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Original Investigation
April 14, 2021

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

Author Affiliations
  • 1Department of Cardiology, Medical University of Vienna, Vienna, Austria
  • 2The Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Hebrew University of Jerusalem, The Faculty of Medicine, Jerusalem, Israel
  • 3Vanderbilt University Medical Center, Nashville, Tennessee
  • 4University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
  • 5The George Institute for International Health, Sydney, Australia
  • 6TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
  • 7Li Ka Shing Knowledge Institute, St Michael’s Hospital, University of Toronto, Ontario, Canada
  • 8Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas
  • 9Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom
  • 10BioPharmaceuticals Research & Development, AstraZeneca, Gothenburg, Sweden
JAMA Cardiol. Published online April 14, 2021. doi:10.1001/jamacardio.2021.0660
Key Points

Question  What is the relative cardiovascular (CV) efficacy and safety of dapagliflozin according to the baseline estimated glomerular filtration rate and urinary albumin to creatinine ratio in patients with type 2 diabetes?

Findings  In this secondary analysis of 17 160 participants included in the DECLARE-TIMI 58 trial, the effect of dapagliflozin (vs placebo) on the relative risk of a composite of CV death and hospitalization for heart failure (HHF) and of major adverse cardiovascular events was similar. However, the absolute risk reduction of CV death and HHF was significantly larger for dapagliflozin-treated patients who had more markers of chronic kidney disease.

Meaning  In this study, the effect of dapagliflozin on the relative risk for CV events was consistent across kidney function and albuminuria status, with the greatest absolute benefit for the composite of CV death or HHF observed among patients with both reduced estimated glomerular filtration rate and albuminuria.

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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