Z. Wu, B. Liu, X. Wang, H. Alessa, OA. Zeleznik, AH. Eliassen, C. Clish, M. Wang, KJ. Mukamal, EB. Rimm, Y. Hu, FB. Hu, et al. (2026). Effect of Low-Carbohydrate and Low-Fat Diets on Metabolomic Indices and Coronary Heart Disease in U.S. Individuals. Journal of the American College of Cardiology, 87(20), 2764-2781. https://doi.org/10.1016/j.jacc.2025.12.038

PubMed 41670561

[Abstract]
BACKGROUND: Low-carbohydrate diet (LCD) and low-fat diet (LFD) patterns are practiced by many in the United States, although their health effects, as well as the role of diet quality in the effects, are not fully understood.

OBJECTIVES: This study aimed to prospectively examine the associations of these diets, which emphasize different quantities and qualities of macronutrients, as well as their objective metabolomic indices, with coronary heart disease (CHD) risk in U.S.

METHODS: We followed 42,720 men in the Health Professionals Follow-Up Study (HPFS) (1986-2016), 64,164 women in the Nurses' Health Study (NHS) (1986-2018), and 91,589 women in NHSII (1991-2019) for CHD incidence. Five LCD and 5 LFD indices were derived based on food frequency questionnaire (FFQ) assessments, each emphasizing different sources and qualities of macronutrients (animal products vs plant-based foods, whole grains vs refined carbohydrates, etc). Multimetabolite scores of LCD and LFD indices assessed using FFQ assessments were developed through elastic net regressions among 1,146 healthy participants in the lifestyle validation studies (LVS), substudies embedded in the NHS/NHSII/HPFS.

RESULTS: During 5,248,916 person-years of follow-up, we documented 20,033 CHD cases. When comparing individuals with the highest LCD scores (emphasizing lower carbohydrate contents) and those with the lowest, the pooled multivariable-adjusted hazard ratios (95% CIs) for CHD were 1.05 (1.01-1.10) for overall LCD, 1.07 (1.02-1.12) for animal LCD, 0.94 (0.90-0.99) for vegetable LCD, 1.14 (1.09-1.20) for unhealthy LCD, and 0.85 (0.82-0.89) for healthy LCD. These estimates were 0.93 (0.89-0.98) for overall LFD, 0.94 (0.90-0.98) for animal LFD, 0.87 (0.83-0.91) for vegetable LFD, 1.12 (1.07-1.17) for unhealthy LFD, and 0.87 (0.83-0.91) for healthy LFD. The healthy versions of the LCD and LFD patterns were also linked to lower triglycerides, higher high-density lipoprotein cholesterol, and lower high-sensitivity C-reactive protein levels, as well as favorable metabolomic profiles, including increased 3-indolepropionic acid and decreased valine. Unhealthy patterns showed opposite associations. Multimetabolite scores of LCD and LFD indices were developed in the LVS (Spearman r = 0.57-0.68) and replicated in NHS, NHSII, and HPFS (r = 0.21-0.38). They showed associations with CHD risk highly consistent with those based on FFQ assessments.

CONCLUSIONS: These findings highlight the critical role of diet quality in determining health effects of low-carbohydrate and low-fat diets on CHD risk. The healthy versions of these diets may exert their health benefits through some common pathways that together entail favorable cardiovascular risk profile and lower CHD risk.