Physicians' Academy for Cardiovascular Education

Thiazolidinedione and sulfonylureas have similar CV benefit for diabetics on top of metformin

Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial

Vaccaro O, Masulli M, Nicolucci A, et al. - Lancet Diab Endocrinol 2017


Good glycemic control can reduce the incidence of CV events and microvascular complications in diabetic patients [1,2]. Metformin is the first-line therapy in these patients, but it achieves appropriate glucose control only in approximately 50% of patients at 3 years after diagnosis [3]. Sulfonylureas and pioglitazone are used as add-on therapy in diabetic patients with inadequate glucose control, however, it is not clear which combination benefits these patients most [4-6].

In this multicenter, randomized, parallel-group study, the long-term effect of a sulfonylurea versus pioglitazone as add-on therapy to metformin was evaluated in regard to the incidence of CV events, glucose control and safety, in diabetic patients inadequately controlled with metformin monotherapy, under usual clinical practice conditions. The study was stopped early on the basis of a futility analysis after a median follow-up of 57.3 months.

Approximately 3.000 men and women, aged 50–75 years, with T2DM for at least 2 years on stable treatment with 2–3 g metformin per day and an HbA1c of 7.0 – 9.0 % (53–75 mmol/mol), and a BMI of 20–45 kg/m2 were recruited. The key exclusion criteria were acute CV events in the previous 6 months, chronic HF, and a serum creatinine concentration greater than 132 μmol/L.

Metformin dose remained unchanged throughout the study, whereas the add-on drugs could be titrated at the investigators’ discretion (15–45 mg for pioglitazone, 5–15 mg for glibenclamide, 30–120 mg for gliclazide, and 2–6 mg for glimepiride were used).

Treatment failure was defined as an HbA1c of 8% (64 mmol/mol) or higher on two consecutive visits 3 months apart. If treatment failure occurred, insulin was added, in a stepwise manner, to the previous treatment, which continued at the same doses. The primary outcome was a composite of the first occurrence of all-cause death, non-fatal MI, non-fatal stroke, or urgent coronary revascularization. The key secondary outcome was a composite of ischemic CV disease, including the first occurrence of sudden death, fatal and non-fatal MI, stroke, leg amputation above the ankle, and any revascularization of the coronary, leg, or carotid arteries.

Main results


In a real world clinical setting, both sulfonylureas and pioglitazone have a similar effect as add-on therapies to metformin regarding the incidence of total CV events in diabetic patients. These findings suggest that in T2DM patients without CV diseases, pioglitazone or a sulfonylurea are suitable alternatives as add-on treatment to metformin, although the combination of metformin and pioglitazone was advantageous in terms of durability of glycemic control and frequency of hypoglycemia.


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Find this article online at Lancet Diabetes Endocrinol