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. 2025 Jul 1;185(7):827-836.
doi: 10.1001/jamainternmed.2025.0686.

SGLT2 Inhibitors and Risk for Hyperkalemia Among Individuals Receiving RAAS Inhibitors

Sara Wing  1   2   3 , Joel G Ray  2   4   5   6   7   8 , Kevin Yau  2   3   4   9 , Nivethika Jeyakumar  5   10 , Sheikh Abdullah  5   10 , Bin Luo  5   10 , David Z I Cherney  2   9 , Ziv Harel  1   2   3   4   5 , Gregory L Hundemer  11 , Thomas A Mavrakanas  12 , Amber O Molnar  13 , Ayodele Odutayo  9   14 , Jeffrey Perl  1   2   3   4   5 , Ann Young  1   2   3   5 , David Charytan  15 , Matthew Weir  16   17 , Ron Wald  1   2   3   4   5   18
Affiliations

SGLT2 Inhibitors and Risk for Hyperkalemia Among Individuals Receiving RAAS Inhibitors

Sara Wing et al. JAMA Intern Med. .

Abstract

Importance: Hyperkalemia is a common complication of taking a renin-angiotensin-aldosterone system inhibitor (RAASi). Post hoc analyses of large randomized clinical trials suggested that the addition of sodium-glucose cotransporter 2 inhibitors (SGLT2i) may attenuate this risk. It is unknown if this observation extends to daily clinical practice.

Objective: To evaluate the association between SGLT2i initiation and hyperkalemia in individuals receiving RAASi with a background of diabetes, heart failure, or chronic kidney disease.

Design, setting, and participants: This population-based retrospective cohort study was conducted in Ontario, Canada, from July 1, 2015, to June 30, 2021. The cohort comprised adults 66 years and older who were prescribed a RAASi and had a history of diabetes or heart failure, an estimated glomerular filtration rate of less than 45 mL/min/1.73 m2, and/or a urine albumin to creatinine ratio of greater than 30 mg/mmol. The data were analyzed between March 28, 2023, and March 22, 2024.

Exposure: The study exposure was a new prescription of an SGLT2i compared to noninitiation of an SGLT2i. Inverse probability of treatment weighting by a propensity score for the receipt of SGLT2i was used to achieve balance of baseline covariates in both exposure groups.

Main outcomes and measures: The primary study outcome was hyperkalemia, defined as a serum potassium of greater than 5.5 mEq/L or an administrative code for an inpatient or outpatient encounter with hyperkalemia within 1 year of the index date.

Results: A total of 20 063 individuals who initiated an SGLT2i (mean [SD] age, 76.9 [6.6] years; 12 020 [59.9%] male) were compared to a pseudopopulation of 19 781 nonusers (mean [SD] age, 76.8 [7.0] years; 11 731 [59.3%] male). In the overall cohort, 95% had diabetes, 17% had heart failure, and 32% had stage 3 to 5 chronic kidney disease. SGLT2i initiation was associated with a lower risk of hyperkalemia (hazard ratio, 0.89 [95% CI, 0.82-0.96]). SGLT2i users had a significantly lower rate of RAASi discontinuation compared to nonusers (36% vs 45%; P < .001).

Conclusions and relevance: This cohort study demonstrated that, among individuals with diabetes, heart failure, or chronic kidney disease who were receiving a RAASi, SGLT2i initiation was associated with a lower risk of hyperkalemia and RAASi discontinuation.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Cherney reported personal fees from Boehringer Ingelheim-Lilly, Merck, AstraZeneca, Sanofi, Mitsubishi-Tanabe, AbbVie, Janssen, AMGEN, Bayer, Prometic, BMS, Maze, Gilead, CSL-Behring, Otsuka, Novartis, Youngene, Lexicon, Inversago, GSK, Biobridge, Vantage, Altimmune, and Novo-Nordisk, and grants from Boehringer Ingelheim-Lilly, Merck, Janssen, Sanofi, AstraZeneca, CSL-Behring, Lexicon, Novo-Nordisk, and Bayer outside the submitted work. Dr Mavrakanas reported personal fees from BMS Canada, Pfizer, Bayer, Janssen, GSK, Servier, and Boehringer Ingelheim and grants from AstraZeneca outside the submitted work. Dr Perl received speaking honoraria from Baxter Healthcare, financial support from Arbor Research Collaborative for Health, an editorial stipend from the International Society for Peritoneal Dialysis, and a stipend from the American Society of Nephrology during the conduct of the study and extending outside the submitted work. Dr Charytan reported personal fees from Merck for advisory board service, AstraZeneca for data safety monitoring board service, Novo Nordisk for consulting and being a site investigator for a clinical trial, and CSL Behring for steering committee service, as well as grants from Boehringer-Lilly Support (with drug donation for clinical trial) outside the submitted work. Dr Wald reported personal fees from Otsuka and AstraZeneca outside the submitted work. No other disclosures were reported.

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