Dapagliflozin and Cardiac, Kidney, and Limb Outcomes in Patients with and without Peripheral Artery Disease in DECLARE-TIMI 58

Marc P. Bonaca, Stephen D. Wiviott, Thomas A. Zelniker, Ofri Mosenzon, Deepak L. Bhatt, Lawrence A. Leiter, Darren K. McGuire, Erica L. Goodrich, Remo Holanda De Mendonca Furtado, John P.H. Wilding, Avivit Cahn, Ingrid A.M. Gause-Nilsson, Per Johanson, Martin Fredriksson, Peter A. Johansson, Anna Maria Langkilde, Itamar Raz, Marc S. Sabatine

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


Background: Patients with peripheral artery disease (PAD) are at heightened risk of cardiovascular complications. The sodium-glucose cotransporter 2 inhibitor dapagliflozin reduces the risk for hospitalization for heart failure (HHF) and kidney events in patients with type 2 diabetes mellitus. An increased risk of amputation has been observed with canagliflozin in 1 previous trial. We examined cardiovascular and kidney efficacy and the risk of limb-related events in patients with and without PAD in an exploratory analysis. Methods: A total of 17 160 patients with type 2 diabetes mellitus, including 1025 (6%) with PAD, were randomized. Key efficacy outcomes were MACE (cardiovascular [CV] death, myocardial infarction, stroke), CV death/HHF, and progression of kidney disease. Amputations, peripheral revascularization, and limb ischemic adverse events were site-reported and categorized by a blinded reviewer. Results: Patients in the placebo arm with PAD versus those without tended to have higher adjusted risk of CV death, myocardial infarction, or stroke (adjusted hazard ratio [HR], 1.23 [95% CI, 0.97-1.56], P=0.094) and significantly higher adjusted risk of CV death/HHF (adjusted HR, 1.60 [95% CI, 1.21-2.12], P=0.0010) and progression of kidney disease (adjusted HR, 1.51 [95% CI, 1.13 - 2.03], P=0.0058), and limb adverse events (adjusted HR, 8.37, P<0.001). The relative risk reductions with dapagliflozin for CV death/HHF (HR, 0.86, PAD; HR, 0.82, no-PAD; P-interaction=0.79) and progression of kidney disease (HR, 0.78, PAD; HR, 0.76, no-PAD; P-interaction=0.84) were consistent regardless of PAD. There were 560 patients who had at least 1 limb ischemic event, 454 patients with at least 1 peripheral revascularization, and 236 patients with at least 1 amputation, with a total of 407 amputations reported. Overall, there were no significant differences in any limb outcome with dapagliflozin versus placebo including limb ischemic adverse events (HR, 1.07 [95% CI, 0.90-1.26]) and amputation (HR, 1.09 [95% CI, 0.84-1.40]), with no significant interactions by a history of PAD versus not (P-interactions=0.30 and 0.093, respectively). Conclusions: Patients with versus without PAD are at a higher risk of CV death of CV death, HHF, and kidney outcomes, and have a consistent benefits for CV death/HHF and progression of kidney disease with dapagliflozin. Patients with PAD had a higher risk of limb events, with no consistent pattern of incremental risk observed with dapagliflozin. Registration: URL: http://www.clinicaltrials.gov; Unique identifier: NCT01730534.

Original languageEnglish (US)
Pages (from-to)734-747
Number of pages14
StatePublished - Aug 25 2020


  • SGLT2i
  • amputation
  • dapagliflozin
  • heart failure
  • kidney complications
  • peripheral artery disease
  • type 2 diabetes mellitus

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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