Rosiglitazone, Pioglitazone Pose Similar CV Risk in Case-Matched Analysis

August 25, 2010

August 25, 2010 (Wilmington, Delaware) The risks of myocardial infarction (MI), heart failure (HF), or death--individually or combined--are about the same in diabetics taking either pioglitazone (Actos, Takeda Pharmaceuticals) or rosiglitazone (Avandia, GlaxoSmithKline), suggests a case-matching cohort study that challenges a good deal of evidence that such risks are greater with the latter drug [1].

The retrospective study included almost 29 000 WellPoint health-plan members who started on one or the other thiazolidinedione (TZD) from 2001 through 2005, with one in each propensity-matched pair treated with rosiglitazone and the other given pioglitazone. After a mean of about 34 months of treatment and follow-up, the same percentage in each drug group--about 4%--had died or suffered one of the cardiovascular end points.

The findings, published online August 24, 2010 in Circulation: Cardiovascular Quality and Outcomes, to a large extent conflict with years of mostly observational data, meta-analyses, and a good deal of expert opinion arguing that rosiglitazone poses greater cardiovascular risk than pioglitazone. Indeed, all as chronicled by heartwire , many contend rosiglitazone should be removed from the market or have its availability restricted.

The controversy has attracted Congressional scrutiny of GlaxoSmithKline's handling of early rosiglitazone safety data and was the focus of political intrigue at the US Food and Drug Administration (FDA). In the saga's latest chapter, the agency has put a damper on an ongoing randomized comparison of the two drugs many hoped would help settle debate over the drug, called TIDE.

As recently covered by heartwire , the FDA put a "partial clinical hold" on enrollment into the TIDE trial while it considers the multilayered message from an advisory panel, a majority of which favored a tightening of restrictions on rosiglitazone use and a substantial minority of which called for the drug's market withdrawal.

Dr David Juurlink (University of Toronto, ON), who isn't connected with the current analysis but led one of the studies suggesting that rosiglitazone poses a greater cardiovascular risk than pioglitazone, said that Wertz et al's study comes up with different conclusions "most likely because they studied relative healthy young patients. Most of the other research is in older patients with longer-standing diabetes and a higher burden of cardiac disease." The average patient in his study compared with the current one, he told heartwire , was about 18 years older and showed far more cardiac risk factors.

"So one is not terribly surprised to see that the researchers, despite a decent sample size, were unable to distinguish the cardiovascular safety profile of rosiglitazone from pioglitazone," he said. "I think it's a well-done study, but I don't think it's generalizable to the majority of patients, and particularly older patients, who are treated with these drugs."

It's not unusual for observational studies of similar questions to produce different results, depending on the population studied, observed Dr Debra A Wertz (HealthCore, Wilmington, DE), an outcomes researcher for a WellPoint subsidiary and lead author of the current analysis.

"We recognize that there are some differences between our study and some other studies out there," she told heartwire . Her group's analysis, Wertz said, "is one more resource to pool from." The analysis was one of the presentations made during the open public-hearing section of FDA advisory meeting, and Wertz believes it will figure into whatever the agency ultimately decides about the fate of rosiglitazone and even TIDE.

Wertz et al acknowledge that their study is of a "commercially insured, relatively young population" that is "less susceptible to an increased risk" than patients in other studies, and that may account for its divergent results. They also suggest that outcomes on the two drugs are similar because both, potentially, could increase risk--something Juurlink doubts, as he has previously stated for heartwire . "There are no studies that suggest that pioglitazone is more dangerous than rosiglitazone," he said, "and my belief, as I said before, is that rosiglitazone is very likely to be worse."

In the absence of any conclusive results from a prospective randomized trial like TIDE, the current analysis isn't a substitute but does provide a limited direct comparison of the two drugs, finding little difference in all-cause mortality or cardiovascular outcomes, individually or as a composite, between the matched patients receiving one or the other TZD.

Outcomes of 14 469 Propensity-Matched* Pairs of Patients Receiving Either Rosiglitazone or Pioglitazone

Parameter Rosiglitazone Pioglitazone
Rate of MI, acute HF, or death (%) 4.16 4.14
Rate of MI, acute HF, or death (per 1000 person-years) 26.38 25.76
Rate of MI (per 1000 person-years) 6.18 6.74
Rate of acute HF (per 1000 person-years) 13.23 11.86
Rate of death (per 1000 person-years) 11.44 11.22

*Propensity matching according to variables reflecting demographics, comorbidities, history of cardiovascular medications, history of cardiovascular conditions, history of diabetes complications, TZD exposure, and other factors

Nor, in multivariate analysis, was there a significantly increased hazard ratio for MI, acute HF, or death for rosiglitazone compared with pioglitazone--HR 1.03 (95% CI 0.91–1.15)--or for each of the clinical end points individually.

Similar findings emerged when the researchers considered only patients aged >65 years, for the composite of MI, acute HF, or death--0.97 (95% CI 0.83–1.12)--and for each end point on its own.

As for what the FDA will ultimately decide about rosiglitazone and TIDE, "this study, as well-done as it is, is not going to, nor should it, influence what's going to happen," Juurlink said.

"The trial has to stop. They've already terminated enrollment in TIDE, but they cannot ethically continue it, because one of the drugs, rosiglitazone, has already had its proverbial knuckles rapped due to safety concerns. And as a result, I don't think there's any other option for them but to remove rosiglitazone from the market or to restrict it heavily," he said. "It's only a matter of time before rosiglitazone ceases to be a therapy to any degree of use."

Lori McLaughlin, public-relations director for WellPoint, confirmed for heartwire that the health-plan company had commissioned the current analysis consistent with its need for data to be used in deciding its degree of coverage for some drugs.

A final decision from the FDA as to rosiglitazone's fate is expected any day, but controversy over the drug and the company that makes it continues to make headlines. On August 12, Time reported that the FDA is investigating whether GlaxoSmithKline illegally held back important rosiglitazone safety data from the FDA in 2006, a charge the company has denied [2]. Last week, the New York Times reported that the FDA and several of its advisory panel members are displeased with the letter sent by GlaxoSmithKline to patients summarizing the July meeting, saying it downplayed concerns about the drug [3].

Wertz and all other coauthors "were employees of HealthCore, a fully owned subsidiary of WellPoint, at the time this study was conducted." The analysis was funded entirely by HealthCore/WellPoint. Juurlink said he has no commercial relationships to disclose.