28-OR: How Early after Treatment Initiation Are the CV Benefits of Empagliflozin Apparent? A Post Hoc Analysis of EMPA-REG OUTCOME
Authors: VERMA SUBODH , LEITER LAWRENCE A. , SHARMA ABHINAV , ZINMAN BERNARD , MATTHEUS MICHAELA , FITCHETT DAVID H. , GEORGE JYOTHIS T. , OFSTAD ANNE PERNILLE , WANNER CHRISTOPH , INZUCCHI SILVIO E. 
Published: June 2020

In the EMPA-REG OUTCOME trial, in patients with type 2 diabetes (T2D) with established atherosclerotic cardiovascular disease (ASCVD), empagliflozin reduced the risk of hospitalization for HF (HHF) by 35% (HR [95%CI] 0.65 [0.50-0.85]), CV death/HHF by 34% (0.66 [0.55-0.79]), and CV death by 38% (0.62 [0.49-0.77]) with an early separation of the cumulative incidence curves. We aimed to explore at what time point after randomization the benefits became apparent. Overall, 7020 patients were treated with empagliflozin 10, 25 mg or placebo. We expressed time trajectories for the effect of pooled empagliflozin doses vs. placebo on HHF, CV death/HHF and CV death based on Hazard Ratios (HRs) (95% CI), and calculated the HR on the day the effect reached significance using Cox proportional hazards models. The reduction in risk with empagliflozin vs. placebo reached significance at day 17 for HHF [0.10 [0.01, 0.87), p=0.0372], and day 27 for CV death/HHF [HR 0.28 (0.08, 0.97), p=0.0445], and sustained significant throughout follow-up (Figure). The benefit on CV death reached significance for the first time at day 59 [HR 0.28 (0.08, 0.96)]. HRs stabilized as the number of patients with events increased over time. The benefit of empagliflozin in reducing the risk of HHF, CV death/HHF and CV death emerged within weeks after treatment initiation in EMPA-REG OUTCOME. The earliest effect appears to be on HHF.

Disclosure
S. Verma: Advisory Panel; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Research Support; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Other Relationship; Self; AstraZeneca, AstraZeneca, Bayer AG, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, Eli Lilly and Company, EOCI Pharmacomm, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Canada Inc., Novo Nordisk A/S, Novo Nordisk A/S, Sanofi, Sanofi, Sun Pharmaceuticals, Toronto Knowledge Translation Working Group. L.A. Leiter: Advisory Panel; Self; Abbott, Amgen, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. Research Support; Self; Amgen, AstraZeneca, Kowa Pharmaceuticals America, Inc., Medicines Company. Speaker’s Bureau; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Medscape, Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. A. Sharma: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Roche Pharma. Research Support; Self; Bristol-Myers Squibb, Merck & Co., Inc. Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation. B. Zinman: Advisory Panel; Self; Abbott, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk Inc., Sanofi-Aventis. M. Mattheus: None. D.H. Fitchett: Consultant; Self; AstraZeneca, Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; Lilly Diabetes. Other Relationship; Self; Novo Nordisk Inc. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. A. Ofstad: Employee; Self; Boehringer Ingelheim International GmbH. C. Wanner: Advisory Panel; Self; Eli Lilly and Company, Merck & Co., Inc., Mundipharma International. Consultant; Self; Boehringer Ingelheim (Canada) Ltd., Sanofi Genzyme. Speaker’s Bureau; Self; AstraZeneca. Other Relationship; Self; Boehringer Ingelheim International GmbH. S.E. Inzucchi: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; Abbott, Merck & Co., Inc., vTv Therapeutics.

Funding
Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance