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

Literature - 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

  • The primary CV composite outcome occurred in 7% of patients in the pioglitazone group, and in 7% of patients in the group of sulfonylureas, corresponding to 1.5 per 100 person-years (PY) in both groups. There were no significant between-group differences in the composite primary outcome (HR: 0.96; 95% CI: 0.74 – 1.26; P = 0.79) or in its components.
  • The key secondary outcome occurred in 5% of patients in the pioglitazone group, corresponding to 1.1 per 100 PY, and in 6% of patients in the sulfonylureas group, corresponding to 1.2 per 100 PY (HR: 0.88; 95% CI: 0.65 – 1.21; P = 0.44).
  • HF occurred in 1% of patients in the pioglitazone group and in 1% of patients in the sulfonylureas group (HR: 1.57; 95% CI: 0.76 – 3.24; P = 0.22).
  • The mean HbA1c over time was slightly lower for patients in the pioglitazone group than for patients in the sulfonylureas group (7.24%; SD: 0.20; vs 7.30%; SD: 0.21; P = 0.01; 55 mm/mol vs 56 mmol/mol).
  • Fewer patients had treatment failure with pioglitazone compared with sulfonylureas (13% vs 20%; HR: 0.63; 95% CI: 0.52 – 0.75; P < 0.0001).
  • The overall incidence of serious adverse events was similar in the pioglitazone and sulfonylureas groups. Severe hypoglycemic events were uncommon, but were more frequent with sulfonylureas. The occurrence of confirmed malignant neoplasms, including bladder cancer, was also similar between groups, as well as the incidence of pathological bone fractures and macular edema.


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.


1. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–53.

2. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359: 1577–89.

3. Turner RC, Cull CA, Frighi V, et al, for the UK Prospective Diabetes Study (UKPDS) Group. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 1999, 281: 2005–12.

4. Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA 2016; 316: 313–24.

5. Abdelmoneim AS, Eurich DT, Light PE, et al. Cardiovascular safety of sulphonylureas: over 40 years of continuous controversy without an answer. Diabetes Obes Metab 2015; 17: 523–32.

6. Dormandy JA, Charbonnel B, Eckland DJA, et al, on behalf of the PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005; 366: 1279–89.

Find this article online at Lancet Diabetes Endocrinol

Facebook Comments


We’re glad to see you’re enjoying PACE-CME…
but how about a more personalized experience?

Register for free