Efficacy and Safety of a Sodium-Glucose Co-Transporter-2 Inhibitor Versus Placebo as an Add-on Therapy for People With Type 2 Diabetes Inadequately Treated With Metformin: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Metformin monotherapy is often insufficient to achieve or sustain glycemic targets in people with type 2 diabetes. Therefore, we performed a systematic review and meta-analysis to assess the efficacy, safety and tolerability of sodium-glucose co-transporter-2 inhibitors versus placebo as add-on therapy after metformin in type 2 diabetes. The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A search was performed in the PubMed, www.clinicaltrials.gov and Cochrane Central Register of Controlled Trials databases for relevant randomized controlled trials up until 30th October 2020 that compared sodium-glucose co-transporter-2 inhibitors versus placebo as add-on therapy to metformin. A random-effects model was used. Thirteen randomized controlled trials (4270 participants) met the inclusion criteria. Compared with placebo, sodium-glucose co-transporter-2 inhibitor treatment, as add-on therapy to metformin, was associated with a significant reduction in HbA1c level (mean difference [MD]: -0.6%, 95% CI: -0.7, -0.5; p<0.01), fasting plasma glucose level (MD: -1.4mmol/l; 95% CI; -1.5, -1.3; p<0.01), weight (MD: -2.0kg; 95% CI: -2.2, -1.8; p<0.01), systolic blood pressure (MD: -4.7mmHg; 95% Cl: -5.4, -3.9; p<0.01) and diastolic blood pressure (MD: -2.0mmHg; 95% Cl: -2.5, -1.5; p<0.01). Significantly more participants achieved HbA1c <7% (odds ratio [OR]: 3.1; 95% CI: 2.6, 3.6; p<0.01) in the sodium-glucose co-transporter-2 inhibitor group. Genital mycotic infections (OR: 2.6; 95% CI: 1.4, 4.6; p<0.01) were more common with sodium-glucose co-transporter-2 inhibitors, but there was no significant statistical difference in urinary tract infections (OR: 1.4; 95% CI: 1.0, 2.0; p=0.06), in hypoglycemia (OR: 1.5; 95% CI: 1.0, 2.4; p=0.07), or in discontinuation rates due to adverse events (OR: 0.9; 95% CI: 0.6, 1.5; p=0.68) between the two groups. In summary, in comparison with placebo, add-on therapy with a sodium-glucose co-transporter-2 inhibitor is significantly more efficacious in lowering HbA1c, fasting plasma glucose, weight and blood pressure in people with type 2 diabetes following inadequate glycemic control with metformin. The rate of discontinuation due to adverse events was similar despite higher risk of genital mycotic infections.