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Cited by 97Diabetes Treatment and ManagementPharmacovigilance and Adverse Drug ReactionsPharmacology and Obesity Treatment

Clinical adverse events associated with sodium-glucose cotransporter 2 inhibitors: a meta-analysis involving 10 randomized clinical trials and 71 553 individuals

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Lin, Donna Shu-Han, Lee, Jen-Kuang, Chen, Wen-Jone·2021·The Journal of Clinical Endocrinology & Metabolism
DOI 10.1210/clinem/dgab274
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Abstract

Context: SGLT2is are first-line antidiabetic agents with demonstrated cardiovascular benefits. Prior meta-analyses have examined adverse events (AEs) associated with these drugs in general, but such knowledge needs to be updated with the results of more recent trials. In addition, the occurrence of various AEs with different underlying diseases is unknown. Objective: This meta-analysis aimed to investigate the occurrence of various AEs associated with sodium–glucose cotransporter 2 inhibitors (SGLT2is) and to examine the level of risk of AEs in patients with different underlying diseases. Methods: We conducted a quantitative meta-analysis of randomized controlled trials (RCTs) retrieved from the MEDLINE and EMBASE databases and the Cochrane library on January 31, 2021. Outcomes of interest included 4 overall safety outcomes (AEs) and 12 specified safety outcomes. Further analyses were performed on various subgroups, which were defined based on the status of diabetes mellitus (DM), atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease, and congestive heart failure, and by the dosage of SGLT2i (high dose vs low dose). Results: Our analysis included 10 eligible studies with a total of 71 553 participants. The meta-analysis showed that SGLT2i led to increased risks of genital infection (risk ratio [RR] 3.56, 95% CI 2.84-4.46), urinary tract infection (RR 1.06, 95% CI 1.00-1.12), diabetic ketoacidosis (RR 2.23, 95% CI 1.36-3.63), and volume depletion (RR 1.14, 95% CI 1.06-1.23). However, the use of SGLT2i was associated with reduced risks of any serious AE (RR 0.92, 95% CI 0.90-0.94), acute kidney injury (AKI) (RR 0.84, 95% CI 0.77-0.91), and hyperkalemia (RR 0.84, 95% CI 0.72–0.99). Within the different subgroups, the risk of amputation was higher in patients with ASCVD than in those without (RR 1.44 vs 0.96, P = .066). Conclusion: The use of SGLT2is is generally safe. SGLT2is may be associated with increased risks of genital infection but are protective against AKI. Of note, the risk of amputation was higher in patients with ASCVD. The key to the safe use of SGLT2is lies in the identification of high-risk populations and close surveillance of patients after treatment.

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  • SGLT2 inhibitors cause a higher rate of genital mycotic infections, especially in women.

    “SGLT2 inhibitors cause a higher rate of genital mycotic infections, especially in women”

    From 13. Older Adults: Standards of Care in Diabetes—2026 (2026) · cites this paper as [144]

    The Specified Safety Outcomes section (page not supplied) reports significantly more genital infections with SGLT2 inhibitors than with placebo (RR 3.56). The paper does not report that the increase is especially pronounced in women, and its own result is for genital infections generally rather than mycotic infections specifically. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • SGLT2 inhibitor use may be associated with a small increase in urinary tract infections.

    “Their use may also be associated with a small increase in urinary tract infections”

    From 13. Older Adults: Standards of Care in Diabetes—2026 (2026) · cites this paper as [144]

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Research works printed but not linked: 29

