Sodium–Glucose Cotransporter 2 Inhibitors for Type 2 Diabetes: A Systematic Review and Meta-Analysis

Study Questions:

What is the efficacy and safety of sodium–glucose cotransporter 2 (SGLT2) inhibitors in adults with type 2 diabetes?

Methods:

MEDLINE, EMBASE, and the Cochrane Library from inception through April 2013 without language restrictions; regulatory authorities’ reports; and gray literature were reviewed. Randomized trials comparing SGLT2 inhibitors with placebo or other medication for type 2 diabetes were extracted. Three reviewers checked data for study characteristics, outcomes of interest, and risk of bias, and three reviewers summarized strength of evidence using the Grading of Recommendations Assessment, Development and Evaluation approach. The authors calculated weighted mean differences and 95% confidence intervals (CIs) for continuous outcomes using an inverse variance random-effects model. For dichotomous outcomes, they calculated odds ratios (ORs) and 95% confidence intervals (CIs) by using the fixed-effects Mantel–Haenszel approach with a treatment group continuity correction for zero events, including trials with zero events in both groups.

Results:

SGLT2 inhibitors were compared with placebo in 45 studies (n = 11,232) and with active comparators in 13 studies (n = 5,175). They had a favorable effect on glycated hemoglobin level (mean difference vs. placebo, −0.66% [95% CI, −0.73% to −0.58%]; mean difference vs. active comparators, −0.06% [CI, −0.18% to 0.05%]). Sensitivity analyses incorporating unpublished data showed similar effect estimates. Compared with other agents, SGLT2 inhibitors reduced body weight (mean difference, −1.80 kg [CI, −3.50 to −0.11 kg]) and systolic blood pressure (mean difference, −4.45 mm Hg [CI, −5.73 to −3.18 mm Hg]). Urinary and genital tract infections were more common with SGLT2 inhibitors (odds ratios, 1.42 [CI, 1.06-1.90] and 5.06 [CI, 3.44-7.45], respectively). Hypoglycemic risk was similar to that of other agents. Results for cardiovascular outcomes and death were inconclusive. An imbalance in incidence of bladder and breast cancer was noted with dapagliflozin compared with control.

Conclusions:

The authors concluded that SGLT2 inhibitors may improve short-term outcomes in adults with type 2 diabetes, but effects on long-term outcomes and safety are unclear.

Perspective:

This meta-analysis reported that SGLT2 inhibitors were associated with glycemic efficacy similar to that of other antidiabetic agents and had a favorable effect on body weight and blood pressure. Risk for hypoglycemia was similar to that of metformin or sitagliptin and lower than that of sulfonylureas. Overall, SGLT2 inhibitors seem to be an effective treatment option for adults with type 2 diabetes and may improve some short-term outcomes, but we need studies to clarify effects on long-term clinical outcomes, diabetic complications, and safety. Future research should also explore differences among individual SGLT2 inhibitors and differences between SGLT2 inhibitors and other antidiabetic agents.

Clinical Topics: Dyslipidemia, Lipid Metabolism

Keywords: Odds Ratio, Hemoglobin A, Bias (Epidemiology), Breast Neoplasms, Blood Pressure, Glucosides, Hypoglycemia, Pyrazines, Sulfonylurea Compounds, Diabetes Complications, Reproductive Tract Infections, Metformin, Cardiovascular Diseases, Sodium-Glucose Transporter 2, Hypoglycemic Agents, Confidence Intervals, Urinary Bladder, Diabetes Mellitus, Triazoles, MEDLINE


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