The Complex Relationship Between HDL/LDL Cholesterol, Stroke and Cardiovascular Disease

Background and Aims: Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of mortality worldwide, with lipid abnormalities playing a central role in disease development. While the causal role of low-density lipoprotein cholesterol (LDL-C) in ASCVD is well-established, the long-term population impact of combined lipid profiles, particularly the HDL-C/LDL-C ratio, remains less clearly quantified. This study aimed to estimate the lifetime burden of cardiovascular outcomes associated with different lipid risk profiles using a patient-level simulation framework. Methods: The authors analyzed projected lifetime ASCVD events across four HDL-C/LDL-C risk strata, ranging from low (≥0.45) to very high (<0.25), using the National Health Model Database of Projected and Estimated Outcomes (NHM-DPEO)-a digital twin of national healthcare systems built from multiple data sources, including national health and demographic statistics and estimates from the relevant literature. The framework is structured as a patient-level simulation model that projects individual health trajectories over a lifetime horizon. Model outputs were assessed for plausibility by comparison with published epidemiological estimates. Results: The NHM simulation revealed a strong, graded relationship between lipid profiles and cardiovascular survival. Life expectancy declined from 80.2 years in the lowest risk group (HDL-C/LDL-C ≥ 0.45) to 63.0 years in the very-high-risk group (HDL-C/LDL-C < 0.25), a reduction of 17.2 years, with 13.7 fewer QALYs. Similarly, participants with LDL-C > 5.0 mmol/L had a life expectancy 13.4 years shorter than those with LDL-C < 3.1 mmol/L. The burden of ASCVD increased exponentially with worsening lipid ratios: MI events rose from 5000 to 73,090 per 100,000 births, with onset in the highest risk group occurring as early as age 20. Ischaemic heart disease followed a similar pattern, showing up to 92% of events attributable to elevated lipid risk. While ischaemic stroke risk displayed a more complex pattern due to earlier MI mortality in high-risk groups, overall cardiovascular mortality and lifetime event burden were dominated by LDL-driven disease. These findings demonstrate that sustained LDL-C reduction and balanced HDL-C/LDL-C ratios confer substantial survival benefits across both sexes and all age groups. Conclusions: This study shows that lipid balance has a decisive influence on cardiovascular survival. Sustained LDL-C reduction and favourable HDL-C/LDL-C ratios markedly extend life expectancy and delay the onset of MI and IHD. The magnitude of this survival benefit highlights the need for early and continuous lipid control as a cornerstone of ASCVD prevention. The NHM quantifies these lifetime effects, offering valuable insights for targeted strategies that improve both longevity and quality of life.