Meta-analysis Reveals Side Effects of Pre-Diabetes Treatment

Patients with insulin resistance and pre-diabetes who used pioglitazone (Actos/Takeda Pharmaceuticals) experienced reduced risk of myocardial infarction, non-fatal stroke, and cardiovascular death, but increased risk of heart failure, bone fracture, and edema.

Previous research found that pioglitazone was associated with reduced risk of major adverse cardiovascular events (MACE) compared to control drugs or placebo in patients with type 2 diabetes. Bruce Ovbiagele, MD, Department of Neurology, Medical University of South Carolina, Charleston, South Carolina, and colleagues conducted the present meta-analysis to determine its risk profile in pre-diabetes and insulin-resistant patients who had not developed frank diabetes.

"Since pre-diabetes and diabetes do not confer the same risk for the different entities of cardiovascular disease," Ovbiagele and colleagues explained, "patients with insulin resistance/pre-diabetes and diabetes were analyzed separately for cardiovascular outcomes."

Nine placebo-controlled, randomized, controlled trials met inclusion criteria, involving over 12,000 participants (range of 121 to 5,238), having mean study duration of 2.7 years (range of one to 4.8 years), with at least one year of post-study follow-up. The Relative Risk (RR) with 95% confidence interval (CI) was used to estimate risk of clinical outcomes between the pioglitazone and control groups.

Pioglitazone was associated with a 23% reduced risk of MACE, and trend towards reducing recurrent, non-fatal stroke risk in pre-diabetic/insulin resistant patients. In patients with diabetes, pioglitazone was associated with 17% reduced risk of MACE. Treatment with pioglitazone in both the pre-diabetic/insulin resistant and diabetic patients was associated with increased risk of heart failure, edema, weight gain and bone fracture.

Ovbiagele and colleagues suspected that the reduction in cardiovascular risk with pioglitazone reflected mechanisms other than the hypoglycemic effect. They noted research demonstrating favorable effects on lipids and atheroma progression, for example. As diabetes is also considered a major cardiovascular risk factor; however, avoiding or delaying its onset with pioglitazone treatment could have also served to reduce risk.

The increased risk for the often-interrelated conditions of edema, weight gain and heart failure has been found with other agents of the thiazolidinedione class. They suggested excluding patients from this treatment if they have a history of heart failure, and to reduce dosage in the event of edema or weight gain.

This finding follows research by others that the thiazolidinediones produce modest bone loss — one cited study found increased bone fracture in women but not in men, but others have showed no gender difference.

In weighing the risk-benefit profile, Ovbiagele and colleagues concluded that the agent could be useful in appropriately selected pre-diabetic and insulin-resistant patients, in addition to patients with type 2 diabetes.

The results of the meta-analysis, “Pioglitazone and Cardiovascular Outcomes in Patients with Insulin Resistance, Pre-diabetes, and type 2 diabetes: a systematic review and meta-analysis,” are published in the January issue of BMJ Open.

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