Marc P Bonaca1, Stephen D Wiviott1, Thomas A Zelniker1, Ofri Mosenzon2, Deepak L Bhatt1, Lawrence A Leiter3, Darren K McGuire4, Erica L Goodrich1, Remo Holanda De Mendonca Furtado5, John P H Wilding6, Avivit Cahn2, Ingrid A M Gause-Nilsson7, Per Johanson7, Martin Fredriksson7, Peter A Johansson7, Anna Maria Langkilde7, Itamar Raz2, Marc S Sabatine1. 1. TIMI (Thrombolysis in Myocardial Infarction) Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital Heart and Harvard Medical School, Boston, MA (M.P.B., S.D.W., T.A.Z., D.L.B., E.L.G., M.S.S.). 2. Diabetes Unit, Hadassah Medical Center, Hebrew University of Jerusalem, Israel (O.M., A.C., I.R.). 3. Li Ka Shing Knowledge Institute, St Michael's Hospital, University of Toronto, Ontario, Canada (L.A.L.). 4. Division of Cardiology, University of Texas Southwestern Medical Center, Dallas (D.K.M.). 5. Hospital Albert Einstein and Instituto do Coracao da Faculdade de Medicina da Universidade de Sao Paulo, Sao Paulo, Brazil (R.H.D.M.F.). 6. Institute of Ageing and Chronic Disease, University of Liverpool, United Kingdom (J.P.H.W.). 7. AstraZeneca Gothenburg, Mölndal, Sweden (I.A.M.G.-N., P.J., M.F., P.A.J., A.M.L.).
Abstract
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: https://www.clinicaltrials.gov; Unique identifier: NCT01730534.
RCT Entities:
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: https://www.clinicaltrials.gov; Unique identifier: NCT01730534.
Authors: José M González-Clemente; María García-Castillo; Juan J Gorgojo-Martínez; Alberto Jiménez; Ignacio Llorente; Eduardo Matute; Cristina Tejera; Aitziber Izarra; Albert Lecube Journal: Diabetes Ther Date: 2022-06-10 Impact factor: 3.595
Authors: Cristóbal Morales; Juan Francisco Merino-Torres; Paloma Moreno-Moreno; María Lainez; Iñigo Tejado; Alfredo Yoldi; Sonsoles Gutiérrez Medina; Alfonso Soto; Manuel A Botana; Virginia Bellido; Irene Caballero Journal: Drugs Context Date: 2022-02-17