Efficacy and safety of adding a fourth oral antidiabetic drug versus metformin dose escalation in patients with type 2 diabetes inadequately controlled on triple oral combination therapy (EFFORT): A 24-week, randomized, open-label, multicenter trial

Aims: To evaluate the efficacy and safety of adding a fourth oral antidiabetic drug versus metformin uptitration in patients with type 2 diabetes inadequately controlled with oral triple therapy. Materials and Methods: In this 24-week, randomized, open-label trial, adults with type 2 diabetes having glycated haemoglobin (HbA_1C) 7.0–9.0% despite oral triple therapy with metformin plus a thiazolidinedione (TZD), sodium–glucose cotransporter 2 inhibitor (SGLT2i), or dipeptidyl peptidase 4 inhibitor (DPP-4i) were randomized to an oral quadruple add-on group or a metformin uptitration group. The quadruple group received the class not previously used (TZD, SGLT2i, or DPP-4i), whereas the metformin uptitration group increased the metformin dose by up to 500 mg per day. The primary endpoint was the change in HbA_1C at week 24. Secondary endpoints included fasting glucose, metabolic parameters, and safety. Results: Hundred and ninety-three were evaluable: 48 in the metformin uptitration group and 145 in the quadruple group. Compared to baseline, HbA_1C at week 24 decreased by 0.70% (interquartile range [IQR] 0.40%, 1.10%) with quadruple therapy and 0.40% (IQR 0.10%, 0.80%) with metformin uptitration (p = 0.002). The rate achieving HbA_1C ≤7.0% was higher in the quadruple group (69.7% vs. 47.9%, p = 0.006). Insulin resistance improved only in the quadruple group and was accompanied by reduced albuminuria. Adverse events were mild and comparable between groups. Conclusions: Oral quadruple therapy achieved greater glycaemic and metabolic improvement without compromising safety, compared with metformin uptitration, supporting its role as an intensification strategy.