Cardiovascular Effects of Pioglitazone and Sulfonylureas in Type 2 Diabetes

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Compared with sulfonylureas, supplemental pioglitazone and metformin offers better cardiovascular protection to patients in the early stages of type 2 diabetes.

Compared with sulfonylureas, supplemental pioglitazone and metformin offer better cardiovascular protection to patients in the early stages of type 2 diabetes (T2D) who are at relatively low risk for cardiovascular disease, according to study results published in The Journal of Clinical Endocrinology & Metabolism.

Sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists have proven cardiovascular benefits in patients with T2D with prior cardiovascular events. However, there is no clear evidence to suggest this effect applies to patients who do not have clinically evident cardiovascular disease, who make up a majority of patients with diabetes. Researchers conducted this study in an effort to identify patients with T2D with varying degrees of pretreatment cardiovascular risk and compare the long-term cardiovascular effects of pioglitazone and sulfonylureas on each class of patients.

In total, 2820 patients from a previous trial were stratified to 4 subgroups based on composite risk for all-cause mortality, nonfatal myocardial infarction, nonfatal stroke, and urgent coronary revascularization. At baseline, average age was 62 years, body mass index (BMI) was 30 kg/m2, and disease duration was 8.5 years. Of the total population, 11.2% reported previous cardiovascular disease.

Given that sex was the primary driver, the researchers’ splitting method classified all female participants as having the lowest cardiovascular risk (class 1). The other 3 classes consisted entirely of men, separated by urinary albumin-to-creatinine ratio (UACR) and BMI: class 2 was men with UACR ≤9 mg/g, class 3 was men with UACR >9 mg/g and BMI ≤28.8 kg/m2, and class 4 was men with UACR >9 mg/g and BMI >28.8 kg/m2.

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Patients in class 4 had the highest risk for the cardiovascular outcomes compared with class 1 (hazard ratio, 5.58), and tended to have greater insulin resistance than the other classes with features such as higher BMI, waist circumference, triglycerides, blood pressure, and UACR and lower high-density lipoprotein cholesterol. In class 4, metformin plus pioglitazone was associated with significantly lower risk for cardiovascular events than metformin and sulfonylureas (hazard ratio, 0.48). As for the other classes, the researchers observed no significant differences between the treatments.

The researchers reported that subgroup analyses were limited as a result of the low rate of recorded major adverse events.

“Our study shows that in clinical practice it is possible to identify [patients with T2D] early in the stage of their disease, when [cardiovascular] risk is relatively low and [cardiovascular] events uncommon, in whom add-on pioglitazone to metformin confers [cardiovascular] protection as compared [with sulfonylureas],” wrote the researchers.

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Vaccaro O, Lucisano G, Masulli M, et al. Cardiovascular effects of pioglitazone or sulphonylureas according to pretreatment risk: moving towards personalized care [published online May 6, 2019]. J Clin Endocrinol Metab. doi:10.1210/jc.2019-00361