Efficacy and safety of pioglitazone, empagliflozin and glimepiride as third-line agents in patients with type 2 diabetes inadequately controlled with metformin and DPP-4 inhibitors: A multicentre, phase 4 randomized controlled trial.

To assess the efficacy and safety of three triple-combination therapies in patients with type 2 diabetes (T2D) inadequately controlled on metformin and a dipeptidyl peptidase-4 (DPP-4) inhibitor. This multicentre, prospective, randomised, open-label, parallel-group, phase 4 study included patients with T2D inadequately controlled on metformin (≥1000 mg) and a DPP-4 inhibitor. Participants were randomised to receive empagliflozin 10 mg/day (n = 61), pioglitazone 15 mg/day (n = 58) or glimepiride 2 mg/day (n = 57). The primary outcome was glycated haemoglobin (HbA1c) level change after 24 weeks of treatment. The mean age, HbA1c level and diabetes duration of the patients were 58.5 ± 10.0 years, 7.8 ± 0.7% and 8.1 ± 5.6 years, respectively. HbA1c level decreased after treatment (-0.78 ± 0.09, empagliflozin; -0.89 ± 0.09, pioglitazone; and -0.93 ± 0.12 glimepiride). No significant differences were observed in HbA1c reduction among the three triple-combination therapies. The proportions of patients with HbA1c < 7.0% were similar across the three regimens (65.6%, empagliflozin; 56.9%, pioglitazone; and 63.2%, glimepiride). Significant weight loss was observed in the empagliflozin group (-1.73 ± 3.14 kg), whereas weight gain was observed in the pioglitazone and glimepiride groups (1.11 ± 3.97 kg and 1.11 ± 4.07 kg, respectively). The glimepiride group reported four hypoglycaemic episodes (6.56%), while none were reported in the other groups. The addition of empagliflozin, pioglitazone, or glimepiride to metformin and DPP-4 inhibitors significantly improved glycaemic control in patients with T2D. The selection of a third agent should be individualized based on the patient characteristics.