Abstract / Summary
Cardiovascular disease (CVD), metabolic dysfunction–associated steatotic liver disease (MASLD), type 2 diabetes mellitus (T2DM), and obesity frequently coexist and share overlapping pathophysiologic mechanisms, collectively constituting a cardiovascular–liver–metabolic (CLM) syndemic. However, the mortality and life expectancy consequences of their co-occurrence remain insufficiently quantified. We included 429,722 UK Biobank and 38,759 National Health and Nutrition Examination Survey (NHANES) participants. CLM burden was defined as the number of coexisting conditions among CVD, MASLD, T2DM, and obesity (range 0–4), and the CLM syndemic as the co-occurrence of all four conditions. Cox proportional hazards and Fine–Gray models were used to assess associations with all-cause and cause-specific mortality, respectively. Life expectancy was estimated using age-specific survival models and expressed as years of life lost relative to participants with no CLM conditions. During median follow-ups of 13.7 years (UK Biobank) and 9.5 years (NHANES), mortality increased stepwise with higher CLM burden. Relative to participants with no CLM conditions, the fully adjusted HRs for all-cause mortality increased with CLM burden, from 1.55 (95% CI 1.51–1.59) for one condition to 2.26 (95% CI 2.18–2.34) for three conditions in the UK Biobank, and from 1.27 (95% CI 1.11–1.47) to 1.90 (95% CI 1.63–2.20) in NHANES. The CLM syndemic was associated with the highest risk of all-cause mortality (UK Biobank: HR 3.58 [95% CI 3.42–3.74]; NHANES: HR 3.10 [95% CI 2.59–3.72]), with the strongest association for CVD mortality (UK Biobank: sHR 8.39 [95% CI 7.51–9.38]; NHANES: sHR 3.88 [95% CI 3.04–4.95]). At age 50 years, life expectancy decreased from 36.9 to 30.0 years in the UK Biobank and from 34.3 to 24.8 years in NHANES. The CLM syndemic was associated with 6.9 (95% CI 6.6–7.2) and 9.5 (95% CI 8.2–10.6) fewer years of life expectancy, respectively. Across two large cohorts, the CLM syndemic was consistently associated with the highest mortality risk, particularly cardiovascular death, and with substantial reductions in life expectancy. These findings support integrated cardiovascular, liver, and metabolic prevention and care strategies to reduce premature mortality and preserve life-years.