Metabolic Health

In a meta-analysis of 22 prospective studies, metabolically healthy obesity defined by the absence of metabolic syndrome carried a higher risk of cardiovascular events than healthy normal weight (pooled RR 1.45, 95% CI 1.20-1.70), but a lower risk than unhealthy normal weight (RR 2.07) or unhealthy obesity (RR 2.31). ^[12] A meta-analysis of prospective cohorts with 4,492,723 participants found increased cardiovascular disease risk in metabolically healthy obesity (RR 1.58, CI 1.34-1.85) versus metabolically healthy normal weight, and the risk remained in the group with no metabolic risk factors. ^[16] Another meta-analysis of 22 prospective studies (584 799 participants) associated metabolically healthy obesity with a higher risk of cardiovascular events (RR 1.50, 95% CI 1.27 to 1.77) but not with increased all-cause mortality (RR 1.18, 95% CI 0.83 to 1.66). ^[3] An Annals of Internal Medicine meta-analysis found increased risk of all-cause mortality or cardiovascular events in metabolically healthy obesity versus metabolically healthy normal weight (RR 1.24, 95% CI 1.02 to 1.55) only when studies with 10 or more years of follow-up were considered, and concluded that there is no healthy pattern of increased weight. ^[6] In cohorts that accounted for physical activity, metabolically healthy obesity carried a 24-33% higher risk of all-cause mortality and cardiovascular disease mortality or morbidity than metabolically healthy normal weight, a borderline significant or non-significant excess, and the one study examining fitness suggested the difference is largely explained by cardiorespiratory fitness. ^[9] In a meta-analysis of 7 prospective studies (7,720,165 participants), transition from metabolically healthy to unhealthy overweight or obesity was associated with a higher risk of incident cardiovascular disease (HR 1.42, 95% CI 1.24-1.60). ^[17] A meta-analysis that included a total of 12 542 390 participants found a significantly increased risk of developing cancer with metabolically healthy obesity than with metabolically healthy non-obesity (OR 1.14, 95% CI 1.05 to 1.23). ^[18]

Metabolically healthy obesity seems to be a transient phenotype and should not be considered a safe condition that does not require obesity treatment, although it may guide personalised, risk-stratified treatment. ^[2] A review reports that most individuals with metabolically healthy obesity transform to metabolically unhealthy obesity over time. ^[13] Based on 17 meta-analyses showing increased risks of type 2 diabetes, cardiovascular disease, cancer, chronic kidney disease and depressive syndrome in obesity without metabolic abnormalities, one review recommends motivating all patients with obesity to change their lifestyle regardless of metabolic defects. ^[19] A meta-analysis that included a total of 17 cohort studies found that transition from metabolically unhealthy to healthy status lowered the risk of type 2 diabetes and cardiovascular disease at both normal weight and overweight or obesity, and that change in metabolic health mattered more than change in body mass index category, leading the authors to suggest prioritising metabolic health parameters over the extent of weight loss. ^[20] In contrast, a Nature Reviews Cardiology review argues that although maintaining optimal cardiometabolic status should be a primary goal, losing body weight and particularly excess visceral adiposity seems necessary to minimise cardiometabolic risk in obesity. ^[21] In a meta-analysis of randomised trials in adults with prediabetes or type 2 diabetes, intermittent fasting decreased glycated haemoglobin (HbA1c, WMD -0.81%) and triglycerides (WMD -0.14 mmol/L) versus a control diet, but did not affect glycaemic markers or lipid profiles versus calorie restriction. ^[22] A meta-analysis of randomised trials in physically inactive adults found that brief exercise snacks improved cardiorespiratory fitness but did not significantly change cardiometabolic outcomes, including body composition, blood pressure and blood lipids. ^[23]