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Cited by 29Potassium and Related DisordersDiabetes Treatment and ManagementChronic Kidney Disease and Diabetes

SGLT2 Inhibitors and Risk for Hyperkalemia Among Individuals Receiving RAAS Inhibitors

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Wing, Sara, Ray, Joel G., Yau, Kevin, Jeyakumar, Nivethika, Abdullah, Sheikh, Luo, Bin, Cherney, David Z. I., Harel, Ziv +9 more·2025·JAMA Internal Medicine
DOI 10.1001/jamainternmed.2025.0686PMC PMC12038716
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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 m 2 , 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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  • Among individuals with diabetes and/or CKD receiving ACE inhibitor or ARB therapy, SGLT2 inhibitor initiation was associated with a lower risk of hyperkalemia (HR 0.89 [95% CI 0.82-0.96]) and ACE inhibitor or ARB therapy discontinuation compared with nonusers (36% vs. 45%; P < 0.001).

    “Among individuals with diabetes and/or CKD receiving an ACE inhibitor or ARB therapy, SGLT2 inhibitor initiation was associated with a lower risk of hyperkalemia (HR 0.89 [95% CI 0.82-0.96])and ACE inhibitor or ARB therapy discontinuation compared with nonusers (36% vs. 45%; P < 0.001) (88).”

    From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [88]

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Authors
Wing, S., Ray, J. G., Yau, K., Jeyakumar, N., Abdullah, S., Luo, B., Cherney, D. Z. I., Harel, Z., Hundemer, G. L., Mavrakanas, T. A., Molnar, A. O., Odutayo, A., Perl, J., Young, A., Charytan, D., Weir, M., & Wald, R.
Affiliations
  • St. Michael's Hospital (CA)
  • Lawson Health Research Institute (CA)
  • University Health Network (CA)
  • University of Ottawa (CA)
  • McGill University Health Centre (CA)
  • McMaster University (CA)
  • Sunnybrook Health Science Centre (CA)
  • New York University (US)
  • Western University (CA)
ORCID
Venue
JAMA Internal Medicine
Publisher
American Medical Association (AMA)
Published
2025-07-01
Volume
185
Issue
7
Pages
827
ISSN
2168-6106 (ISSN-L)
DOI
10.1001/jamainternmed.2025.0686
PMC
PMC12038716
OpenAlex
W4409886135
Cited by
29
References
32
Citations by year
2026: 23 · 2025: 6
FWCI
19.06
Type
journal article
Language
en
Open access
Locations
  • JAMA Internal Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (submittedVersion)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Potassium and Related Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
Keywords
SGLT2 inhibitors, hyperkalemia, renin-angiotensin-aldosterone system inhibitors, drug-drug interactions, chronic kidney disease, heart failure, diabetes mellitus, older adults, adverse drug reactions, propensity score weighting, real-world evidence, prescribing patterns, antihypertensive therapy, albuminuria
MeSH terms
Sodium-Glucose Transporter 2 Inhibitors, Aged, Angiotensin-Converting Enzyme Inhibitors, Diabetes Mellitus, Type 2, Female, Heart Failure, Humans, Hyperkalemia, Male, Ontario, Renin-Angiotensin System, Retrospective Studies, Risk Factors, Renal Insufficiency, Chronic

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