Non-HDL-C and age-stratified mortality risk in the US general population: a population-based cohort study

Abstract

Introduction: Non-high-density lipoprotein cholesterol (non-HDL-C) is a well-established residual causal risk factor for the progression of atherosclerotic cardiovascular disease. However, studies of large, broadly generalizable populations are lacking, and the effect of non-HDL-C on all-cause and cause-specific mortality, particularly in different age groups, remains uncertain.

Methods: We conducted a population-based cohort study using data from the National Health and Nutrition Examination Survey from 1999 to 2018. Participants were divided into six groups according to non-HDL-C levels (≤100, 101-130, 131-160, 161-190, 191-220, >220 mg/dL). Multivariable Cox proportional hazards models were used to calculate hazard ratios (HR) and corresponding 95% confidence intervals (CI). Restricted cubic spline curves and subgroup analysis were also performed to further explore the association between non-HDL-C and mortality.

Results: Of 51,252 individuals (mean age 48.1 ± 19.2 years), 7,605 (14.8%) died during follow-up. Both low and high non-HDL-C levels were significantly associated with increased risk of all-cause and cause-specific mortality, suggesting a U-shaped association. Thresholds of 156, 142, 162, and 152 mg/dL were identified for all-cause, cardiovascular, cancer, and other-cause mortality, respectively. We observed significant interactions between non-HDL-C and age for all-cause and cardiovascular mortality (P interaction<0.05 for each). The association of high non-HDL-C (>220 mg/dL) with all-cause and cardiovascular mortality was strongest in adults aged <50 years (HR, 1.51 [1.09-2.08] and 1.97 [1.07-3.12], respectively), intermediate in adults aged 50 to 69 years, and weakest in adults aged ≥70 years.

Conclusion: Non-HDL-C was U-shaped associated with all-cause and cause-specific mortality in the US general population. However, in younger adults (<50 years), the higher the non-HDL-C, the higher the risk of cardiovascular and all-cause mortality. These observations support clear public health messaging and strict adherence to primary prevention strategies for atherosclerosis in younger adults. This has important implications for the development of age-specific interventions to reduce mortality associated with non-HDL-C levels.

Keywords: NHANES data; age; cardiovascular disease; mortality; non-HDL cholesterol.

Figure 1

All-cause and cause-specific mortality risks by non-HDL-C on continuous and categorical scales. Associations between non-HDL-C and all-cause (A,B), cause-specific mortality (C–H) on continuous and categorical scales. HRs (solid lines) and 95% CIs (shaded areas) are based on restricted cubic splines with Cox model adjusted for age, sex, ethnicity, systolic blood pressure, body mass index, HDL cholesterol, ASCVD, diabetes mellitus, COPD, renal dysfunction, cancer, fasting status. The blue histograms show the distribution of non-HDL-C in the population. Model I, unadjusted. Model II, adjusted for age, sex, ethnicity, systolic blood pressure, body mass index, HDL cholesterol, ASCVD, diabetes mellitus, COPD, renal dysfunction, cancer, fasting status. HDL, high-density lipoprotein. Non-HDL-C, non-high-density lipoprotein cholesterol. ASCVD, atherosclerotic cardiovascular disease. COPD, chronic obstructive pulmonary disease.

Figure 2

Multivariable adjusted hazard ratios with 95% confidence intervals for all-cause and cardiovascular mortality all-cause (A) and cardiovascular mortality (B). for the highest and lowest level of non-HDL-C group. The highest level group (>220 mg/dL) vs. the reference group (131–160 mg/dL) of non-HDL-C and the lowest level group (≤100 mg/dL) vs. the reference group of (131–160 mg/dL) of non-HDL-C, respectively. p for interaction was examined by including a two-factor interaction term between the examined non-HDL-C and each covariate in the Cox proportional hazards regression. Analyses were adjusted for age, sex, ethnicity, systolic blood pressure, body mass index, HDL cholesterol, ASCVD, diabetes mellitus, COPD, renal dysfunction, cancer, fasting status. BMI, body mass index. HDL, high-density lipoprotein. Non-HDL-C, non-high-density lipoprotein cholesterol. ASCVD, atherosclerotic cardiovascular disease. COPD, chronic obstructive pulmonary disease.

Figure 3

All-cause and cause-specific mortality risks by age and non-HDL-C. Adjusted hazards ratio for all-cause mortality (A), cardiovascular mortality (B), cancer mortality (C), and other-cause mortality (D) by continuous non-HDL-C and ages<50, 50 to 69, and ≥70 years. The blue histograms show the distribution of non-HDL-C in the population. Adjustment variables include age, sex, ethnicity, systolic blood pressure, body mass index, HDL cholesterol, ASCVD, diabetes mellitus, COPD, renal dysfunction, cancer, fasting status. Non-HDL-C, non-high-density lipoprotein cholesterol. HDL, high-density lipoprotein. ASCVD, atherosclerotic cardiovascular disease. COPD, chronic obstructive pulmonary disease.