Systematic analysis of relationships between serum lipids with all-cause and cause-specific mortality: Evidence from prospective cohort studies of UK Biobank and Women's Health Initiative

Background & aims

Serum lipids, including lipoproteins, cholesterol, and triglycerides, are important modifiable factors influencing human health. However, the associations among different serum lipid profiles and mortality remain insufficiently understood, particularly regarding potential causality and population heterogeneity. This prospective study aims to systematically investigate the relationships between serum lipid concentrations of different densities and sizes with all-cause and cause-specific mortality.

Methods

Cox proportional and Fine–Gray subdistribution hazard models were applied to investigate the associations of 54 lipid concentrations with all-cause and cause-specific mortality (including cardiovascular disease (CVD), cancer, and respiratory disease) in the UK Biobank cohort of 441,448 individuals with 17-year follow-up. Cohorts of 120,967 and 44,168 individuals from the Women's Health Initiative (WHI) with 16-year follow-up and a large-scale meta-analysis were utilized for external replication. We further assessed the underlying causality using Mendelian randomization (MR) and possible modifiers using multiple subgroup analyses.

Results

During a median follow-up of 13.8 years, 39,290 deaths occurred, including 7399 from CVD, 18,928 from cancer, and 2707 from respiratory disease. We identified 160 significant associations between lipid concentrations and all-cause and cause-specific mortality. Importantly, most were inverse, with decreased lipid levels linked to increased risk of premature death [hazard ratios (HRs): 0.70–0.98 per standard deviation (SD)]. In contrast, positives were observed for HDL (large/very large) and triglyceride concentrations [HRs: 1.02–1.25 per SD], indicating increased mortality risk with higher levels. Most lipoproteins and cholesterol exhibited nonlinearly correlations with mortality, especially the significant U-shaped in total/HDL. However, MR showed that elevations in several lipids were associated with increased all-cause and CVD-specific mortality risk. Multiple subgroup analyses revealed that age, sex, and lipid-modifying drugs modified the lipid-mortality relationship; specifically, higher lipid concentrations increased mortality risk in younger adults not taking lipid-modifying drugs, but decreased mortality in older adults taking lipid-modifying drugs. The majority of associations were replicated in the WHI and external cohorts.

Conclusion

Our study systematically reported a large number of associations between serum lipid concentrations and mortality. Subgroup-based population heterogeneity analysis suggests that age, sex, and lipid-modifying drugs could be modifiers for the lipid-mortality relationship. These findings provide more guidance for lipid management and individualized prevention.