The association of the non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) and healthy lifestyle with cardiovascular disease incidence: a cohort study in the UK Biobank

The non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) has emerged as a novel lipid metric with potential utility in cardiovascular risk assessment. However, its predictive value in European populations and its interplay with comprehensive lifestyle factors remain inadequately characterized. To investigate the independent and joint associations of NHHR and a healthy lifestyle score (HLS) with the risk of incident cardiovascular disease (CVD) and its subtypes in a large prospective cohort. This study included 400,968 participants from the UK Biobank who were free of CVD at baseline. NHHR was calculated as the ratio of non-high-density lipoprotein cholesterol (non-HDL-C) to high density lipoprotein cholesterol (HDL-C). An HLS (0–5) was constructed based on smoking, alcohol consumption, physical activity, diet, and sleep duration. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CVD, coronary heart disease (CHD), and stroke. Over a median follow-up of 12.98 years, 40,809 incident CVD cases, 33,578 incident CHD cases, and 11,801 incident stroke cases were recorded. Restricted cubic spline analyses showed significant non-linearity for CVD, CHD and stroke (all P for non-linearity <0.001), but the curves were essentially flat below the median NHHR and increased monotonically thereafter; these non-linear analyses are therefore reported as exploratory. From the median upward, higher NHHR was consistently associated with higher risk of total CVD and CHD In linear trend analyses, higher NHHR remained associated with increased risks of total CVD and CHD (both P for trend <0.05), but not with stroke in a simple monotonic manner. Evidence of interaction between HLS and NHHR was restricted to CVD and CHD and did not persist in the fully adjusted model (P for interaction 0.022 for CVD and 0.037 for CHD with demographic adjustment plus BMI; 0.051 and 0.072 respectively after further adjustment for the individual lifestyle components). The association of NHHR with stroke was weak and was not statistically significant in the fully adjusted model. In this large European prospective cohort, NHHR was independently associated with incident CVD and CHD, with a graded association across the upper range of the exposure and a weaker, statistically inconsistent association with stroke. Evidence of interaction with lifestyle was limited to a fragile, underpowered effect in the smallest and healthiest stratum and did not survive full adjustment; it should therefore be regarded as exploratory rather than as reliable effect modification. These findings require confirmation in independent cohorts, and they do not support causal inference.