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Background: Sodium-glucose cotransporter-2 inhibitors are foundational therapy in patients with heart failure with reduced ejection fraction (HFrEF), but underlying mechanisms of benefit are not well defined. We sought to investigate the relationships between sodium-glucose cotransporter-2 inhibitor treatment, changes in metabolic pathways, and outcomes using targeted metabolomics. Methods: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) was a placebo-controlled trial of dapagliflozin in HFrEF. We performed targeted mass spectrometry profiling of 63 metabolites (45 acylcarnitines [markers of fatty acid oxidation], 15 amino acids, and 3 conventional metabolites) in plasma samples at randomization and 12 weeks. Using mixed models, we identified principal components analysis–defined metabolite clusters that changed differentially with treatment and examined the relationship between change in metabolite clusters and change in Kansas City Cardiomyopathy Questionnaire scores and NT-proBNP (N-terminal probrain natriuretic peptide). Models were adjusted for relevant clinical covariates and nominal P P Results: Among the 234 DEFINE-HF participants with targeted metabolomic data, the mean age was 62.0±11.1 years, 25% were women, 38% were Black, and mean ejection fraction was 27±8%. Dapagliflozin increased ketone-related and short-chain acylcarnitine as well as medium-chain acylcarnitine principal components analysis–defined metabolite clusters compared with placebo (nominal P =0.01, false discovery rate–adjusted P =0.08 for both clusters). However, ketosis (β-hydroxybutyrate levels >500 μmol/L) was achieved infrequently (3 [2.5%] in dapagliflozin arm versus 1 [0.9%] in placebo arm) and supraphysiologic levels were not observed. Increases in long-chain acylcarnitine, long-chain dicarboxylacylcarnitine, and aromatic amino acid metabolite clusters were associated with decreases in Kansas City Cardiomyopathy Questionnaire scores (ie, worse quality of life) and increases in NT-proBNP levels, without interaction by treatment group. Conclusions: In this study of targeted metabolomics in a placebo-controlled trial of sodium-glucose cotransporter-2 inhibitors in HFrEF, we observed effects of dapagliflozin on key metabolic pathways, supporting a role for altered ketone and fatty acid biology with sodium-glucose cotransporter-2 inhibitors in patients with HFrEF. Only physiologic levels of ketosis were observed. In addition, we identified several metabolic biomarkers associated with adverse HFrEF outcomes. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02653482.

Oxytocin (OT), the brain's most abundant neuropeptide, plays an important role in social salience and motivation. Clinical trials of the efficacy of OT in autism spectrum disorder (ASD) have reported mixed results due in part to ASD's complex etiology. We investigated whether genetic and epigenetic variation contribute to variable endogenous OT levels that modulate sensitivity to OT therapy. To carry out this analysis, we integrated genome-wide profiles of DNA-methylation, transcriptional activity, and genetic variation with plasma OT levels in 290 participants with ASD enrolled in a randomized controlled trial of OT. Our analysis identified genetic variants with novel association with plasma OT, several of which reside in known ASD risk genes. We also show subtle but statistically significant association of plasma OT levels with peripheral transcriptional activity and DNA-methylation profiles across several annotated gene sets. These findings broaden our understanding of the effects of the peripheral oxytocin system and provide novel genetic candidates for future studies to decode the complex etiology of ASD and its interaction with OT signaling and OT-based interventions. LAY SUMMARY: Oxytocin (OT) is an abundant chemical produced by neurons that plays an important role in social interaction and motivation. We investigated whether genetic and epigenetic factors contribute to variable OT levels in the blood. To this, we integrated genetic, gene expression, and non-DNA regulated (epigenetic) signatures with blood OT levels in 290 participants with autism enrolled in an OT clinical trial. We identified genetic association with plasma OT, several of which reside in known autism risk genes. We also show statistically significant association of plasma OT levels with gene expression and epigenetic across several gene pathways. These findings broaden our understanding of the factors that influence OT levels in the blood for future studies to decode the complex presentation of autism and its interaction with OT and OT-based treatment.

Prediabetes is a recognized entity but has been incompletely characterized in a contemporary context. We sought to characterize participants with prediabetes with extensive multi-dimensional clinical and laboratory data and to identify predictors of progression to diabetes. The Project Baseline Health Study (PBHS) is a multi-site prospective U.S. cohort study of 2502 adults with deep clinical phenotyping at enrollment. At enrollment and follow-up, participants were classified by diabetes status (diabetes [DM], prediabetes [preDM], or no diabetes [noDM]) based on glucose, A1c, medications, and self-reported medical history. Principal component analysis (PCA) was performed on 1clinical, survey, and lab variables to create orthogonal factors composed of correlated variables, which were compared between groups using linear models. Logistic regression was used to identify factors associated with progression from preDM to DM. At enrollment, 16participants had noDM; 544 had preDM; and 352 had DM. Over up to 4 years of follow-up, 52 participants with preDM developed DM. PCA identified 33 factors composed of clusters of clinical variables; 24 factors differed significantly by diabetes status: 6 factors significantly differed between noDM and both preDM and DM after adjustment for multiple comparisons, including factors with variables of glucose measures, anthropometry and physical function (q= 1.3 × 10−21) , red blood cell indices (q= 8.3 × 10−10) , lung function (q= 2.0 × 10−6) , cardiac function (q= 0.001) , and risk of chronic disease. Five factors were significantly associated with progression to DM, including factors of anthropometry and physical function [OR (95% CI) 0.6 (0.5,0.9) ], hematologic measures, and cardiac function. Conclusions: PBHS participants with preDM demonstrated pathophysiologic changes in cardiac, pulmonary, and hematology measures and declines in physical function that precede DM and could be markers of higher risk of progression to DM and complications. Disclosure R.Chatterjee montgomery: Research Support; Bristol-Myers Squibb Company, Epigenomics AG. L.C.Kwee: None. N.Pagidipati: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, ESPERION Therapeutics, Inc., Consultant; Boehringer Ingelheim International GmbH, Novo Nordisk, Research Support; Amgen Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Eggland's Best, Eli Lilly and Company, Novartis AG, Novo Nordisk, Sanofi, Verily Life Sciences. A.F.Hernandez: Consultant; Merck & Co., Inc., Novo Nordisk, Research Support; AstraZeneca, Boehringer Ingelheim International GmbH. F.Rodriguez: Advisory Panel; Amgen Inc., Consultant; HealthPals, Novartis Pharmaceuticals Corporation, Novo Nordisk, Stock/Shareholder; Carta Healthcare, Inc. K.W.Mahaffey: Consultant; Novo Nordisk. L.Palaniappan: Consultant; Amgen Inc. S.H.Shah: Research Support; Verily Life Sciences. Funding The Baseline Health Study and this analysis were funded by Verily Life Sciences, San Francisco, California.