Cardiovascular Effects of Pioglitazone or Sulfonylureas According to Pretreatment Risk: Moving Toward Personalized Care.

Context: Hypoglycemic drugs with proven cardiovascular (CV) benefits are recommended for patients with type 2 diabetes and CV disease. Whether the beneficial effects extend to those at lower risk remains unclear.

Aim: We investigated the long-term CV effects of pioglitazone or sulfonylureas (SUs) across the spectrum of pretreatment CV risk.

Methods: Among 2820 participants of the TOSCA.IT trial, four subgroups with different risk of outcome-a composite of all-cause death, nonfatal myocardial infarction, nonfatal stroke, urgent coronary revascularization-were identified by the RECursive Partitioning and AMalgamation (RECPAM) method. Within each group, the effect of SUs or pioglitazone on the outcome was evaluated.

Results: Sex was the first splitting variable, followed by urinary albumin-to-creatinine ratio (UACR) (>9 mg/g or ≤9 mg/g) and body mass index (BMI) (>28.7 or ≤28.7 kg/m2). Female patients had the lowest risk (reference); male patients with UACR >9 mg/g and BMI >28.7 kg/m2 had the highest risk [hazard ratio (HR), 5.58; 95% CI, 3.32 to 9.69]. Patients in this group present a cluster of conditions suggestive of marked insulin resistance (higher BMI, waist circumference, triglycerides, blood pressure, and UACR and lower high-density lipoprotein cholesterol) than the other groups. Treatment with pioglitazone in this group was associated with a significantly lower occurrence of the outcome than SUs (HR, 0.48; 95% CI, 0.25 to 0.76). No significant difference between study treatments was observed in the other RECPAM classes.

Conclusions: It is possible to identify patients with type 2 diabetes early in the stage of their disease and who are largely free from evident CV disease in whom add-on pioglitazone to metformin confers CV protection as compared with SUs.