Adding novel protein biomarkers to routine clinical risk factors may identify people with type 2 diabetes and acute coronary syndrome who are at highest risk for cardiovascular (CV) outcomes and death.
Methods: Bio-banked baseline serum from 5128 of 6069 ELIXA (Evaluating Lixisenatide in Acute Coronary Syndrome) trial (NCT 01147250) participants was analyzed to identify independent risk factors for incident major adverse CV events (MACE, defined as a nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) , and death. A multiplex analysis of 1.8 ml of serum measured the concentration of 49 proteins. Forward-selection Cox models that identified proteins that independently predicted these outcomes were compared to previously validated biomarkers identified in the Outcomes Reduction with an Initial Glargine Intervention (ORIGIN) trial data (NCT00069784) .
Results: Forty-two proteins were analyzed in 4957 participants who had 630 (12.7%) MACE outcomes and 349 (7.0%) deaths during a median follow-up period of 2.1 years. When added to clinical risk factors, the independent hazard ratios (HR; 95% confidence intervals) of MACE per standard deviation (SD) were NT-proBNP (1.54; 1,41, 1.68) , osteoprotegerin (1.18; 1.08, 1.30) and trefoil factor 3 (1.18, 1.08, 1.29) . HRs per SD for death were NT-proBNP (2.01; 1.78, 2.29) , osteoprotegerin (1.34; 1.18, 2.52) and angiopoietin-2 (1.28; 1.15, 1.44) . C statistics for MACE and death were 0.70 (0,68, 0.72) and 0.79 (0.76, 0.81) respectively compared to 0.63 (0.61, 0.65) and 0.66 (0.63, 0.69) for clinical variables alone. These proteins had all been previously identified and validated in ORIGIN. Notably, NT-proBNP alone plus clinical risk factors yielded C statistics of 0.69 (0.67, 0.71) and 0.78 (0.75, 0.80) for MACE and death respectively.
Conclusion: NT-proBNP and other proteins independently predict CV outcomes in people with type 2 diabetes following acute coronary syndrome. Adding other biomarkers only marginally increased NT-proBNP's prognostic value.
H. C. Gerstein: Advisory Panel; Abbott, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Viatris Inc., Consultant; Kowa Company, Ltd., Other Relationship; DKSH, Eli Lilly and Company, Sanofi, Zuellig Pharma Holdings Pte. Ltd., Research Support; AstraZeneca, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. S. Hess: Employee; Sanofi. B. Claggett: Consultant; Amgen Inc., Biogen, Cardurion, Corvia, MyoKardia, Novartis AG. J. Tardif: Consultant; AstraZeneca, DalCor Pharmaceuticals, HLS Therapeutics Inc., Pendopharm, Other Relationship; DalCor Pharmaceuticals, Research Support; Amarin Corporation, AstraZeneca, Ceapro Inc., DalCor Pharmaceuticals, ESPERION Therapeutics, Inc., Ionis Pharmaceuticals, Novartis Pharmaceuticals Corporation, Pfizer Inc., REGENXBIO Inc., Sanofi. M. A. Pfeffer: Consultant; AstraZeneca, Boehringer Ingelheim and Eli Lilly Alliance, Corvidia Therapeutics, GlaxoSmithKline plc., Lexicon Pharmaceuticals, Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, Peerbridge, Sanofi, Other Relationship; DalCor Pharmaceuticals, National Heart, Lung, and Blood Institute, Research Support; Novartis Pharmaceuticals Corporation.