Seven RCTs (2,847 participants) were included in the review. Trials lasted between three months and two years. Three trials met all 5 Jadad criteria, two met 4, and two met 3.
The addition of SGLT2 inhibitors to metformin resulted in a statistically significant decrease in glycated haemoglobin at 12 to 24 weeks (MD -0.47%, 95% CI -0.66 to -0.27; seven RCTs), compared with metformin plus placebo. The effect was similar at one year (three RCTs) and at two years (two RCTs), but the results were not statistically significant. Heterogeneity was high (over 80%) at each time point.
There was a statistically significant reduction in fasting plasma glucose at 12 to 24 weeks (MD -1.16 millimoles per litre; mmol/L, 95% CI -1.56 to -0.75; seven RCTs), and at two years (MD -0.55 mmol/L, 95% CI -0.99 to -0.11; two RCTs), compared with metformin plus placebo. Heterogeneity was high at 12 to 24 weeks (Ι²=82%). Body weight was also statistically significantly reduced at all three time points (no substantial heterogeneity). Systolic and diastolic blood pressure were statistically significantly reduced at 12 to 24 weeks, but not at two years (no heterogeneity).
The safety profile was similar between SGLT2 inhibitors plus metformin and metformin plus placebo. The percentage of participants with at least one drug-related adverse event was 19 in the treatment group and 13 in the control group. A higher percentage of patients receiving SGLT2 inhibitors plus metformin had suspected genital infections (8%, compared with 2% for placebo).
From a visual assessment of the funnel plots, the authors concluded that there was low publication bias.