Appraisal of Non-Cardiovascular Safety for Sodium–Glucose Co-Transporter 2 Inhibitors: A Systematic Review and Meta-Analysis of Placebo-Controlled Randomized Clinical Trials
Open accessAbstract
Background The cardiovascular safety of sodium-glucose co-transporter 2 (SGLT2) inhibitors has been well reported, only limited data and no comparisons have been published on their non-cardiovascular safety, which was the focus of our study. Methods and findings We systematically searched MEDLINE, EMBASE, and Cochrane Library (5th Sep 2018) for 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. 70 researches (83 studies enrolling 36958 patients in 78 publications) were identified. SGLT2 inhibitors was 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. Whereas, 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), 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.
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A meta-analysis of clinical trials reported that genital mycotic infections occurred in 6% of participants assigned to an SGLT2 inhibitor, compared with 1% of those assigned to placebo.
“A meta-analysis of clinical trials reported that genital mycotic infections occurred in 6% of participants assigned to an SGLT2i, compared with 1% of those assigned to placebo (65).”
From Diabetes management in chronic kidney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) (2022) · cites this paper as [65]
The Results > Safety Outcomes section reports that genital mycotic infections were more frequent with SGLT2 inhibitors than with placebo (RR 3.71). It does not give the claimed 6% and 1% incidence figures; its 21.1% and 16.5% figures refer to infections overall, not genital mycotic infections. Page numbers are unavailable in our copy. (LLM, conf=0.88)
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- Authors
- Shi, F.-H., Li, H., Shen, L., Zhang, Z., Jiang, Y.-H., Hu, Y.-M., Liu, X.-Y., Gu, Z.-C., Ma, J., & Lin, H.-W.
- Affiliations
- Shanghai Jiao Tong University (CN)
- Memorial Healthcare System (US)
- Corresponding author
- Gu, Zhi-Chun
- Ma, Jing
- Lin, Hou-Wen
- Venue
- Frontiers in Pharmacology
- Publisher
- Frontiers Media SA
- Published
- 2019-09-19
- Volume
- 10
- Pages
- 1066-1066
- ISSN
- 1663-9812 (ISSN-L)
- PMC
- PMC6764217
- OpenAlex
- W2969385099
- Cited by
- 30
- References
- 35
- Citations by year
- 2026: 2 · 2025: 4 · 2024: 1 · 2023: 2 · 2022: 10 · 2021: 5 · 2020: 5 · 2018: 1
- FWCI
- 0.77
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Pharmacology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Shanghai Pharmacological Society (2016ZB0304)
- National Natural Science Foundation of China (81670728)
- Shanghai Municipal Education Commission (20181807)
- Shanghai Jiao Tong University (CXYJY2019QN004, CXYJY2019ZD001)
- School of Medicine, Shanghai Jiao Tong University (CXYJY2019QN004, CXYJY2019ZD001)
- Fundamental Research Funds for the Central Universities (17JCYB11)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Pharmacovigilance and Adverse Drug Reactions
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Keywords
- SGLT2 inhibitors, serious adverse events, mortality, gastroenteritis, joint pain, hypertension, peripheral edema, infection, genital mycotic infections, osmotic diuresis, type 2 diabetes, placebo comparison
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