GlaxoSmithKline responds to Journal of the American Medical Association articles

GlaxoSmithKline believes that conclusions drawn from the most recent meta-analyses published by Drs. Nissen et. al. and Furberg et. al. in the Journal of the American Medical Association do not confirm a difference in the safety profile of Avandia (rosiglitazone) and Actos (pioglitazone).

These analyses reflect limitations that are common to all meta-analyses, by the authors' own admission. These analyses do not yield data robust enough to guide doctors in selecting appropriate diabetes treatments for their patients. Comparisons between different meta-analyses with different endpoints and patient populations are even more unreliable.

The Actos meta-analysis is based on a small number of studies (19) provided directly by Takeda, and is heavily biased by data from the PROactive study (5,238 patients) which contributed 80 percent of the endpoint data. The patient population in the PROactive study was at high risk of cardiovascular disease.

PROactive compared diabetic patients on Actos to those on placebo. Patients taking Actos to control blood sugar might be expected to have fewer cardiovascular events than those who were not controlled on medication, consistent with the primary results of PROactive (Hazard Ratio 0.90 p=0.095). However, as described by FDA in the recent Advisory Committee, at six months PROactive actually showed an increased risk of heart attack (HR 1.2). -- Applying the endpoint of CV death, myocardial infarction and stroke to the data on Avandia across long-term clinical trials to enable a closer like-for-like comparison with the Actos meta-analysis shows no statistical difference between Avandia and comparators (a hazard ratio of 1.03). In RECORD, a study specifically designed to look at cardiovascular events, no real difference was seen between Avandia and comparators (HR 0.96). In all of these analyses, the Avandia and the Actos hazard ratios (HR 0.82 for Actos in Nissen meta-analysis) do not suggest an increased risk versus the comparators. -- No long-term, head-to-head clinical trial data specifically evaluates cardiovascular risk between Avandia and Actos; however, the head-to-head data that does exist, and the overwhelming majority of comparative observational data, show no significant differences in CV events.

The JAMA article on Avandia is yet another iteration of previously analyzed data, and offers no new information on the safety of Avandia. The suggested increase in heart attack cited comes from a selective re-analyses of previously published and highly selective data from only four of 116 available studies, and reflects a difference of only 11 events in 14,291 patients between Avandia and control. In this limited meta-analysis, in the context of all the other evidence, we believe it is inappropriate for the author to advise doctors to disregard the FDA's advice which is to keep patients who are effectively controlling their diabetes on Avandia. These data have been presented to an expert advisory panel of the FDA, which voted to keep Avandia available to patients -- a vote that reflects the role of this medicine as an important treatment option to help diabetes patients control their blood sugar.

The conclusions of these meta-analyses conflict with the wealth of accumulated data on Avandia -- including 116 clinical trials in more than 52,000 patients and epidemiological studies of databases in over 1 million patients. Analyzed studies show no difference in the ischemic cardiovascular effects of Avandia versus other oral anti-diabetic medicines, including Actos.

1. Across this extensive data set, the number of heart attacks is small, and Avandia is shown to have a comparable cardiovascular profile to the two most prescribed oral anti-diabetic medicines -- metformin and sulfonylurea -- apart from the well characterized fluid-related events common to both Avandia and Actos. 2. In three epidemiological studies of databases with more than one million diabetic patients, the risk of heart attack was similar for Avandia compared to other anti-diabetic agents. A database study comparing Avandia to Actos showed no difference between the two. 3. Two large epidemiology studies presented to the FDA Advisory Committee and conducted independently of GSK by WellPoint and by the Department of Defense/Tricare also showed no increased rates of heart attack between Avandia and Actos.

Importantly, only Avandia has been shown to control blood sugar for up to five years and to be 32 percent more effective than metformin and 63 percent more effective than sulfonylurea in maintaining blood sugar control over the long-term. We know from clinical studies that effective treatment of diabetes requires intensive, long-term, day-to-day control of blood sugar levels to reduce the risk of serious complications (e.g., blindness, kidney failure, limb amputation, nerve injury) and ultimately save lives. Avandia is the most widely studied oral medication for Type 2 Diabetes, and is an important option for physicians who often need to prescribe several different diabetes medicines in combination to help their patients maintain blood sugar control.

The FDA is engaged in a full, objective analysis of the science, and will make its independent recommendations on the appropriate use of oral anti- diabetic medicines. GSK continues to support Avandia as safe and effective when used appropriately.