Panel Recommends Easing Restrictions on Rosiglitazone Despite Concerns About Cardiovascular Safety.

Three years ago, amid concerns that rosiglitazone (Avandia) increases the risk of myocardial infarction and death due to cardiovascular causes, the US Food and Drug Administration (FDA) severely curtailed use of the blood glucose–lowering drug. But now an FDA advisory committee has recommended easing the severe restrictions on prescribing rosiglitazone, used to treat type 2 diabetes mellitus, even though cardiovascular safety concerns remain.


At the joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee, held June 5 and 6 at FDA headquarters in Silver Spring, Maryland, 13 members voted to modify the highly restrictive risk evaluation and mitigation strategy (REMS) applying to use of rosiglitazone, 7 voted to remove the REMS altogether, 5 voted to keep the REMS as is, and 1 voted for removal of rosiglitazone from the market. The REMS restricts access to rosiglitazone so that only prescribers who acknowledge the potential increased risk of myocardial infarction are prescribing the drug. The REMS also restricts rosiglitazone to patients who are already taking the drug or who are unable to achieve glycemic control with other medications and, in consultation with their physician, have decided not to take pioglitazone (Actos, the only other thiazolidinedione marketed in the United States) for medical reasons.

The vote was somewhat of a reversal from a 2010 FDA meeting of the same advisory committees (although with somewhat different personnel) in which 10 members voted to restrict availability of rosiglitazone and 12 voted to remove it entirely from the market, while another 3 voted to leave the label unchanged and 7 voted to add warnings. The 2010 vote, and subsequent action by the FDA, followed a decade of increasing concerns about the drug’s cardiovascular safety.

An advisory panel, after hearing testimony by researchers, is recommending the US Food and Drug Administration ease severe restrictions on rosiglitazone.

Rosiglitazone was given FDA approval in 1999 and quickly became a blockbuster drug for its manufacturer, GlaxoSmithKline (then SmithKline Beecham), ultimately generating more than $2 billion in annual sales, with about 120 000 US patients taking the medication. But researchers began to sound a safety alarm just a year later. Then, in 2007, a meta-analysis found that rosiglitazone increased the risk of myocardial infarction by more than 40% compared with a control (placebo or comparator drug) (Nissen SE and Wolski K. N Engl J Med. 2007;356[24]:2457-2471). And just before the 2010 advisory meeting, another study, observational and retrospective, found that compared with pioglitazone, rosiglitazone increased the risk of stroke, heart failure, and death (Graham DJ et al. JAMA. 2010;304[4]:411-418).

Even as studies were attacking the cardiovascular safety of rosiglitazone, a randomized controlled trial, RECORD, published results showing that compared with a treatment combination of metformin and sulfonylurea, rosiglitazone did not increase the risk of overall cardiovascular morbidity or mortality, although it did increase the risk of heart failure and some fractures (the latter mainly in women) (Home PD et al.Lancet. 2009;373[9681]:2125-2135). But at the 2010 advisory committee meeting, RECORD faced stiff criticism, as its design was open label, with GlaxoSmithKline employees having access to the data, and it appeared some data were missing. The FDA ultimately instituted the REMS, and today only about 3000 US patients take the drug.

The questions surrounding RECORD were such that the FDA asked the company to fund a readjudication of the data. That readjudication was the main reason for the June advisory committee meeting. There, results from the readjudication, performed by the Duke Clinical Research Institute, confirmed the original findings of RECORD. The readjudication gave some of the advisory panel members enough confidence to vote to ease prescribing restrictions on rosiglitazone, but others said the reexamination could never overcome the design flaws of the study.

David Juurlink, MD, PhD, head of the division of clinical pharmacology at the University of Toronto in Canada, who was not a panel member but who has raised cardiovascular safety concerns about rosiglitazone, said he found the RECORD readjudication reassuring to a point. “I have more confidence in the RECORD trial than I did before, but it’s not a well designed or executed trial,” Juurlink said. “So Duke had a flawed study to readjudicate, and it was ‘garbage in, garbage out.’”

Steven Nissen, MD, department chair of cardiovascular medicine at the Cleveland Clinic and coauthor of the 2007 meta-analysis, said he thought the June advisory meeting was intended by the FDA to get a recommendation to ease access to rosiglitazone—not only because of the readjudication of RECORD, but also to take pressure off the agency from critics who wondered why the drug was still on the market.

“The panel basically voted to keep the drug on restricted access, and from my perspective, it’s a good outcome,” Nissen said. “This is really about a bureaucracy that never wants to admit it made a mistake. It is tragic for public health that the people who approve the drug in the first place remain to act against the drug. It’s like a parent admitting their child is ugly.”

Jerry Avorn, MD, professor of medicine, Harvard Medical School, and chief of the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital in Boston, questioned why the FDA even called for this advisory meeting. “For a drug that has quite impressive evidence of cardiovascular toxicity and heart failure and hip fracture, why would I want access to it?” Avorn said. “With all the pressing work regarding drug approvals and postmarketing surveillance, this seems like an odd prioritization for FDA’s time.”

Harlan Krumholz, MD, professor of medicine at Yale University School of Medicine in New Haven, Connecticut, called the hearing a waste of time. “I was perplexed why this merited 2 days of the FDA’s time and why there were changes in the recommendations when, by and large, the evidence remained the same since the previous meeting.”

But others justified the meeting, saying the evidence was still open for debate.

Sanjay Kaul, MD, MPH, director of the vascular physiology and thrombosis research laboratory at the Burns and Allen Research Institute at Cedars-Sinai Medical Center in Los Angeles, who was a member of both the 2013 and 2010 advisory panels, voted both times for restricting access to rosiglitazone, although at the latest meeting he favored easing the restrictions. He believes the safety evidence, both in 2010 and today, remains inconclusive. “This is a drug that was virtually killed on the basis of evidence that is not very convincing at best and dubious at worst,” Kaul said. “When confronted with uncertainty and the data are not of high quality, I say let the physicians make the choice on whether to give a medicine or not.”

Source: JAMA

FDA Approves New Cholesterol-Cutting Combination Drug .

The FDA has approved a new ezetimibe-atorvastatin tablet (brand name, Liptruzet) for lowering cholesterol in patients with primary or mixed hyperlipidemia, and in those with homozygous familial hypercholesterolemia.

In a trial of some 620 patients, the once-daily tablet reduced LDL cholesterol by 53% at the lowest dose (10/10 mg) and 61% at the highest dose (10/80 mg). Common side effects include changes in liver function tests, muscle pain, memory loss, and tendon problems.

The combination treatment has not been shown to improve cardiovascular outcomes better than atorvastatin, which has some cardiologists questioning the FDA’s decision. Steven Nissen, chairman of cardiology at the Cleveland Clinic, says in Forbes that the agency seems to be “tone deaf” to concerns “about approving drugs with surrogate endpoints like cholesterol without evidence of a benefit for the disease [cardiologists] are truly trying to treat — cardiovascular disease.”

Source: Forbes