Lipoprotein(a), high-sensitivity C-reactive protein, and risk of incident ASCVD in individuals without standard modifiable risk factors

BACKGROUND: The prognostic value of jointly assessing lipoprotein(a) [Lp(a)] and high-sensitivity C-reactive protein (hsCRP) in primary prevention among individuals without standard modifiable risk factors (SMuRFs) remains unclear. METHODS: We analyzed 50,450 UK Biobank participants free of cardiovascular disease at baseline who were SMuRF-less, defined as absence of current smoking, obesity, hypertension, dyslipidemia, and diabetes. Elevated Lp(a) and hsCRP were defined using cohort-specific 75th percentile cutoffs and established clinical thresholds. Incident atherosclerotic cardiovascular disease (ASCVD), defined as nonfatal myocardial infarction, nonfatal ischemic stroke, or cardiovascular death, was ascertained. Associations were evaluated using Fine-Gray competing-risk regression models to estimate subdistribution hazard ratios (sHRs) with 95% confidence intervals (CI), accounting for competing non-cardiovascular death. RESULTS: Over 15 years of follow-up, 1,104 (2.2%) incident ASCVD events occurred. Using cohort-specific cutoffs, elevated hsCRP was associated with higher ASCVD risk (sHR 1.35, 95% CI 1.16-1.57), while elevated Lp(a) showed a more modest association (sHR 1.24, 95% CI 1.06-1.45). In joint analyses, isolated elevations of hsCRP or Lp(a) were each associated with increased risk, with the highest risk observed among individuals with concurrent elevations (sHR 1.64, 95% CI 1.28-2.09), without evidence of interaction. Similar patterns were observed using clinical cutoffs (Lp(a) ≥125 nmol/L; hsCRP ≥2.0 mg/L), with concurrent elevation conferring the greatest risk (sHR 1.74, 95% CI 1.17-2.59). CONCLUSIONS: In SMuRF-less individuals, Lp(a) and hsCRP independently predict ASCVD risk. These findings suggest that combined assessment of Lp(a) and hsCRP may provide complementary information for risk characterization among SMuRF-less adults in primary prevention.