Appraisal of Non-Cardiovascular Safety for Sodium-Glucose Co-Transporter 2 Inhibitors: A Systematic Review and Meta-Analysis of Placebo-Controlled Randomized Clinical Trials

Fang-Hong Shi; Hao Li; Long Shen; Zhen Zhang; Yi-Hong Jiang; Yao-Min Hu; Xiao-Yan Liu; Zhi-Chun Gu; Jing Ma; Hou-Wen Lin

doi:10.3389/fphar.2019.01066

Appraisal of Non-Cardiovascular Safety for Sodium-Glucose Co-Transporter 2 Inhibitors: A Systematic Review and Meta-Analysis of Placebo-Controlled Randomized Clinical Trials

Front Pharmacol. 2019 Sep 19:10:1066. doi: 10.3389/fphar.2019.01066. eCollection 2019.

Authors

Fang-Hong Shi¹, Hao Li², Long Shen³, Zhen Zhang⁴, Yi-Hong Jiang⁵, Yao-Min Hu⁵, Xiao-Yan Liu¹, Zhi-Chun Gu¹, Jing Ma⁵, Hou-Wen Lin¹

Affiliations

¹ Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
² Department of Pharmacy, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
³ Department of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
⁴ Pharmacy Department, Memorial Healthcare System, Hollywood, FL, United States.
⁵ Department of Endocrinology and Metabolism, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

Abstract

Background: Whereas the cardiovascular safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors has been well reported, there is limited data from controlled clinical trials regarding the non-cardiovascular safety. This was the focus of our study. Methods and Findings: We systematically searched MEDLINE, EMBASE, and Cochrane Library (5^th Sep 2018) for randomized controlled trials (RCTs) that reported safety data for SGLT2 inhibitors and placebo. Relative risks (RRs) and their 95% confidence intervals (CIs) were pooled using random-effects models. Seventy RCTs (83 studies enrolling 36,958 patients in 78 publications) were identified. SGLT2 inhibitors were associated with a lower risk of serious adverse events (RR 0.90, 95% CI 0.86 to 0.94, P < 0.001), death (RR 0.78, 95% CI 0.64 to 0.94, P < 0.05), gastroenteritis (RR 0.38, 95% CI 0.20 to 0.72, P < 0.05), arthralgia (RR 0.72, 95% CI 0.54 to 0.96, P < 0.05), hypertension (RR 0.61, 95% CI 0.50 to 0.75, P < 0.001), and edema/peripheral edema (RR 0.49, 95% CI 0.33 to 0.72, P < 0.001) compared to placebo. SGLT2 inhibitors were associated with higher risk of infections compared to placebo (RR 1.27, 95% CI 1.17 to 1.37, P < 0.001), especially for genital mycotic infection (GMI) (RR 3.71, 95% CI 3.19 to 4.32, P < 0.001). Other significant effects were observed for osmotic diuresis-related AEs (RR 2.73, 95% CI 2.20 to 3.40, P < 0.001), volume-related AEs (RR 1.26, 95% CI 1.08 to 1.46, P < 0.05), renal-related AEs (RR 1.36, 95% CI 1.02 to 1.80, P < 0.05), hypoglycemia (RR 1.18, 95% CI 1.10 to 1.26, P < 0.001), and increased blood ketone bodies (RR 2.00, 95% CI 1.01 to 3.97, P < 0.05). Subgroup and sensitivity analyses strengthened the robustness of primary results. Conclusion: Results from RCTs confirmed lower risk of death, serious adverse events, hypertension, and edema associated with type 2 diabetes mellitus (T2DM) patients treated with SGLT2 inhibitors when compared with placebo. The use of SGLT2 inhibitors were associated with higher risk of infection, osmotic diuresis, volume depletion effects, renal related AEs, and higher blood ketone bodies when compared with placebo.

Keywords: meta-analysis; non-cardiovascular safety; randomized controlled trials; sodium-glucose co-transporter 2 inhibitors; systematic review; type 2 diabetes mellitus.

Publication types

Systematic Review