Aims: We explored the manifestations of individual weight loss (WL) response to long-term lifestyle interventions on cardiometabolic risk.
Methods and results: We pooled data from three large long-term lifestyle WL-intervention trials: 24-month DIRECT (ClinicalTrials.gov: NCT00160108; n = 322; 87% adherence), 18-month CENTRAL (ClinicalTrials.gov: NCT01530724; n = 278; 86% adherence), and 18-month DIRECT PLUS (ClinicalTrials.gov: NCT03020186; n = 294; 89% adherence). We analyzed longitudinal changes in cardiometabolic risk markers, including anthropometrics, blood biomarkers, and magnetic-resonance-imaging-assessed fat depots, and measured DNA-methylation, proteomics, and metabolomics. Among trial completers (n = 761, mean age = 50.4 years; 89% men, baseline body-mass-index = 30.1 kg/m2), mean WL was -3.3 kg (-3.5%). We classified participants as Successful-WL (36%) with relative-WL > 5%, WL-Resistant (28%) who did not lose or gained weight, and Moderate-WL (36%) with WL between 0% and 5%. Successful-WL achieved the greatest improvements in multiple health indicators. However, the WL-Resistant also showed some significant improvements, with increased high-density-lipoprotein-cholesterol (HDLc) and decreased leptin and visceral fat (P < 0.05 vs. baseline). Overall, each 1 kg sustained lifestyle-induced WL was associated with improvements in lipid markers and insulin resistance [HDLc (+1.44%), triglycerides (-1.37%), insulin (-2.46%), HOMA-IR (-2.71%), leptin (-2.79%)] and intrahepatic-fat regression (-0.49 absolute-units)] and modest but significant change in systolic and diastolic blood pressures (-0.26% and -0.36%). We identified 12 significant methylation sites that are associated with Successful-WL (FDR < 0.05; AUC = 0.73).
Conclusion: While only ∼one-third of individuals achieved long-term WL, the Moderate-WL and WL-Resistant individuals could benefit improvements in visceral adiposity and cardiometabolic risk by shifting towards a healthy lifestyle pattern, beyond WL. Site-pecific DNA methylation may predict an individual's likelihood of successful WL.
Registration: NCT00160108, NCT01530724, NCT03020186.
Keywords: Epigenetics; Intervention trials; Lifestyle; Metabolomics; Nutrition; Proteomics; Weight-loss.
In a pooled analysis of over 700 participants from three long-term lifestyle intervention trials, only one-third achieved significant WL (>5%). However, even individuals resistant to WL demonstrated meaningful health benefits. These benefits included improvements in cardiometabolic markers such as increased HDL cholesterol, reduced visceral fat, and lower leptin levels, suggesting that lifestyle changes can enhance metabolic health independent of weight reduction. Additionally, researchers identified specific DNA methylation patterns that may predict an individual's likelihood of achieving successful WL through lifestyle modification.
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