Incretins Predict Response to Enteral Nutrition Strategies in the EDEN Trial: A Secondary Analysis

RATIONALE: The Early versus Delayed Enteral Nutrition (EDEN) trial found no significant difference in mortality between trophic and full enteral nutrition strategies in acute respiratory distress syndrome (ARDS) patients. Heterogeneity of treatment effect (HTE) has been identified in prior ARDS trials. We previously identified intestine-derived incretin hormones (glucose-dependent insulinotropic peptide [GIP] and glucagon-like peptide [GLP]-1 as potential predictive biomarkers in the response to nutrition. OBJECTIVES: To investigate incretins as biomarkers predictive of HTE in EDEN. METHODS: GIP, GLP-1, and host immune response biomarkers were measured from pre-intervention EDEN plasma samples. We investigated HTE with 60-day mortality as a primary outcome by testing interaction of treatment with circulating incretin levels in analyses adjusted for demographics, severity of illness, diabetes mellitus, and circulating interleukin-6, and assessed mortality by treatment arm across incretin tertiles. We additionally tested for HTE by de novo ARDS subphenotypes and by risk of mortality. MEASUREMENTS & MAIN RESULTS: 889 participants were included (452 randomized to trophic and 437 to full enteral nutrition). GIP predicted HTE to enteral nutrition strategies (adjusted interaction p-value 0.01) with lower mortality from trophic feeds (14.1% vs 27.2% in full) in patients in the highest GIP tertile but similar mortality in other tertiles. GLP-1, ARDS subphenotypes, and baseline risk of mortality did not predict HTE. CONCLUSIONS: GIP was unique among incretins in predicting HTE to enteral nutrition strategies in EDEN. Further studies are needed to validate our findings as GIP might serve as a biomarker to guide level of enteral nutrition for ARDS patients.