  1. Gerstein HC, Miller ME, Byington RP, et al.; Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of in- tensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24):2545-2559.
  2. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK prospective dia- betes study (UKPDS) group. Lancet. 1998;352(9131):837-853.
  3. Wilcox T, De Block C, Schwartzbard AZ, Newman JD. Diabetic agents, from metformin to SGLT2 inhibitors and GLP1 re- ceptor agonists: JACC focus seminar. J Am Coll Cardiol. 2020;75(16):1956-1974.
  4. Zhang XL, Zhu QQ, Chen YH, et al. Cardiovascular safety, long-term noncardiovascular safety, and efficacy of sodium- glucose cotransporter 2 inhibitors in patients with type 2 dia- betes mellitus: a systemic review and meta-analysis with trial sequential analysis. J Am Heart Assoc. 2018;7(2):e007165.
  5. Kim H, Lee S-H, Cho J-H, et al. Discontinuation rate and reason for discontinuation after sodium-glucose cotransporter 2 in- hibitor prescription in real clinical practice. J Clin Pharm Ther. 2020;45(6):1271-1277.
  6. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and car- diovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357.
  7. Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med. 2021;384(2):129-139.
  8. Cannon CP, Pratley R, Dagogo-Jack S, et al.; VERTIS CV Investigators. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383(15):1425-1435.
  9. Dave CV, Schneeweiss S, Patorno E. Comparative risk of genital infections associated with sodium-glucose co-transporter-2 in- hibitors. Diabetes Obes Metab. 2019;21(2):434-438.
  10. Adimadhyam S, Schumock GT, Calip GS, Smith Marsh DE, Layden BT, Lee TA. Increased risk of mycotic infections asso- ciated with sodium-glucose co-transporter 2 inhibitors: a pre- scription sequence symmetry analysis. Br J Clin Pharmacol. 2019;85(1):160-168.
  11. Puckrin R, Saltiel MP, Reynier P, Azoulay L, Yu OHY, Filion KB. SGLT-2 inhibitors and the risk of infections: a systematic re- view and meta-analysis of randomized controlled trials. Acta Diabetol. 2018;55(5):503-514.
  12. Fralick M, MacFadden DR. A hypothesis for why sodium glu- cose co-transporter 2 inhibitors have been found to cause genital infection, but not urinary tract infection. Diabetes Obes Metab. 2020;22(5):755-758.
  13. Liu J, Li L, Li S, et al. Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis. Sci Rep. 2017;7(1):2824.
  14. Liu J, Li L, Li S, et al. Sodium-glucose co-transporter-2 in- hibitors and the risk of diabetic ketoacidosis in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2020;22(9):1619-1627.
  15. Kim YG, Jeon JY, Han SJ, Kim DJ, Lee KW, Kim HJ. Sodium- glucose co-transporter-2 inhibitors and the risk of ketoacid- osis in patients with type 2 diabetes mellitus: a nationwide population-based cohort study. Diabetes Obes Metab. 2018;20(8):1852-1858.
  16. Douros A, Lix LM, Fralick M, et al. Sodium-glucose cotransporter-2 inhibitors and the risk for diabetic keto- acidosis: a multicenter cohort study. Ann Intern Med. 2020;173(6):417-425.
  17. Wang L, Voss EA, Weaver J, et al. Diabetic ketoacidosis in patients with type 2 diabetes treated with sodium glucose co-transporter 2 inhibitors versus other antihyperglycemic agents: an obser- vational study of four US administrative claims databases. Pharmacoepidemiol Drug Saf. 2019;28(12):1620-1628.
  18. Burke KR, Schumacher CA, Harpe SE. SGLT2 inhibitors: a systematic review of diabetic ketoacidosis and related risk factors in the primary literature. Pharmacotherapy. 2017;37(2):187-194.
  19. Clark A, Mohammed AS, Raut A, Moore S, Houlden R, Awad S. Prevalence and clinical characteristics of adults presenting with sodium-glucose cotransporter-2 inhibitor-associated diabetic ketoacidosis at a Canadian Academic Tertiary Care Hospital. Can J Diabetes. 2021;45(3):214-219.
  20. Bamgboye AO, Oni IO, Collier A. Predisposing factors for the development of diabetic ketoacidosis with lower than anticipated glucose levels in type 2 diabetes patients on SGLT2-inhibitors: a review. Eur J Clin Pharmacol. 2021;77(5):651-657.
  21. Menne J, Dumann E, Haller H, Schmidt BMW. Acute kidney injury and adverse renal events in patients receiving SGLT2- inhibitors: a systematic review and meta-analysis. PLoS Med. 2019;16(12):e1002983.
  22. Cahn A, Melzer-Cohen C, Pollack R, Chodick G, Shalev V. Acute renal outcomes with sodium-glucose co-transporter-2 inhibitors: real-world data analysis. Diabetes Obes Metab. 2019;21(2):340-348.
  23. Heyward J, Mansour O, Olson L, Singh S, Alexander GC. Association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and lower extremity amputation: a systematic review and meta-analysis. PLoS One. 2020;15(6):e0234065.
  24. Huang CY, Lee JK. Sodium-glucose co-transporter-2 in- hibitors and major adverse limb events: a trial-level meta- analysis including 51 713 individuals. Diabetes Obes Metab. 2020;22(12):2348-2355.
  25. Miyashita S, Kuno T, Takagi H, et al. Risk of amputation as- sociated with sodium-glucose co-transporter 2 inhibitors: a meta-analysis of five randomized controlled trials. Diabetes Res Clin Pract. 2020;163:108136.
  26. Fralick M, Kim SC, Schneeweiss S, Everett BM, Glynn RJ, Patorno E. Risk of amputation with canagliflozin across categories of age and cardiovascular risk in three US nationwide databases: cohort study. BMJ. 2020;370:m2812.
  27. Ueda P, Svanström H, Melbye M, et al. Sodium glu- cose cotransporter 2 inhibitors and risk of serious ad- verse events: nationwide register based cohort study. BMJ. 2018;363:k4365.
  28. Adimadhyam S, Lee TA, Calip GS, Smith Marsh DE, Layden BT, Schumock GT. Risk of amputations associated with SGLT2 in- hibitors compared to DPP-4 inhibitors: a propensity-matched cohort study. Diabetes Obes Metab. 2018;20(12):2792-2799.
  29. Huang CY, Lee JK. Sodium-glucose co-transporter-2 inhibitors and major adverse limb events: a trial-level meta-analysis including 51 713 individuals. Diabetes Obes Metab. 2020;22(12):2348-2355.

