Interplay of HDL cholesterol and apoB and the risk of incident atherosclerotic cardiovascular disease in UK Biobank

BACKGROUND: Apolipoprotein B (apoB) is the most accurate causal lipid factor associated with increased risk of atherosclerotic cardiovascular disease (ASCVD). While high HDL cholesterol has been considered protective, HDL-C-raising therapies have not shown benefit. OBJECTIVE: To assess whether HDL-C provides independent information from apoB and whether HDL-C modifies the effect of apoB on ASCVD risk. METHODS: 293,872 UK Biobank participants aged 37-73, free of CVD, not on lipid-lowering medication, and with complete standard risk factor data were followed for 10 years for incident ASCVD. Cox proportional hazard models, adjusted for standard risk factors, including log-triglycerides, used apoB and HDL-C residuals (regressed on each other) as primary exposures. Interaction between apoB and HDL-C was tested separately. RESULTS: When HDL-C residual was added to a model with apoB, both were significant: HRs per 1 SD were 1.16 (95% CI: 1.15-1.18; p < 0.001) for apoB and 0.85 (95% CI: 0.84-0.87; p < 0.001) for HDL-C residual. Similarly, adding apoB residual to a model with HDL-C yielded HRs of 1.14 (95% CI: 1.12-1.16; p < 0.001) for apoB residual and 0.84 (95% CI: 0.82-0.85; p < 0.001) for HDL-C. The apoB-HDL-C interaction was significant: HR 0.95 (95% CI: 0.93-0.96; p < 0.001), consistent across sexes. CONCLUSIONS: High HDL-C is associated with lower ASCVD risk, independent of apoB, and it attenuates the effect of high apoB on ASCVD risk. These findings suggest HDL-C's role in primary ASCVD prevention warrants re-evaluation. However, findings from an observational study, such as this, do not establish causation.