TY - JOUR
T1 - Individual response to lifestyle interventions
T2 - A pooled analysis of three long-term weight loss trials
AU - Yaskolka Meir, Anat
AU - Tsaban, Gal
AU - Rinott, Ehud
AU - Zelicha, Hila
AU - Schwarzfuchs, Dan
AU - Gepner, Yftach
AU - Rudich, Assaf
AU - Shelef, Ilan
AU - Blüher, Matthias
AU - Stumvoll, Michael
AU - Ceglarek, Uta
AU - Isermann, Berend
AU - Klöting, Nora
AU - Keller, Maria
AU - Kovacs, Peter
AU - Qi, Lu
AU - Wang, Dong D.
AU - Liang, Liming
AU - Hu, Frank B.
AU - Stampfer, Meir J.
AU - Shai, Iris
N1 - Publisher Copyright:
© 2025 The Author(s). Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved.
PY - 2025/11/1
Y1 - 2025/11/1
N2 - 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.
AB - 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.
KW - Epigenetics
KW - Intervention trials
KW - Lifestyle
KW - Metabolomics
KW - Nutrition
KW - Proteomics
KW - Weight-loss
UR - https://www.scopus.com/pages/publications/105021350515
U2 - 10.1093/eurjpc/zwaf308
DO - 10.1093/eurjpc/zwaf308
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C2 - 40472282
AN - SCOPUS:105021350515
SN - 2047-4873
VL - 32
SP - 1660
EP - 1670
JO - European Journal of Preventive Cardiology
JF - European Journal of Preventive Cardiology
IS - 16
ER -