Avandia Study Gets Mixed Reviews

Many physicians and patients have embraced rosiglitazone (Avandia, GlaxoSmithKline) for its efficient blood glucose-lowering effects, easily delivered in pill form.¹ In 2006 alone, U.S. patients filled 11 million prescriptions for the drug, which earned GlaxoSmithKline (GSK) an estimated $3 billion, despite a number of risks described on Avandia's label.^2,3

These risks include fluid retention, peripheral edema, macular edema, and weight gain.³ The label also notes a risk of heart failure, which the Food and Drug Administration (FDA) is requiring be boxed more prominently on the labels of both Avandia and the other approved drug in its class—pioglitazone (Actos, Takeda).

Last year GSK quietly added a potential heart attack risk to the label, but it took a study published in June in the New England Journal of Medicine (NEJM) to focus major attention on that risk. The study, led by Steven E. Nissen, MD, head of cardiovascular medicine at the Cleveland Clinic, stirred a furor in the medical community with its finding of an increased incidence of heart attacks among diabetes patients—who already have a significantly increased risk for cardiovascular disease (CVD).⁴

“The whole reason you try to lower blood glucose is to lower diabetes patients' risk of heart disease, so a drug that increases cardiovascular risks is a real problem,” Nissen says.

However, GSK rejects Nissen's findings outright and claims other research—much of it ongoing—has not indicated heightened heart attack risk.⁵ Meanwhile, some politicians and prominent medical researchers call media coverage alarmist and question the study's soundness.⁶

“Nissen did the analysis with incomplete access to the data,” says Jay Skyler, MD, director of University of Miami's Division of Endocrinology, Diabetes & Metabolism and a former president of the American Diabetes Association (ADA). Skyler notes Nissen used pooled rather than original patient data that would have included their baseline CVD status and time to event. “This study should really be considered a hypothesis,” he says.

A CONTROVERSIAL STUDY

Nissen acknowledges the lack of original source data in his analysis of 42 short-term clinical trials available on the GSK and FDA Web sites. The trials involved close to 28,000 patients on rosiglitazone versus other diabetes drugs or placebo.

At a June 6 congressional hearing, Rep. Darrell E. Issa (R-Calif.) hammered Nissen about his statistical methods, saying, “You chose to leave out meta-data in which nobody died—in which nobody had a heart attack.”

Nissen defended himself: “You can't use trials in which there is no evidence. It simply can't be done,” he says.

Other analysts say the relative heart attack and death risks in the Nissen study sound higher in percentages than actual, brokenout numbers: There were 86 heart attacks and 39 heart-related deaths among 15,560 rosiglitazone patients, compared with 72 heart attacks and 22 deaths among 12,283 nonrosiglitazone patients.

“So it's actually a 0.1% higher risk per 1,000 people,” says Sue Kirkman, ADA's vice president of clinical affairs.

But degree of risk is beside the point, in the view of Sidney Wolfe, MD, director of the Health Research Group at the watchdog organization Public Citizen. The drug should pose no risk, and beyond that, should reduce cardiac risks, he says.

“A diabetes drug is only important or effective if it prevents cardiovascular problems, and Avandia doesn't prevent them; if anything, it makes them worse,” says Wolfe, who has called on the FDA to withdraw the drug, or at the very least issue a “black-box” warning about the heart attack risk.²

THE BIGGER RESEARCH PICTURE

Nissen says the FDA knew of rosiglitazone's potential ischemic risks last summer, when it received pooled data from 42 randomized controlled trials.⁷ That data, submitted by GSK, revealed a 30% excess risk of myocardial ischemic events in 8,604 rosiglitazone-treated patients versus 5,633 other patients on insulin, sulfonylureas, metformin, or various combinations thereof. ⁷

At the congressional hearing, ADA President-elect John Buse, MD, PhD, indicated that he had alerted the FDA of CVD concerns with thiazolidinediones (TZDs) back in 2000. But the FDA points out that other rosiglitazone trials have not revealed such concerns. For instance, A Diabetes Outcome Progression Trial (ADOPT), a randomized double-blind study of 4,351 type 2 diabetes patients without underlying CVD, found no ischemic risk of rosiglitazone, compared with metformin and glyburide.¹

However, in February, GSK warned of an increased incidence of fractures found in women participating in ADOPT.⁸ Significantly more female patients who received rosiglitazone experienced fractures of the upper arm, hand, or foot than did female patients who received the other two drugs.

Another study, the Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM), suggests rosiglitazone, but not ramipril, helped forestall diabetes in 5,300 patients with prediabetes.⁹ The analysis also indicates no increased risk of heart attack, stroke, or cardiovascular death in rosiglitazone-treated patients. The FDA has yet to review that data.

TZD UNCERTAINTY

Rosiglitazone is not the only controversial TZD. In the drug class's troubled history, troglitazone (Rezulin, Parke-Davis/Warner-Lambert) was pulled from the market in 2000 for liver toxicity, and several other TZDs have failed to win FDA approval.¹⁰

Rosiglitazone's lone-approved fellow TZD, pioglitazone, also is being scrutinized. A large-scale trial of the drug, The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive), reveals fewer strokes and heart attacks but more heart failure in patients on the drug.^11–13 Another investigation, the Carotid IntimaMedia Thickness in Atherosclerosis Using Pioglitazone (CHICAGO) study, indicates the drug may slow arterial thickening.¹⁴ And a study of pioglitazone versus rosiglitazone suggests better lipid-lowering for pioglitazone (DOC News, February 2005, page 2).¹⁵

Meanwhile, longer-term studies—Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) and two others involving rosiglitazone—are ongoing. In June, NEJM published an interim analysis of RECORD that was inconclusive regarding heart attacks among rosiglitazone patients.¹⁶ Editorials accompanying the analysis criticized RECORD for being too small and not looking specifically enough at heart attack outcomes.^17–19

Moncef Slaoui, GSK's research and development chairman, expresses disappointment with the NEJM editorials. “They cherry-pick data points, when the overall data show Avandia is comparable [to other widely used oral diabetes medications],” Slaoui says.

But Nissen agrees with the NEJM editorials. “We're in a very tough quandary here in that we don't have the data that definitely answer the [heart attack] question,” he says. “We just have the meta-analysis, which is all we're ever going to have because it looks like RECORD isn't going to give us the answer either.” ▪

FDA Hearing on Rosiglitazone to Be Held July 30

The Food and Drug Administration (FDA) has scheduled a July 30 advisory committee meeting to examine ischemic/thrombotic risks and thiazolidinediones (TZDs), particularly rosiglitazone (Avandia, GlaxoSmithKline).

The agency also has requested that Takeda Pharmaceutical Co. Ltd., manufacturer of pioglitazone (Actos), study that drug's cardiovascular safety. The July meeting follows a June 6 House Committee on Oversight and Government Reform hearing on Avandia. For more on the upcoming meeting, see www.fda.gov/opacom/hpmeetings.html.