Lifestyle-Induced Visceral Fat Loss as a Key Target for Durable Cardiometabolic Health: MRI-Assessed 5- and 10-Year Follow-Up After 2 Clinical Trials

BACKGROUND: During the 18-month CENTRAL (Effect of Weight-Loss Diet Strategies and Exercise on Dynamics of Body Fat Depots and Metabolic Rate) and DIRECT-PLUS (Effects of Green-Mediterranean Diet via the Gut-Fat-Brain Axis) randomized controlled trials, participants achieved considerable reductions in abdominal and ectopic fat. We examined the long-term postintervention cardiometabolic profile associated with these changes. METHODS: We invited participants from CENTRAL (2012–2014) and DIRECT-PLUS (2017–2018), which evaluated dietary patterns (low-fat, healthy dietary guidelines and Mediterranean diet variants, including standard, low-carbohydrate, and polyphenol-enriched “green” Mediterranean diets) combined with structured physical activity. Participants underwent additional magnetic resonance imaging of visceral adipose tissue, deep subcutaneous adipose tissue (SAT), superficial SAT, intrahepatic fat, and intrapancreatic fat, along with clinical follow-up measurements, 5 and 10 years after completion of the trials. RESULTS: We reached 366 out of 381 eligible participants (96%) for follow-up. Despite complete weight regain, waist circumference and abdominal fat depots, including visceral adipose tissue, deep SAT, and superficial SAT, partially preserved their intervention-induced achievements at long-term follow-up (false discovery rate ≤0.01 for all). In contrast, postintervention reductions of intrahepatic fat and intrapancreatic fat were fully and excessively gained during follow-up, respectively (false discovery rate ≤0.01 for both). Each 10% intervention-induced loss of visceral adipose tissue, superficial SAT, and intrapancreatic fat were associated with long-term postintervention improvements in Metabolic Score for Insulin Resistance, composite risk score, and Metabolic Syndrome Severity Score (meta-analysis models adjusted to weight change, Mediterranean diet adherence, and physical activity scores at follow-up, and further measures; all P <0.05). Only 10% visceral adipose tissue loss, however, was independently associated with a 28% lower risk of incident type 2 diabetes (hazard ratio, 0.72 [95% CI, 0.54–0.94]; multivariable model) during follow-up. CONCLUSIONS: This 5- and 10-year follow-up of 18-month clinical trials suggests that diet and physical activity lifestyle interventions may yield long-term improvements in cardiometabolic measures despite weight regain. A 10% reduction in visceral fat due to lifestyle interventions may reduce future type 2 diabetes risk by nearly 30%. Visceral fat loss rather than weight loss emerges as a key target for durable cardiometabolic health. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01530724; URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03020186.