388-P: Interrelationship between Hypoglycemia and CV and Mortality Outcomes in Type 2 Diabetes in the CARMELINA Trial
Authors: ROSENSTOCK JULIO , KAHN STEVEN E. , JOHANSEN ODD ERIK , COOPER MARK E. , MARX NIKOLAUS , ALEXANDER JOHN H. , TOTO ROBERT D. , WANNER CHRISTOPH , PFARR EGON , SCHNAIDT SVEN , GEORGE JYOTHIS , EYNATTEN MAXIMILIAN VON , MCGUIRE DARREN K. , PERKOVIC VLADO , ZINMAN BERNARD 
Published: June 2019

Severe hypoglycemia is associated with high CV and mortality risk. CARMELINA (CArdiovascular and Renal Microvascular outcomE study with LINAgliptin) evaluated the CV safety and kidney outcomes of LINA in 6979 subjects with type 2 diabetes and cardio-renal disease (mean age 65.9 years, HbA1c 8.0%, eGFR 54.6 ml/min/1.73m2) and demonstrated CV safety of LINA with respect to the primary composite outcome of CV death/MI/stroke (3P-MACE) and no effect on all-cause mortality. We assessed interrelationships between time to first severe hypoglycemia or plasma glucose &lt; 54 mg/dL, which occurred in 557 (15.9%) and 572 (16.4%) in the LINA and placebo (PBO) groups, and 3P-MACE or all-cause mortality, using adjusted Cox models. Hypoglycemia preceded 3P-MACE in 146 participants (at median 58 days in n=74 LINA; at 55 days in n=72 PBO), and was associated with a 43% higher risk (HR 1.43 [95% CI 1.23, 1.66]), when adjusted for region and hypoglycemia. Higher adjusted risk of all-cause mortality was also associated with preceding hypoglycemia (HR 1.31 [1.11, 1.53]) in 129 participants who died (at median 65 days in n=65 LINA; at 49 days in n=64 PBO). More frequent hypoglycemia was associated with a greater magnitude of incremental risk (Figure A) that attenuated with further adjustment. (Figure B).
In conclusion, preceding hypoglycemia was independently associated with increased risk for 3P-MACE and mortality.

Disclosure
J. Rosenstock: Research Support; Self; AstraZeneca, Bristol-Myers Squibb Company, Genentech, Inc., GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Melior Pharmaceuticals, Inc., Bukwang Pharm. Co., Ltd., Merck & Co., Inc., Oramed Pharmaceuticals, PegBio Co., Ltd., Pfizer Inc. Other Relationship; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. S.E. Kahn: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. Consultant; Self; Neurimmune. Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S. O. Johansen: Employee; Self; Boehringer Ingelheim International GmbH. M.E. Cooper: Advisory Panel; Self; AstraZeneca, Lilly Diabetes. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Servier. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. Speaker's Bureau; Self; Bayer AG, Merck Sharp & Dohme Corp., Novartis AG. N. Marx: Advisory Panel; Self; Amgen Inc., AstraZeneca, Bayer Vital GmbH, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Research Support; Self; Boehringer Ingelheim International GmbH. Speaker's Bureau; Self; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Lilly Diabetes, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Other Relationship; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. J.H. Alexander: Advisory Panel; Self; CSL Behring, Novo Nordisk A/S. Consultant; Self; AbbVie Inc., Bristol-Myers Squibb Company, Pfizer Inc., Quantum Genomics, Zafgen, Inc. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, CSL Behring, National Institutes of Health. Research Support; Spouse/Partner; Sanofi. Research Support; Self; U.S. Food and Drug Administration. R.D. Toto: Advisory Panel; Self; Relypsa, Inc. Board Member; Self; Akebia Therapeutics. Consultant; Self; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Quest Diagnostics, Vifor Pharma, WebMD. Research Support; Self; National Institute of Diabetes and Digestive and Kidney Diseases. C. Wanner: Advisory Panel; 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. E. Pfarr: None. S. Schnaidt: Employee; Self; Boehringer Ingelheim Pharma GmbH & Co. KG. J. George: Employee; Self; Boehringer Ingelheim International GmbH. M. von Eynatten: Employee; Self; Boehringer Ingelheim International GmbH. D.K. McGuire: Consultant; Self; Eisai Co., Ltd., Eli Lilly and Company, Pfizer Inc. Research Support; Self; Janssen Pharmaceuticals, Inc. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. V. Perkovic: Advisory Panel; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Baxter, Bayer US, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Durect Corporation, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Janssen Research & Development, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Pharmalink, Relypsa, Inc., Roche Pharma, Sanofi, Servier, Vitae. Research Support; Self; Australian National Health and Medical Research Council. Other Relationship; Self; AbbVie Inc., Boehringer Ingelheim Pharmaceuticals, Inc., GlaxoSmithKline plc., Janssen Research & Development, Pfizer Inc. 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.

Funding
Boehringer Ingelheim; Eli Lilly and Company