The Endocrine Society shares the concerns of the article’s authors and the FDA about the potential risk to patients using this drug. However, we also feel that no precipitous action should be taken by the FDA or the medical community based on this meta-analysis, given the study’s substantial limitations as pointed out by both the article’s authors and by those writing the accompanying editorial (Bruce Psaty, M.D., Ph.D. and Curt Furberg, M.D., Ph.D.). We agree that a circumspect interpretation of the data is warranted given that the vast majority of the adverse events were not pre-defined nor subsequently validated/adjudicated; reclassification of such events could lead to substantial changes in the calculated odds ratios and consequently in the study’s conclusions. Further hampering a definitive interpretation of the findings is the authors’ lack of access to source data, thereby precluding critical time-to-event and dose-response analysis. Other points of concern include the extensive use of unpublished data (only 11 of 42 studies used in the meta-analysis were peer-reviewed); the small size of the studies (none were powered to evaluate the cardiovascular risks); and the similarity of the crude incidence rates of myocardial infarction in the two groups (5.5 per 1000 patients for rosiglitazone vs 5.9 per 1000 patients for control).

The FDA has stated that an interim report from the RECORD study - a long-term trial of rosiglitazone begun four years ago that is powered to assess cardiovascular risks (4500 patients randomized) – did not note such adverse effects. Of relevance, a 2005 report of an adequately powered, prospective study of another drug in this thiazolidinedione class also did not suggest an increase in cardiovascular events.

We would urge that the RECORD study be continued until its planned completion date in 2009 unless its Data Safety Monitoring Committee finds specific cause to stop it. Premature termination of this important study would leave the medical community without a definitive answer to the key question of the safety of rosiglitazone and would leave a cloud over other members of the thiazolidinedione class, a vital part of the current armamentarium in the treatment of diabetes.

What should providers do at this juncture? Given our concerns about the current study, as noted above, we feel that providers should react in a measured way. The firestorm of publicity surrounding this article, and the ensuing barrage of phone calls from patients, may well require a response from providers. Switching patients from rosiglitazone to another drug in the same class is not risk-free, both because the NEJM study’s findings might represent a class effect and because the impact of any drug substitution can be unpredictable. Fortunately, numerous drugs in several different classes have become available over the past decade for providers’ use in the treatment of diabetes; such options may be helpful in dealing with this situation. Providers with the ability to identify patients currently taking rosiglitazone from an electronic medical record or other data base may wish to take a pro-active stance by contacting them. Whether by proactive contact or in response to a patient’s inquiry, the provider should counsel each person about the findings of the study, discussing the study’s implications on an individual basis, and reviewing the risks and benefits of remaining on rosiglitazone versus changing therapy. It would also seem prudent, given the very high baseline risk of cardiovascular events in patients with diabetes, to redouble efforts to reduce other cardiovascular risk factors by aggressive treatment of the co-morbidities of hyperlipidemia and hypertension in those diabetic patients taking medications with postulated cardiovascular side effects.

Finally, this NEJM study highlights the need for strict and transparent post-marketing surveillance of all new drugs. Such an approach would complement the existing use of surrogate markers to gauge effectiveness when new drugs for the treatment of chronic illnesses are evaluated by the FDA and would facilitate continued innovation in pharmaceutical research.