Weighing the benefits and risks of thiazolidinediones

Patients with type 2 diabetes have a 2- to 4-fold increased incidence of coronary artery disease than those without diabetes. Thiazolidinediones are a class of oral glucose-lowering agents used to treat patients with type 2 diabetes and insulin resistance.¹ They bind to and activate nuclear peroxisome proliferator-activated receptors, which are transcription factors regulating more than 100 different genes involved in glucose and lipid metabolism, inflammation, and vascular tone. The agents currently available, rosiglitazone (Avandia) and pioglitazone (Actos), approved for use in 1999, differ in their ability to interact with coactivators, which explains some different biological effects. Although thiazolidinediones improve glycemic control, the common side effects of weight gain and edema limit their use. Despite 8 years of clinical experience with these drugs, there are few studies specifically evaluating cardiovascular outcomes.

A subgroup analysis of 2445 patients with type 2 diabetes and previous myocardial infarction (MI) from the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) appears in the

CAD and Diabetes feature article

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. The study results showed a nonsignificant 12% risk reduction in the primary PROactive end point of macrovascular events or death in the pioglitazone group compared with the placebo group. The rate of heart failure requiring hospitalization was higher in the pioglitazone group than in the placebo group (7.5% vs 5.2%, respectively; = .022), although fatal heart failure was not significantly different (1.4% vs 0.9%, respectively; = .283). A new meta-analysis from Lincoff et al² using data from 16,390 patients enrolled in 19 controlled pioglitazone trials (including PROactive) found a significant 18% ( = .005) risk reduction in the composite end point of death, MI, or stroke in patients receiving pioglitazone compared with controls, although the data was not statistically significant when each end point was examined separately.

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Recent controversy has surrounded rosiglitazone after the publication of a flawed meta-analysis by Nissen and Wolski questioned the cardiovascular safety of rosiglitazone, stating it was associated with a significant 43% increase in MI and an increase in cardiovascular death of borderline significance.³ In response, an unplanned interim analysis of a cardiovascular outcomes trial of 4447 patients with type 2 diabetes treated with add-on rosiglitazone or a combination of metformin (Fortamet, Glucophage, Riomet) plus a sulfonylurea was published.⁴ After a mean follow-up period of 3.75 years, there were no statistically significant differences between the rosiglitazone and control groups regarding MI and death from cardiovascular or any other causes (hazard ratio [HR], 1.11; = .26). There were 47 subjects with heart failure in the rosiglitazone group vs 22 in the control group (HR, 2.15; = .003). The data were inconclusive as to whether treatment with rosiglitazone results in a higher rate of MI than therapy with metformin or a sulfonylurea. There are also new pooled data demonstrating a 2-fold increased incidence of fractures of the distal upper and lower limbs in women taking rosiglitazone and pioglitazone.⁵

Although thiazolidinediones may still be useful as third-line agents to control glycemia in difficult-to-treat patients with type 2 diabetes, their benefit (durability and insulin-sparing effects) must be weighed against their risks. Decreasing cardiovascular events and improving survival in patients with type 2 diabetes require evidence-based treatment strategies, including the use of statins for lipid management, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for blood pressure management, and aspirin therapy, along with metformin and other agents to achieve glycemic targets.