Adverse data from a meta-analysis published in New England Journal of Medicine in 2007 evoked concern about a possible increased CV risk associated with rosiglitazone use [7,10]. Using a fixed-effects analytic model with data from 42 randomized clinical trials, this analysis concluded that rosiglitazone was associated with an approximately 43% increased risk of myocardial infarction (odds ratio [OR], 1.43; 95% confidence interval [CI], 1.03 to 1.98) and an approximately 64% increased risk of CV death (OR, 1.64; 95% CI, 0.98 to 2.74) [7].

The interpretation of these study results have been debated extensively [11,12]. These meta-analyses consisted of predominantly small, short-term, nonadjudicated treatment trials in lower-risk populations [7,13]. Nissen's analysis used the number of events rather than time to event without consideration of follow-up, and some trials with no events were excluded. None of the trial included in the reports focused primarily on CV safety in patients treated with rosiglitazone [11,12,13]. Furthermore, studies were combined on the basis of a lack of statistical heterogeneity, despite substantial variability in control groups, inclusion criteria, follow-up, and outcome assessment. Indeed, other researchers have analyzed the same group of studies using different statistical methods and found no link between heart attack and rosiglitazone [11].

Nevertheless, additional meta-analyses suggested an increased risk of adverse CV events among patients with type 2 diabetes treated with rosiglitazone [6,14,15]. Due to this possible association with myocardial infarction, rosiglitazone was withdrawn from the European market by the European Medicines Agency in 2010 [16]. At the same time, the FDA imposed restrictions on the prescription and use of the diabetes drug rosiglitazone [17]; the drug has also been removed from the Korean market.

In 2013, the FDA lifted restrictions on the prescription and use of rosiglitazone after re-evaluation of the Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes (RECORD) trial, which showed no increase in the risk of CV morbidity or mortality attributable to rosiglitazone [18,19]. The RECORD trial is the only completed prospective trial to evaluate CV safety in patients treated with rosiglitazone [13].

The rosiglitazone experience aroused awareness of potential CV risk associated with diabetes agents and prompted the FDA to issue new guidelines about CV risk. The approval process for new agents must include a demonstration of no unacceptable increase in CV risk [10]. This requires a meta-analysis of important CV events in phase 2/3 to achieve an upper 95% CI <1.3 to qualify for approval without requiring a postmarketing CV trial, provided that the overall benefits and risks support drug approval. If the upper 95% CI is >1.8, additional phase 3 safety studies are required before resubmission for marketing authorization. If the overall risk-benefit balance supports drug approval but the upper CI lies between 1.3 and 1.8, then a postmarketing CV trial usually required to demonstrate an upper 95% CI <1.3 [10,20]. In practice, each sponsor of a recently approved drug has undertaken such a study, even if the phase 2/3 CV events conform to an upper 95% CI <1.3; such postmarketing studies appear to be almost obligatory [10,21].

Along with rosiglitazone, pioglitazone is also a member of the TZD class of drugs. Thus, there is a question of whether use of the other marketed TZD, pioglitazone, carries similar risks [15]. A large CV outcomes trial with pioglitazone, the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PRO-active) trial, was performed to evaluate the effects of pioglitazone on CV morbidity and mortality in high-risk patients with type 2 diabetes. The PROactive trial was a prospective, randomized, controlled trial in 5,238 patients with type 2 diabetes who had evidence of CV disease. These patients were randomized to pioglitazone, titrated to 45 mg daily, or matching placebo with a background of usual glucose-lowering medications. In that study, treatment with pioglitazone produced a nonsignificant reduced risk of coronary and peripheral vascular events (hazard ratio [HR], 0.90; 95% CI, 0.80 to 1.02; P=0.10). As a secondary endpoint, pioglitazone reduced the composite of all-cause mortality, nonfatal myocardial infarction, and stroke (HR, 0.84; 95% CI, 0.72 to 0.98; P=0.03) [22]. More recently, in the Insulin Resistance Intervention after Stroke (IRIS) trial, which included 3,876 nondiabetic patients with insulin resistance and ischemic stroke or transient ischemic attack, patients who were assigned to the pioglitazone group showed a statistically significant 24% reduction in strokes and myocardial infarction compared with placebo recipients over 4.8 years [23]. In addition, a meta-analysis of CV outcome from 19 randomized clinical trials, with a total enrollment of 16,390 diabetic patients, showed that pioglitazone was associated with a significantly lower risk of the composite of death, myocardial infarction, and stroke (HR, 0.82; 95% CI, 0.72 to 0.94; P=0.005) [24].

However, there remains a major concern about the increase in heart failure associated with pioglitazone treatment. Serious congestive heart failure was increased by pioglitazone in both the PROactive trial and the meta-analysis, although without an associated increase in mortality [22,24].