Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes: a meta-analysis of randomized controlled trials for 1 to 2years

Aims: To evaluate the mid long-term efficacy and safety of sodium-glucose cotransporter 2 (SGLT2) inhibitors in adults with type 2 diabetes mellitus (T2DM).

Methods: Three databases including Pubmed, Embase, and Cochrane Library were searched for randomized controlled trials (RCTs) of SGLT2 inhibitors that lasted for at least 52weeks. Two reviewers retrieved the literature and evaluated study quality using the Modified Jadad Score Scale. The outcome measures were pooled using random or fixed effects models.

Results: Fourteen articles of 13 RCTs were included in this meta-analysis. Compared to a placebo, the SGLT2 inhibitors significantly reduced glycated hemoglobin (HbA1c) [for 1year result, weighted mean differences (WMDs): -0.491%; 95% confidence intervals (CIs): -0.573 to -0.410; I(2)=39.9%, for 2years result, WMD: -0.503%; 95% CI: -0.742 to -0.265; I(2)=70.7%], fasting plasma glucose (FPG) (for 1year result, WMD: -0.809; 95% CI: -0.858 to -0.761; I(2)=56.4%; for 2years result, WMD: -0.764; 95% CI: -1.026 to -0.501; I(2)=39.4%), body weight (BW) (for 1year result, WMD: -2.477; 95% CI: -2.568 to -2.385; I(2)=0.0%; for 2years result, WMD: -2.990; 95% CI: -3.642 to -2.337; I(2)=0.0%), systolic blood pressure (SBP) (for 1year result, WMD: -2.874; 95% CI: -4.528 to -1.220; I(2)=98.1%; for 2years result, WMD: -7.500; 95% CI: -7.698 to -7.302) and diastolic blood pressure (DBP) (for 1year result, WMD: -1.950; 95% CI: -2.890 to -1.010; I(2)=98.0%; for 2years result, WMD: -2.197; 95% CI: -3.112 to -1.283). Compared to oral antidiabetic drugs (OADs), the SGLT2 inhibitors also reduced HbA1c, FPG, BW, SBP and DBP significantly. Compared to a placebo, the SGLT2 inhibitors increase the risk of hypoglycemia [odds ratios (ORs): 1.214; 95% CI: 1.036 to 1.423; I(2)=47.7%], urinary infection (OR: 1.477; 95% CI: 1.172 to 1.861; I(2)=46.6%) and genital tract infections (OR: 4.196; 95% CI: 2.332 to 7.549; I(2)=52.7%). Compared to OADs, SGLT2 inhibitors showed a remarkable reduction of hypoglycemia incidence (OR: 0.202; 95% CI: 0.059 to 0.691; I(2)=97.8%), but increased the incidence of genital tract infections (OR: 5.715; 95% CI: 4.339 to 7.528; I(2)=0.0%) and urinary infection (OR: 1.192; 95% CI: 0.990 to 1.434; I(2)=45.3%). SGLT2 inhibitors did not decrease estimated glomerular filtration rate (eGFR) when comparing with placebos [(for absolute value change, WMD: 0.629mL/min/1.73m(2); 95% CI: -1.250 to 2.508; I(2)=0.0%); (for percent change, WMD: -2.274%; 95% CI: -5.410 to 0.861; I(2)=54.5%)] and OADs (for percent change, WMD: 0.356%; 95% CI: -0.967 to 1.679; I(2)=0.0%).

Conclusion: SGLT2 inhibitors have favorable effects on combating hyperglycemia for mid long-term; likewise, they have additional benefits beyond glycemic control such as reducing body weight and lowering blood pressure.