Cited by

Sorted by citations

Authors
Lin, D. S.-H., Lee, J.-K., & Chen, W.-J.
Affiliations
  • National Taiwan University Hospital (TW)
  • National Taiwan University (TW)
Corresponding author
Lee, Jen-Kuang
ORCID
Venue
The Journal of Clinical Endocrinology & Metabolism
Publisher
The Endocrine Society
Published
2021-04-24
Volume
106
Issue
7
Pages
2133-2145
ISSN
  • 0021-972X (ISSN-L)
  • 1945-7197
DOI
10.1210/clinem/dgab274
OpenAlex
W3157553597
Cited by
97
References
9
Citations by year
2026: 25 · 2025: 21 · 2024: 19 · 2023: 12 · 2022: 16 · 2021: 4
FWCI
1.96
Type
journal article
Language
en
Open access
Licence
academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
Locations
  • The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Ministry of Science and Technology of Taiwan (MOST 108-2221-E-002-163-, MOST 109-2221-E-002-083-)
  • National Taiwan University Hospital (107-EDN11, 108-N4406, 108EDN02, 109-O20, 109-S4579, 109-EDN11, 110-S5045, 110-O08)
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, drug safety, genital tract infection, urinary tract infection, diabetic ketoacidosis, hypovolemia, acute kidney injury, hyperkalemia, atherosclerotic cardiovascular disease, chronic kidney disease, congestive heart failure, diabetes mellitus, amputation, drug dosing, antidiabetic drugs, cardiovascular benefits
MeSH terms
Sodium-Glucose Transporter 2 Inhibitors, Adult, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Female, Humans, Hypoglycemic Agents, Male, Risk Factors, Urinary Tract Infections, Randomized Controlled Trials as Topic, Diabetic Ketoacidosis, Renal Insufficiency, Chronic, Reproductive Tract Infections, Drug-Related Side Effects and Adverse Reactions

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