Trajectories of Blood Lipid Concentrations Over the Adult Life Course and Risk of Cardiovascular Disease and All-Cause Mortality: Observations From the Framingham Study Over 35 Years

Background: Elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides, and non-high-density lipoprotein cholesterol (non-HDL-C) and low high-density lipoprotein cholesterol (HDL-C) concentrations correlate with atherosclerotic cardiovascular disease (ASCVD) and mortality. Therefore, understanding how lipid trajectories throughout adulthood impact ASCVD and mortality risk is essential. Methods and Results: We investigated 3875 Framingham Offspring participants (54% women, mean age 48 years) attending ≥1 examination between 1979 and 2014. We evaluated longitudinal correlates of each lipid subtype using mixed-effects models. Next, we clustered individuals into trajectories through group-based modeling. Thereafter, we assessed the prospective association of lipid trajectories with ASCVD and mortality. Male sex, greater body mass index, and smoking correlated with higher TC, LDL-C, triglycerides, non-HDL-C, and lower HDL-C concentrations. We identified 5 TC, HDL-C, and LDL-C trajectories, and 4 triglycerides and non-HDL-C trajectories. Upon follow-up (median 8.2 years; 199 ASCVD events; 256 deaths), elevated TC (>240 mg/dL), LDL-C (>155 mg/dL), or non-HDL-C (>180 mg/dL) concentrations conferred >2.25-fold ASCVD and mortality risk compared with concentrations <165 mg/dL, <90 mg/dL, and <115 mg/dL, respectively ([TC hazard ratio (HR)_ASCVD=4.17, 95% CI 1.94–8.99; TC HR_death=2.47, 95% CI 1.28–4.76] [LDL-C HR_ASCVD=5.09, 95% CI 1.54–16.85; LDL-C HR_death=4.04, 95% CI 1.84–8.89] [non-HDL-C HR_ASCVD=4.60, 95% CI 1.98–10.70; LDL-C HR_death=3.74, 95% CI 2.03–6.88]). Consistent HDL-C concentrations <40 mg/dL were associated with greater ASCVD and mortality risk than concentrations >70 mg/dL (HR_ASCVD=3.81, 95% CI 2.04–7.15; HR_death=2.88, 95% CI 1.70–4.89). Triglycerides trajectories were unassociated with outcomes. Conclusions: Using a longitudinal modeling technique, we demonstrated that unfavorable lipid trajectories over 35 years confer higher ASCVD and mortality risk later in life.