Cardiovascular adverse events have been evaluated in a meta-analysis of 52 clinical trials, in long-term, prospective, randomized, controlled trials, and in observational studies.

Meta-Analysis of Major Adverse Cardiovascular Events in a Group of 52 Clinical Trials: A meta-analysis was conducted retrospectively to assess cardiovascular adverse events reported across 52 double-blind, randomized, controlled clinical trials (mean duration 6 months).1 These trials had been conducted to assess glucose-lowering efficacy in type 2 diabetes. Prospectively planned adjudication of cardiovascular events did not occur in most of the trials. Some trials were placebo-controlled and some used active oral antidiabetic drugs as controls. Placebo-controlled trials included monotherapy trials (monotherapy with rosiglitazone versus placebo monotherapy) and add-on trials (rosiglitazone or placebo, added to sulfonylurea, metformin, or insulin). Active control trials included monotherapy trials (monotherapy with rosiglitazone versus sulfonylurea or metformin monotherapy) and add-on trials (rosiglitazone plus sulfonylurea or rosiglitazone plus metformin, versus sulfonylurea plus metformin). A total of 16,995 patients were included (10,039 in treatment groups containing rosiglitazone, 6,956 in comparator groups), with 5,167 patient-years of exposure to rosiglitazone and 3,637 patient-years of exposure to comparator. Cardiovascular events occurred more frequently for patients who received rosiglitazone than for patients who received comparators (see Table 3).

a Events are not exclusive: i.e., a patient with a cardiovascular death due to a myocardial infarction would be counted in 4 event categories (myocardial infarction; myocardial infarction, cardiovascular death, or stroke; cardiovascular death; all-cause death).

In this analysis, a statistically significant increased risk of myocardial infarction with rosiglitazone versus pooled comparators was observed. Analyses were performed using a composite of major adverse cardiovascular events (myocardial infarction, stroke, and cardiovascular death), referred to hereafter as MACE. Rosiglitazone had a statistically non-significant increased risk of MACE compared to the pooled comparators. A statistically significant increased risk of myocardial infarction and statistically non-significant increased risk of MACE with rosiglitazone was observed in the placebo-controlled trials. In the active-controlled trials, there was no increased risk of myocardial infarction or MACE. (See Figure 1 and Table 4.)

Figure 1. Forest Plot of Odds Ratios (95% Confidence Intervals) for MACE and Myocardial Infarction in the Meta-Analysis of 52 Clinical Trials

RSG = rosiglitazone

Of the placebo-controlled trials in the meta-analysis, 7 trials had patients randomized to rosiglitazone plus insulin or insulin. There were more patients in the rosiglitazone plus insulin group compared to the insulin group with myocardial infarctions, MACE, cardiovascular deaths, and all-cause deaths (see Table 5). The total number of patients with stroke was 5 (0.5%) and 4 (0.5%) in the rosiglitazone plus insulin and insulin groups, respectively. The use of rosiglitazone in combination with insulin may increase the risk of myocardial infarction [See Warnings and Precautions (5.1).]

ND = not defined

a Events are not exclusive: i.e., a patient with a cardiovascular death due to a myocardial infarction would be counted in 4 event categories (myocardial infarction; myocardial infarction, cardiovascular death, or stroke; cardiovascular death; all-cause death).

Myocardial Infarction Events in Large, Long-Term, Prospective, Randomized, Controlled Trials of Rosiglitazone: Data from 3 large, long-term, prospective, randomized, controlled clinical trials of rosiglitazone were assessed separately from the meta-analysis.6-8 These 3 trials included a total of 14,067 patients (treatment groups containing rosiglitazone N = 6,311; comparator groups N = 7,756), with patient-year exposure of 24,534 patient-years for rosiglitazone and 28,882 patient-years for comparator. Patient populations in the trials included patients with impaired glucose tolerance, patients with type 2 diabetes who were initiating oral agent monotherapy, and patients with type 2 diabetes who had failed monotherapy and were initiating dual oral agent therapy. Duration of follow-up exceeded 3 years in each trial.

In each of these trials, there was a statistically non-significant increase in the risk of myocardial infarction for rosiglitazone versus comparator medications.

In a long-term, randomized, placebo-controlled, 2x2 factorial trial intended to evaluate rosiglitazone, and separately ramipril (an angiotensin converting enzyme inhibitor [ACEI]), on progression to overt diabetes in 5,269 subjects with glucose intolerance, the incidence of myocardial infarction was higher in the subset of subjects who received rosiglitazone in combination with ramipril than among subjects who received ramipril alone but not in the subset of subjects who received rosiglitazone alone compared to placebo.6 The higher incidence of myocardial infarction among subjects who received rosiglitazone in combination with ramipril was not confirmed in the two other large (total N = 8,798) long-term, randomized, active-controlled clinical trials conducted in patients with type 2 diabetes, in which 30% and 40% of patients in the two trials reported angiotensin-converting enzyme inhibitor use at baseline.7,8

There have been no adequately designed clinical trials directly comparing rosiglitazone to pioglitazone on cardiovascular risks. However, in a long-term, randomized, placebo-controlled cardiovascular outcomes trial comparing pioglitazone to placebo in patients with type 2 diabetes mellitus and prior macrovascular disease, pioglitazone was not associated with an increased risk of myocardial infarction or total mortality.9

The increased risk of myocardial infarction observed in the meta-analysis and large, long-term controlled clinical trials, and the increased risk of MACE observed in the meta-analysis described above, have not translated into a consistent finding of excess mortality from controlled clinical trials or observational studies. Clinical trials have not shown any difference between rosiglitazone and comparator medications in overall mortality or CV-related mortality. 

Mortality in Observational Studies of Rosiglitazone Compared to Pioglitazone: Three observational studies in elderly diabetic patients (age 65 years and older) found that rosiglitazone statistically significantly increased the risk of all-cause mortality compared to use of pioglitazone.2-4 One observational study5 in patients with a mean age of 54 years found no difference in all-cause mortality between patients treated with rosiglitazone compared to pioglitazone and reported similar results in the subpopulation of patients >65 years of age. One additional small, prospective, observational study10 found no statistically significant differences for CV mortality and all-cause mortality in patients treated with rosiglitazone compared to pioglitazone.