Review of Rosiglitazone for type 2 diabetes mellitus

Jul 18 2007

Little evidence supports using rosiglitazone (Avandia) to improve the quality or length of life among adults with diabetes, according to a systematic review of data by German researchers.

Furthermore, data suggest that the drug might worsen complications of the disease such as weight gain, swelling, bone fractures and heart disease. The new review supports findings from an analysis of studies, published in May, which reported an increased risk of death from cardiovascular causes in patients taking the medication.

On May 21, the Food and Drug Administration issued a safety alert saying, “Patients who are taking Avandia, especially those who are known to have underlying heart disease or who are at high risk of heart attack, should talk to their doctor about this new information.”

“The benefit-risk ratio of rosiglitazone therapy in type 2 diabetes mellitus needs urgent clarification,” say the authors of the latest review, led by Bernd Richter, M.D., of Heinrich-Heine University. “New safety data … should lead to a very cautious approach to rosiglitazone use. If possible, other antidiabetic medications should be employed.”

The findings are particularly alarming because heart disease accounts for nearly 70 percent of deaths among people with diabetes. Type 2 diabetes affects about 18 million to 20 million Americans, according to the American Diabetes Association.

The review appears in the latest issue of The Cochrane Library , a publication of The Cochrane Collaboration, an international organization that evaluates medical research. Systematic reviews draw evidence-based conclusions about medical practice after considering both the content and quality of existing medical trials on a topic.

The authors pooled data from 18 randomized controlled trials including more than 8,000 participants. About half of the patients took rosiglitazone and the others received either an alternative medication or a placebo. Most of the trials lasted about 6 months, although the longest one followed patients for four years.

All of the published studies aimed primarily to evaluate metabolic or glycemic control, which is the drug's ability to lower blood sugar levels, the review authors say. Rosiglitazone treatment produced about the same reductions as other oral antidiabetic drugs.

When the reviewers looked at “patient-oriented” results of the treatments such as side effects, diabetic complications or death, they found a more negative picture. The pooled data revealed that patients taking rosiglitazone gained up to 11 pounds in body weight and that the chance of developing edema (swelling) doubled. These changes indicate that the drug causes fluid retention, which can lead to shortness of breath and heart failure.

The largest single trial included in the review involved more than 4,000 patients and showed evidence of raised cardiovascular risk, as well as increased numbers of broken bones in women.

“Existing treatment strategies concentrating on lowering of blood sugar alone are not sufficient due to the complex nature of the diabetic condition,” Richter said. “The use of proxy indicators like metabolic control is not sufficient to approve drugs that many patients have to take for the rest of their lives.”

He advises patients who suffer from heart disease, especially congestive heart failure, to speak with their doctors about switching to another antidiabetic treatment. “If you are a woman — and especially if you are thin — you probably should avoid this medication due to the risk of bone fractures,” he said.

Avandia manufacturer GlaxoSmithKline takes issue with the use of meta-analyses in a May 12 statement, saying they are “not the most rigorous way to reach definite conclusions about adverse events.” Citing several recent and ongoing clinical trials, the company says, “GSK stands firmly behind the safety of Avandia when used appropriately and we believe its significant benefits continue to outweigh any treatment risks.”

Richter, however, said that even a tiny risk associated with a drug such as rosiglitazone, prescribed to millions of people, “will eventually translate into grave consequences.”

“In view of the potential cardiovascular risks and in the absence of evidence of other health advantages, except for laboratory measures of glycemic control, the rationale for prescribing rosiglitazone at this time is unclear,” say public health experts Bruce Psaty, M.D., and Curt Furberg, M.D., in a New England Journal of Medicine editorial published June 14. The journal published the initial analysis of Avandia.

“Rosiglitazone represents a major failure of the drug-use and drug-approval processes in the United States,” Psaty and Furberg write, comparing the situation to the withdrawal of the painkiller rofecoxib (Vioxx) from worldwide markets in 2004.

The Cochrane reviewers concur, saying, “Current drug approval for antidiabetic medications and possibly all new drugs needs to be changed.” However, they also question “whether new studies with rosiglitazone will be ethical given the fact that less-dangerous therapeutic alternatives exist.”

The Food and Drug Administration will hold a joint meeting of two drug-safety advisory committees to discuss rosiglitazone on July 30 in Gaithersburg, Md. The meeting is open to the public and the FDA will accept electronic and written comments.

For more information on the FDA drug-safety meeting, see www.fda.gov/OHRMS/DOCKETS/98fr/E7-10850.htm.

Richter B, et al. Rosiglitazone for type 2 diabetes mellitus (Review). Cochrane Database of Systematic Reviews 2007, Issue 3.

The Cochrane Collaboration is an international nonprofit, independent organization that produces and disseminates systematic reviews of health care interventions and promotes the search for evidence in the form of clinical trials and other studies of interventions. Visit http://www.cochrane.org for more information.