The following is GlaxoSmithKline's response to the retrospective analysis by the Institute for Clinical Evaluative Sciences (ICES) titled "Thiazolidinediones and Cardiovascular Outcomes in Older Patients with Diabetes".
GSK believes that the ICES retrospective analysis of the Ontario Drug Benefit (ODB) database has significant limitations and generates misleading conclusions regarding acute myocardial infarction and death. These conclusions are inconsistent with a more robust body of evidence from large, long-term, prospective, well-designed clinical studies, including ADOPT and RECORD.
-- These long-term trials in diabetic patients comparing rosiglitazone to other oral anti-diabetic medicines show no increased risk for cardiovascular events compared to other commonly used medications, other than the well-known risk of congestive
heart failure (CHF) with thiazolidinedione (TZDs). -- RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in
Diabetes) was specifically designed to evaluate the cardiovascular safety of rosiglitazone, and is therefore the most robust data available. A recently published interim analysis for myocardial infarction and death from cardiovascular causes, or from any cause, showed no statistically significant difference between rosiglitazone in combination with either
metformin or sulfonylurea vs. the active comparators of metformin plus sulfonylurea.
In addition, the RESULT clinical study specifically examined an elderly diabetic population, ages 59 to 89, in which 43 percent of the patients were greater than 70 years of age, and demonstrated the safety profile of rosiglitazone to be consistent with the control medicine (sulfonylurea).
Importantly, the results of this study do not reproduce what is already known about the risk of CHF in TZD users. TZDs can cause fluid retention which can lead to or exacerbate heart failure. TZDs also have a similar increased risk of CHF. Yet, in this analysis, pioglitazone is not associated with an increased risk of CHF (Adjusted RR of 0.91 (95% CI = 0.52-1.59) whereas rosiglitazone is associated with 2 fold-increased risk of CHF (Adjusted RR = 1.98 and 95% CI=1.44-2.72) compared to oral anti-diabetic combination therapy. This is inconsistent with the product labeling.
Moreover, the authors of this retrospective analysis fail to acknowledge the findings of large epidemiological studies, encompassing over 1.3 million patients with type 2 diabetes, as well as other similar studies presented during the recent FDA Advisory Committee meeting. These studies have investigated whether use of rosiglitazone in the real world setting is associated with an increase in myocardial infarction or coronary revascularization. The majority of these studies show that rosiglitazone is not associated with an increased risk of myocardial infarction compared to other anti-diabetic agents.
GSK cites the following as examples of the limitations of this retrospective analysis: