Hyperlipidaemia and inflammation are known contributors to cardiovascular risk, but their combined impact, particularly in patients on treatment, requires further clarification. A new longitudinal analysis of UK Biobank data has found that low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) [Lp(a)], and high-sensitivity C-reactive protein (Hs-CRP) are independent and synergistic predictors of major adverse cardiovascular events (MACEs), regardless of whether patients are receiving cholesterol-lowering medication.¹

This longitudinal cohort study analysed data from 322,922 participants (55.9% women) aged 38 to 73 years from the UK Biobank, all of whom were free from MACE at baseline.¹ The cohort was stratified into two groups: those not using cholesterol-lowering medication (n=280,002) and those who were (n=42,920).

The primary outcome was the incidence of MACE, a composite including fatal and non-fatal myocardial infarction, ischaemic stroke, chronic ischaemic heart disease, sudden cardiac arrest, angina pectoris, percutaneous coronary intervention, or coronary artery bypass surgery. The median follow-up period was 13.7 years.

Over the follow-up period, 31,295 participants (9.69%) experienced an incident MACE. The incidence was substantially higher in the group using cholesterol-lowering medication (18.6%) compared to non-users (8.32%).

All three biomarkers—LDL-C, Lp(a), and Hs-CRP—were found to be independent predictors of MACE. LDL-C was the strongest predictor. For each standard deviation increase in biomarker levels:

• Non-users: MACE risk increased by 13% for LDL-C, 8% for Lp(a), and 6% for Hs-CRP.
• Users: MACE risk increased by 11% for LDL-C, 7% for Lp(a), and 6% for Hs-CRP.

A synergistic effect was also evident. Compared to individuals with all three biomarkers at or below the 75th percentile, those with all three above this threshold had a 77% higher risk of MACE among non-users and a 58% higher risk among users of cholesterol-lowering medication.

The findings underscore that elevated levels of LDL-C, Lp(a), and Hs-CRP are associated with a heightened risk of future atherothrombotic events, with a combined effect that significantly increases this risk. Similar findings on the additive risk of these biomarkers have been reported in other large cohorts, such as the Women’s Health Study.²

The authors of the UK Biobank analysis concluded, “Hyperlipidaemia and inflammation independently and synergistically contribute to an increased risk for incident cardiovascular events. The magnitude of risk is more closely related to serum biomarker concentrations than to the use or not of cholesterol-lowering medications.” This suggests that assessing all three markers may be crucial for comprehensive risk stratification, even in patients already on lipid-lowering therapy.

The study authors noted that while their observational findings are significant, randomised clinical trials are needed to determine the effectiveness of a 'triple therapy' approach that aggressively targets lipids and inflammation to reduce MACE risk before it can be adopted into clinical practice.

This study was funded by University Medicine Greifswald, the Wellcome Trust, Medical Research Council, and others.

References

1. Markus MRP, Ittermann T, Mariño Coronado J, et al. Low-density lipoprotein cholesterol, lipoprotein(a) and high-sensitivity C-reactive protein are independent predictors of cardiovascular events. Eur Heart J 2025;46(39):3863–3874. https://doi.org/10.1093/eurheartj/ehaf281

2. Ridker PM, Moorthy MV, Cook NR, et al. Inflammation, cholesterol, lipoprotein(a), and 30-year cardiovascular outcomes in women. N Engl J Med 2024;391:2087–97. https://doi.org/10.1056/NEJMoa2405182

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