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Cited by 52Diabetes Treatment and ManagementChronic Kidney Disease and DiabetesHeart Failure Treatment and Management

Effect of Dapagliflozin on Cardiovascular Outcomes According to Baseline Kidney Function and Albuminuria Status in Patients With Type 2 Diabetes: A Prespecified Secondary Analysis of a Randomized Clinical Trial

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Zelniker, Thomas A., Raz, Itamar, Mosenzon, Ofri, Dwyer, Jamie P., Heerspink, Hiddo H. J. L., Cahn, Avivit, Goodrich, Erica L., Im, Kyungah +8 more·2021·JAMA Cardiology
DOI 10.1001/jamacardio.2021.0660PMC PMC8047725
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Abstract

Importance: Sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, promote renal glucose excretion and reduce cardiovascular (CV) deaths and hospitalizations for heart failure (HHF) among patients with type 2 diabetes. The relative CV efficacy and safety of dapagliflozin according to baseline kidney function and albuminuria status are unknown. Objective: To assess the CV efficacy and safety of dapagliflozin according to baseline estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR). Design, Setting, and Participants: This secondary analysis of the randomized clinical trial Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 compared dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and a baseline creatinine clearance of 60 mL/min or higher. Patients were categorized according to prespecified subgroups of baseline eGFR (<60 vs ≥60 mL/min/1.73 m2), urinary albumin to creatinine ratio (UACR; <30 vs ≥30 mg/g), and of chronic kidney disease (CKD) markers using these subgroups (0, 1, or 2). The study was conducted from May 2013 to September 2018. Interventions: Dapagliflozin vs placebo. Main Outcomes and Measures: The dual primary end points were major adverse cardiovascular events (myocardial infarction, stroke, and CV death) and the composite of CV death or HHF. Results: At baseline, 1265 patients (7.4%) had an eGFR below 60 mL/min/1.73 m2, and 5199 patients (30.9%) had albuminuria. Among patients having data for both eGFR and UACR, 10 958 patients (65.1%) had an eGFR equal to or higher than 60 mL/min/1.73 m2 and an UACR below 30 mg/g (mean [SD] age, 63.7 [6.7] years; 40.1% women), 5336 patients (31.7%) had either an eGFR below 60 mL/min/1.73 m2 or albuminuria (mean [SD] age, 64.1 [7.1] years; 32.6% women), and 548 patients (3.3%) had both (mean [SD] age, 66.8 [6.9] years; 30.5% women). In the placebo group, patients with more CKD markers had higher event rates at 4 years as assessed using the Kaplan-Meier approach for the composite of CV death or HHF (3.9% for 0 markers, 8.3% for 1 marker, and 17.4% for 2 markers) and major adverse cardiovascular events (7.5% for 0 markers, 11.6% for 1 marker, and 18.9% for 2 markers). Estimates for relative risk reductions for the composite of CV death or HHF and for major adverse cardiovascular events were generally consistent across subgroups (both P > .24 for interaction), although greater absolute risk reductions were observed with more markers of CKD. The absolute risk difference for the composite of CV death or HHF was greater for patients with more markers of CKD (0 markers, -0.5%; 1 marker, -1.0%; and 2 markers, -8.3%; P = .02 for interaction). The numbers of amputations, cases of diabetic ketoacidosis, fractures, and major hypoglycemic events were balanced or numerically lower with dapagliflozin compared with placebo for patients with an eGFR below 60 mL/min/1.73 m2 and an UACR of 30 mg/g or higher. Conclusions and Relevance: The effect of dapagliflozin on the relative risk for CV events was consistent across eGFR and UACR groups, with the greatest absolute benefit for the composite of CV death or HHF observed among patients with both reduced eGFR and albuminuria. Trial Registration: ClinicalTrials.gov Identifier: NCT01730534.

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  • Early changes in kidney function may be detected by increases in albuminuria before changes in eGFR, and this also significantly affects cardiovascular risk.

    “Early changes in kidney function may be detected by increases in albuminuria before changes in eGFR (41), and this also significantly affects cardiovascular risk.”

    From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [41]

    The Study Population section (page not provided) identifies 4,650 patients with albuminuria as their only CKD marker, supporting that albuminuria can identify kidney dysfunction without reduced eGFR. But these are baseline measurements; the paper does not establish that albuminuria increases before an individual's eGFR changes. The CV Outcomes by Markers of CKD section (page not provided) also reports higher cardiovascular event rates among patients with albuminuria alone. (LLM, conf=0.84)

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  • Early changes in kidney function may be detected by increases in albuminuria before changes in eGFR, and this also significantly affects cardiovascular risk.

    “Early changes in kidney function may be detected by increases in albuminuria before changes in eGFR (41), and this also significantly affects cardiovascular risk.”

    From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [41]

    The Study Population section reports albuminuria in patients whose eGFR was not below 60 mL/min/1.73 m², supporting its use as a marker when eGFR is preserved. The CV Outcomes by Markers of CKD in the Placebo Group section also reports higher cardiovascular event rates among patients with albuminuria alone. But these are baseline categories, not evidence that albuminuria increased before an individual's eGFR changed. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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Authors
Zelniker, T. A., Raz, I., Mosenzon, O., Dwyer, J. P., Heerspink, H. H. J. L., Cahn, A., Goodrich, E. L., Im, K., Bhatt, D. L., Leiter, L. A., McGuire, D. K., Wilding, J. P. H., Gause-Nilsson, I., Langkilde, A. M., Sabatine, M. S., & Wiviott, S. D.
Affiliations
  • Medical University of Vienna (AT)
  • Hebrew University of Jerusalem (IL)
  • Vanderbilt University Medical Center (US)
  • University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
  • Brigham and Women's Hospital (US)
  • St. Michael's Hospital (CA)
  • The University of Texas Southwestern Medical Center (US)
  • University of Liverpool (GB)
  • BioPharmaceuticals Research & Development, AstraZeneca, Gothenburg, Sweden
  • AstraZeneca (Sweden) (SE)
Corresponding author
Wiviott, Stephen D.
ORCID
Venue
JAMA Cardiology
Publisher
American Medical Association (AMA)
Published
2021-07-01
Volume
6
Issue
7
Pages
801
ISSN
2380-6583 (ISSN-L)
DOI
10.1001/jamacardio.2021.0660
PMC
PMC8047725
OpenAlex
W3154959553
Semantic Scholar
d5b6a0b4977fbb73fb46a4688e54e8f1768aefc8
Cited by
52
References
35
Citations by year
2026: 5 · 2025: 11 · 2024: 10 · 2023: 12 · 2022: 13 · 2021: 1
FWCI
6.72
Type
journal article
Language
en
Open access
Locations
  • JAMA Cardiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
Funders
Brigham and Women's Hospital
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
Keywords
dapagliflozin, SGLT2 inhibitors, type 2 diabetes, cardiovascular outcomes, estimated glomerular filtration rate, albuminuria, chronic kidney disease, major adverse cardiovascular events, heart failure hospitalization, cardiovascular mortality, subgroup analysis, renal function, drug safety in kidney disease, myocardial infarction, stroke, renal glucose excretion
MeSH terms
Sodium-Glucose Transporter 2 Inhibitors, Aged, Albuminuria, Benzhydryl Compounds, Cardiovascular Diseases, Creatinine, Diabetes Mellitus, Type 2, Female, Glomerular Filtration Rate, Glucosides, Heart Failure, Humans, Male, Middle Aged, Treatment Outcome, Renal Insufficiency, Chronic

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