July 2007 Cochrane Review Of Trials Contends That Avandia Is No Better Than Other Diabetes Drugs While Being Associated With Serious Side Effects

(Posted by Tom Lamb at DrugInjuryWatch.com)

On July 30, 2007 the FDA will convene a Joint Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee for the purpose of considering the risk-benefit analysis of GlaxoSmithKline’s controversial diabetes drug Avandia (rosiglitazone). 

Among the doctors who will be participating are:

• Curt Furberg, M.D.
• Steven Nissen, M.D.
• Thomas Pickering, M.D.
• David Schade, M.D.
• Morris Schambelan, M.D.
• John Teerlink, M.D.

Less than two weeks before this FDA meeting about Avandia, a new analysis published by The Cochrane Library asserted that Avandia "does not have a positive impact on patients’ quality of life and is not clinically superior to other antidiabetic drugs", according to a July 19, 2007 piece published online by PharmaTimes.

The following extended excerpt from a July 18, 2007 article for Heartwire by Sue Hughes brings us up-to-date on this latest development in the Avandia safety debate:

A new Cochrane review of rosiglitazone (Avandia, GlaxoSmithKline [GSK]) has found no evidence of any benefits of the drug over other diabetes medications and, because of side effects such as edema, fractures, and possible increased risk of MI, the review advises a “very cautious approach to rosiglitazone use" and recommends that if possible, other antidiabetic medications should be employed [footnote omitted].

The review, which is published online on July 18, 2007, in the Cochrane Database of Systematic Reviews, was led by Dr Bernd Richter (Heinrich-Heine University, Düsseldorf, Germany). It examined only published studies of at least 24 weeks in duration of rosiglitazone in type 2 diabetics.

Richter commented to heartwire: “We are not adding any more information on cardiovascular risk. The recent New England Journal of Medicine meta-analysis by Nissen et al [footnote omitted] has more information on cardiovascular risk than our study, as we included only published studies in diabetic patients, and the only one large enough to look at cardiovascular risk was the ADOPT trial. Our review is looking more at the bigger picture for rosiglitazone. We wanted to look at the whole risk/benefit ratio. We didn’t find any benefits of rosiglitazone over other drugs for type 2 diabetes, but the drug is clearly associated with increased risks of edema, fractures, and weight gain. These adverse effects, together with the suggestion of an increased cardiovascular risk, lead us to conclude that doctors should think twice about using rosiglitazone, as we have good alternatives."

The review included 18 trials, which randomized 3888 patients with type 2 diabetes to rosiglitazone treatment. The median duration of treatment was 26 weeks. The longest duration was four years (the ADOPT trial). Richer et al report that in these studies rosiglitazone did not positively influence patient-oriented outcomes such as mortality, morbidity, adverse effects, costs, and health-related quality of life. Metabolic control as measured by glycosylated hemoglobin A1c (HbA1c) did not demonstrate clinically relevant differences from other oral antidiabetic drugs. Occurrence of edema was more than doubled; the single large randomized trial (ADOPT) indicated increased cardiovascular risk, and new data on raised fracture rates in women reveal extensive action of rosiglitazone in various body tissues, they add.

The rather predictable rebuttal from GlaxoSmithKline was reported in a July 17, 2007 Reuters article about this new Cochrane review of Avandia:

Glaxo, however, said Richter’s analysis provided no new evidence about the use of Avandia in clinical practice.

"It’s looking at a very thin slice of the total available evidence for rosiglitazone and really ignoring a huge amount of research," Ronald Krall, chief medical officer of the world’s second-largest drugmaker, said in a telephone interview.

Krall said Glaxo had studied Avandia in more than 52,000 patients, and this much larger dataset showed Avandia had a similar safety profile to other oral antidiabetic drugs.

One suspects that while the July 30 joint meeting of these two FDA advisory committees may help some doctors understand when, if ever, Avandia use is a good option for their diabetic patients, this growing debate over the safety of Avandia will continue well beyond that event.

• FDA Briefing Document for Avandia July 30 Meeting: PDF file – 436 pages
• GlaxoSmithKline Briefing Document for Avandia July 30 Meeting: PDF file – 192 pages

P.S.  FDA Advisory Panel Vote Is 22-1 In Favor Of Avandia; Glaxo’s Diabetes Drug Will Stay On U.S. Market  (7/30/07)