Ofri Mosenzon1,2, Stephen D Wiviott3, Hiddo J L Heerspink4, Jamie P Dwyer5, Avivit Cahn6,2, Erica L Goodrich3, Aliza Rozenberg6,2, Meir Schechter6,2, Ilan Yanuv6,2, Sabina A Murphy3, Thomas A Zelniker3,7, Ingrid A M Gause-Nilsson8, Anna Maria Langkilde8, Martin Fredriksson8, Peter A Johansson8, Deepak L Bhatt3, Lawrence A Leiter9, Darren K McGuire10,11, John P H Wilding12, Marc S Sabatine3, Itamar Raz6,2. 1. Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem, Israel ofrim@hadassah.org.il. 2. Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel. 3. TIMI Study Group, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. 4. University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. 5. Vanderbilt University Medical Center, Nashville, TN. 6. Diabetes Unit, Department of Endocrinology and Metabolism, Hadassah Medical Center, Jerusalem, Israel. 7. Division of Cardiology, Medical University of Vienna, Vienna, Austria. 8. BioPharmaceuticals R&D, AstraZeneca Gothenburg, Gothenburg, Sweden. 9. Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada. 10. Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX. 11. Parkland Health and Hospital System, Dallas, TX. 12. Department of Cardiovascular and Metabolic Medicine, University of Liverpool, Liverpool, U.K.
Abstract
OBJECTIVE:Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) cardiovascular outcome trial, which included populations with lower cardiorenal risk. RESEARCH DESIGN AND METHODS: DECLARE-TIMI 58 randomized 17,160 patients with type 2 diabetes, creatinine clearance >60 mL/min, and either atherosclerotic cardiovascular disease (CVD; 40.6%) or risk-factors for CVD (59.4%) todapagliflozin or placebo. Urinary albumin-to-creatinine ratio (UACR) was tested at baseline, 6 months, 12 months, and yearly thereafter. The change in UACR over time was measured as a continuous and categorical variable (≤15, >15 to <30, ≥30 to ≤300, and >300 mg/g) by treatment arm. The composite cardiorenal outcome was a ≥40% sustained decline in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and cardiovascular or renal death; specific renal outcome included all except cardiovascular death. RESULTS:Baseline UACR was available for 16,843 (98.15%) participants: 9,067 (53.83%) with ≤15 mg/g, 2,577 (15.30%) with <15 to >30 mg/g, 4,030 (23.93%) with 30-300 mg/g, and 1,169 (6.94%) with >300 mg/g. Measured as a continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared with placebo, across all UACR and eGFR categories (all P < 0.0001). Sustained confirmed ≥1 category improvement in UACR was more common in dapagliflozin versus placebo (hazard ratio 1.45 [95% CI 1.35-1.56], P < 0.0001). Cardiorenal outcome was reduced with dapagliflozin for subgroups of UACR ≥30 mg/g (P < 0.0125, P int eraction = 0.033), and the renal-specific outcome was reduced for all UACR subgroups (P < 0.05, P interaction = 0.480). CONCLUSIONS: In DECLARE-TIMI 58, dapagliflozin demonstrated a favorable effect on UACR and renal-specific outcome across baseline UACR categories, including patients with normal albumin excretion. The results suggest a role for SGLT2i also in the primary prevention of diabetic kidney disease.
RCT Entities:
OBJECTIVE:Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve albuminuria in patients with high cardiorenal risk. We report albuminuria change in the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI 58) cardiovascular outcome trial, which included populations with lower cardiorenal risk. RESEARCH DESIGN AND METHODS: DECLARE-TIMI 58 randomized 17,160 patients with type 2 diabetes, creatinine clearance >60 mL/min, and either atherosclerotic cardiovascular disease (CVD; 40.6%) or risk-factors for CVD (59.4%) to dapagliflozin or placebo. Urinary albumin-to-creatinine ratio (UACR) was tested at baseline, 6 months, 12 months, and yearly thereafter. The change in UACR over time was measured as a continuous and categorical variable (≤15, >15 to <30, ≥30 to ≤300, and >300 mg/g) by treatment arm. The composite cardiorenal outcome was a ≥40% sustained decline in the estimated glomerular filtration rate (eGFR) to <60 mL/min/1.73 m2, end-stage kidney disease, and cardiovascular or renal death; specific renal outcome included all except cardiovascular death. RESULTS: Baseline UACR was available for 16,843 (98.15%) participants: 9,067 (53.83%) with ≤15 mg/g, 2,577 (15.30%) with <15 to >30 mg/g, 4,030 (23.93%) with 30-300 mg/g, and 1,169 (6.94%) with >300 mg/g. Measured as a continuous variable, UACR improved from baseline to 4.0 years with dapagliflozin, compared with placebo, across allUACR and eGFR categories (all P < 0.0001). Sustained confirmed ≥1 category improvement in UACR was more common in dapagliflozin versus placebo (hazard ratio 1.45 [95% CI 1.35-1.56], P < 0.0001). Cardiorenal outcome was reduced with dapagliflozin for subgroups of UACR ≥30 mg/g (P < 0.0125, P int eraction = 0.033), and the renal-specific outcome was reduced for allUACR subgroups (P < 0.05, P interaction = 0.480). CONCLUSIONS: In DECLARE-TIMI 58, dapagliflozin demonstrated a favorable effect on UACR and renal-specific outcome across baseline UACR categories, including patients with normal albumin excretion. The results suggest a role for SGLT2i also in the primary prevention of diabetic kidney disease.
Authors: Olga González-Albarrán; Cristóbal Morales; Manuel Pérez-Maraver; José Juan Aparicio-Sánchez; Rafael Simó Journal: Diabetes Ther Date: 2022-06-15 Impact factor: 3.595
Authors: Marcus Säemann; Daniel Cejka; Sabine Schmaldienst; Alexander R Rosenkranz; Gert Mayer Journal: Wien Klin Wochenschr Date: 2022-10-17 Impact factor: 2.275
Authors: Simke W Waijer; Priya Vart; David Z I Cherney; Glenn M Chertow; Niels Jongs; Anna Maria Langkilde; Johannes F E Mann; Ofri Mosenzon; John J V McMurray; Peter Rossing; Ricardo Correa-Rotter; Bergur V Stefansson; Robert D Toto; David C Wheeler; Hiddo J L Heerspink Journal: Diabetologia Date: 2022-04-21 Impact factor: 10.460