Individual response to lifestyle interventions: a pooled analysis of three long-term weight loss trials
European Journal of Preventive Cardiology, 2025
Yaskolka Meir A., Tsaban G., Rinott E., Zelicha H., Schwarzfuchs D., Gepner Y., Rudich A., Shelef I., Blüher M., Stumvoll M., Ceglarek U., Isermann B., Klöting N., Keller M., Kovacs P., Qi L., Wang D., Liang L., Hu F., Stampfer M., Shai I.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Metabolic Diseases CVD | Pathophysiology | Plasma |  Olink Target 96 |
Abstract
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-specific DNA methylation may predict an individual’s likelihood of successful WL.
Registration
NCT00160108, NCT01530724, NCT03020186.