor prognosis,” he said.

McMurray presented a second post hoc analysis of RECORD at Monday’s Clinical Trial Update session. This followed a controversial meta-analysis that found a 43% increased risk for myocardial infarction (MI) versus control.

The prevalence of ischemic heart disease in the RECORD trial was 15 “20%, McMurray reported, although patients with a recent major CV event or planned CV intervention were excluded.

As already revealed in the main study report, the risk for suffering a first fatal or nonfatal MI did not differ significantly between the two study groups (HR=1.14). According to new data presented on Monday, outcomes following nonfatal MI were also comparable between the treatment groups, with similar rates of recurrent MI and unstable angina.

In the overall study population, the rosiglitazone and metformin/sulfonylurea groups had comparable risks for developing the following: acute coronary syndromes (ACS, HR=1.05); ACS or “other” hospitalization attributed to angina pectoris (HR=0.99); and ACS, other angina hospitalization, or coronary revascularization (HR=0.94).

McMurray ended his presentation by showing an analysis of total cardiovascular events, which revealed no difference between the treatment groups with regard to death, hospital admission, or revascularization. There were a total of 221 such events (in 127 patients) in the rosiglitazone groups and 230 events (in 128 patients) in the metformin/sulfonylurea groups.

He concluded: “In the RECORD trial, there was no statistically significant excess of ‘first’ MI, unstable angina, or other coronary outcomes in subjects treated with rosiglitazone plus metformin or a sulfonylurea compared to those treated with the combination of metformin plus a sulfonylurea.”

A third post hoc analysis of RECORD has also been performed, McMurray noted. This focused on the risk for bone fractures and confirms other studies showing that there is an increased risk for fractures in rosiglitazone-treated patients. The analysis will be presented at a future meeting.

MedWire (www.medwire-news.md) is an independent clinical news service provided by Current Medicine Group, a part of Springer Science+Business Media. © Current Medicine Group Ltd; 2009

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