Efficacy and tolerability of initial triple combination therapy with metformin, dapagliflozin and saxagliptin compared with stepwise add‐on therapy in drug‐naïve patients with type 2 diabetes (TRIPLE‐AXEL study): A multicentre, randomized, 104‐week, open‐label, active‐controlled trial

Abstract Aim To evaluate the efficacy and tolerability of an initial triple combination therapy (TCT) compared with conventional stepwise add‐on therapy (SAT) in patients with newly diagnosed type 2 diabetes (T2D). Materials and Methods This multicentre, randomized, 104‐week, open‐label trial randomized 105 patients with drug‐naïve T2D (with HbA1c level ≥ 8.0%, < 11.0%) to the TCT (1000 mg of metformin, 10 mg of dapagliflozin and 5 mg of saxagliptin once daily) or SAT (initiated with metformin, followed by glimepiride and sitagliptin) groups. The primary outcome was the proportion of patients who achieved an HbA1c level of less than 6.5% without hypoglycaemia, weight gain of 5% or higher, or discontinuation of drugs because of adverse events at week 104. Results HbA1c reduction from baseline at week 104 was similar between the groups (the least squares mean change was −2.56% in the TCT group vs. –2.75% in the SAT group). The primary outcome was achieved in 39.0% and 17.1% of the TCT and SAT groups, respectively, with a risk difference of 22.0 (95% confidence interval 3.0, 40.8; P = .027). HbA1c level less than 6.5% at week 104 was 46.3% in both the TCT and SAT groups, whereas the incidence of hypoglycaemia, weight gain, or discontinuation of drugs was 16.7% and 62.0% in the TCT and SAT groups, respectively ( P < .001). TCT was well‐tolerated and had fewer adverse events than SAT. Conclusions Among newly diagnosed patients with T2D, initial TCT effectively lowered HbA1c levels with higher tolerability and safety than SAT for 104 weeks, suggesting a novel strategy for initial combination therapy in T2D patients.