GlaxoSmithKline has issued the following response to an article in the New England Journal of Medicine (NEJM) on Avandia (rosiglitazone maleate), a widely used and highly effective treatment for type 2 diabetes.
GSK strongly disagrees with the conclusions reached in the NEJM article, which are based on incomplete evidence and a methodology that the author admits has significant limitations.
The NEJM paper is based on an analysis of summary information that combines a number of studies - a meta-analysis - which is not the most rigorous way to reach definite conclusions about adverse events. Each study is designed differently and looks at unique questions: for example, individual studies vary in size and length, in the type of patients who participated, and in the outcomes they investigate. The data compiled from these varied studies is complex and can be conflicting.
Importantly, the editorial in the NEJM states: "A few events either way might have changed the findings for myocardial infarction or for death from cardiovascular causes. In this setting, the possibility that the findings were due to chance cannot be excluded. In their discussion, the authors properly emphasize the fragility of their findings."
In contrast to a meta-analysis, the most scientifically rigorous way to examine the safety and benefits of a medicine is to conduct large scale, long- term clinical trials in patients with the disease. Several trials of this type have been ongoing for many years. To date concerns regarding patient safety have not been identified by the independent Safety Monitoring Boards for these trials. Several trials have been completed and the results published. For example, GSK's long-term, landmark study 'ADOPT' (A Diabetes Outcome Progression Trial) - one of the longest clinical trials in people with type 2 diabetes to date - directly compared both the safety and effectiveness of Avandia with other oral anti-diabetic medicines in over 4,300 patients studied for up to 6 years.
Data from ADOPT showed that the overall risk of serious, cardiovascular events (CV death, myocardial infarction, and stroke, or MACE endpoint) for patients on Avandia was comparable to metformin and sulfonylurea (glyburide) - two of the most commonly used medicines to treat type 2 diabetes. ADOPT showed comparable rates of cardiovascular deaths: Avandia - 5 reports out of 1,456 patients, or 0.34%; metformin - 4 out of 1,454, or 0.28%; and glyburide - 8 out of 1,441 or 0.56%. The ADOPT clinical trial did show a small increase in reports of myocardial infarction among the Avandia-treated group (Avandia: 24 out of 1,456 or 1.65%) vs metformin (20 out of 1,454 or 1.38%) vs glyburide (14 out of 1,441 or 0.97%); however, the number of events is too small to reach a reliable conclusion about the role any of the medicines may have played in this finding. Importantly, ADOPT also demonstrated that Avandia was superior to metformin and sulfonylurea regarding long-term control of blood sugar over five years, which is a key goal in managing diabetes to avoid the long-term complications of the disease.
In another long-term study, DREAM - which followed over 5,200 patients at high risk of developing of type 2 diabetes for a period of three to five years - Avandia monotherapy showed no increase in cardiovascular risk when compared to placebo.