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In EMPA-REG OUTCOME, EMPA in 7020 patients with type 2 diabetes mellitus and CV disease significantly reduced 3P-MACE (14%), CV death (38%), all-cause death (32%) and heart failure hospitalization (HHF) (35%.) In addition, HbA1c was reduced but not associated with increased hypo. We investigated the relationship between on-trial hypo with a range of CV outcomes, using adjusted Cox regression models with time-varying covariate for hypo. We employed two hypo definitions: HYPObroad: time to first symptomatic hypo adverse event (AE) with plasma glucose [PG] ≤ 70mg/dL, any hypo AE with PG HYPO broad occurred in 28% of participants in each group, whereas HYPO strict in 19%. In the placebo group, hypo was associated with an increased risk of HHF using both HYPO broad (HR 1.91, [95% CI: 1.25, 2.93], Fig A) or HYPO strict (1.72 [1.06, 2.78]) and for myocardial infarction (MI) using only HYPO broad (1.56 [1.06, 2.29], Fig A.) EMPA reduced 3P-MACE, CV and all-cause death, and HHF, regardless of occurrence (Fig B) or severity of hypo (p-for interactions > 0.05). In conclusion, in this post hoc analysis, hypo was associated with an increased risk of MI and HHF but no other investigated CV outcomes. Hypoglycemia did not influence the cardio-protective effect of EMPA. Disclosure B. Zinman: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc. Consultant; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc. D.H. Fitchett: Speaker’s Bureau; Self; Boehringer Ingelheim International GmbH, Lilly Diabetes. Other Relationship; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. M. Mattheus: Employee; Self; Boehringer Ingelheim Pharma GmbHC Self; Bayer AG, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp. Board Member; Self; Boehringer Ingelheim International GmbH. Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Mitsubishi Tanabe Pharma Corporation. J.T. George: None. O. Vedin: Employee; Self; Boehringer Ingelheim International GmbH. S.E. Inzucchi: Consultant; Self; vTv Therapeutics, Zafgen, Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. O. Johansen: Employee; Self; Boehringer Ingelheim International GmbH. Funding Boehringer Ingelheim; Eli Lilly and Company