Combination Therapy with an SGLT2 Inhibitor as Initial Treatment for Type 2 Diabetes: A Systematic Review and Meta-Analysis

BACKGROUND: Guidelines differ with regard to indications for initial combination pharmacotherapy for type 2 diabetes. AIMS: To compare the efficacy and safety of (i) sodium-glucose cotransporter 2 (SGLT2) inhibitor combination therapy in treatment-naïve type 2 diabetes adults; (ii) initial high and low dose SGLT2 inhibitor combination therapy. METHODS: PubMed, Embase and Cochrane Library were searched for randomised controlled trials (RCTs) of initial SGLT2 combination therapy. Mean difference (MD) for changes from baseline (HbA1c, weight, blood pressure) after 24⁻26 weeks of treatment and relative risks (RR, safety) were calculated using a random-effects model. Risk of bias and quality of evidence was assessed. RESULTS: = 3749) there was moderate quality evidence that SGLT2 inhibitor/metformin combination therapy resulted in a greater reduction in HbA1c (MD (95% CI); -0.55% (-0.67, -0.43)) and weight (-2.00 kg (-2.34, -1.66)) compared with metformin monotherapy, and a greater reduction in HbA1c (-0.59% (-0.72, -0.46)) and weight (-0.57 kg (-0.89, -0.25)) compared with SGLT2 inhibitor monotherapy. The high dose SGLT2 inhibitor/metformin combination resulted in a similar HbA1c but greater weight reduction; -0.47 kg (-0.88, -0.06) than the low dose combination therapy. The RR of genital infection with combination therapy was 2.22 (95% CI 1.33, 3.72) and 0.69 (95% CI 0.50, 0.96) compared with metformin and SGLT2 inhibitor monotherapy, respectively. The RR of diarrhoea was 2.23 (95% CI 1.46, 3.40) with combination therapy compared with SGLT2 inhibitor monotherapy. CONCLUSIONS: Initial SGLT2 inhibitor/metformin combination therapy has glycaemic and weight benefits compared with either agent alone and appears relatively safe. High dose SGLT2 inhibitor/metformin combination therapy appears to have modest weight, but no glycaemic benefits compared with the low dose combination therapy.