IL-6, Not hsCRP, Modified Lp(a)-Associated CAD Risk

Interleukin-6 (IL-6) was associated with significant effect modification of the relationship between elevated lipoprotein(a) [Lp(a)] and incident coronary artery disease (CAD), whereas the more commonly used inflammatory marker high-sensitivity C-reactive protein (hsCRP) was not, according to a UK Biobank analysis published in JAMA Cardiology.¹ The findings provide additional evidence that IL-6–related inflammation may help explain why cardiovascular risk varies among individuals with elevated Lp(a).

“Overall, our findings support the hypothesis that low-grade inflammation may modify the Lp(a)-associated risk for incident CAD and offer new insights into improving risk stratification and management of patients with elevated Lp(a),” wrote the researchers of the study. “In this context, IL-6 could aid in identifying individuals most likely to benefit from Lp(a)-lowering or anti-inflammatory therapies.”

Investigators analyzed 43,512 UK Biobank participants without prevalent CAD or aortic valve stenosis (AS) at baseline, all of whom had Lp(a), hsCRP, neutrophil-to-lymphocyte ratio (NLR), and Olink-based interleukin measurements available. Among participants, 6975 (16.0%) had Lp(a) concentrations of at least 125 nmol/L, 24,079 (55.3%) were women, and the mean (SD) age was 56.5 (8.2) years. Median (Q1-Q3) follow-up was 13.5 (12.7-14.3) years for incident CAD and 13.6 (12.9-14.4) years for incident AS.

IL-6 Emerges as the Key Modifier

Participants with Lp(a) concentrations of at least 125 nmol/L had a higher risk of incident CAD than those with lower concentrations. Among the inflammatory biomarkers evaluated, IL-6 demonstrated the strongest association with both incident CAD and AS. IL-6 also significantly modified the association between elevated Lp(a) and incident CAD. Compared with participants in the lowest IL-6 quartile, those in the highest quartile experienced a stronger association between elevated Lp(a) and CAD risk (HR, 1.43; 95% CI, 1.25-1.63 vs HR, 1.09; 95% CI, 0.85-1.38; P for interaction = .008).

Neither hsCRP nor the interleukin-1 pathway markers IL-1β and IL-18 significantly modified the association between Lp(a) and CAD risk. Although the interaction between Lp(a) and NLR was suggestive (P for interaction = .02), it did not remain statistically significant after adjustment for multiple comparisons.

For AS, elevated Lp(a) and several inflammatory biomarkers, including IL-6, hsCRP, and NLR, were each independently associated with incident disease. However, none of the inflammatory biomarkers significantly modified the association between elevated Lp(a) and AS risk, indicating that the effect of Lp(a) on AS risk was consistent across levels of systemic inflammation measured in this study.

Biological Rationale

The authors note a plausible biological mechanism: the LPA gene contains an IL-6 response element, and IL-6 inhibition has been associated with reductions in Lp(a) concentrations in prior studies, supporting IL-6 as a potentially more specific marker than hsCRP in this context. With the IL-6 antagonist ziltivekimab already under investigation in 2 large cardiovascular outcomes trials, the authors suggest an opportunity to determine whether targeting IL-6 signaling preferentially reduces cardiovascular risk among patients with elevated Lp(a).

“In this primary prevention cohort study, Lp(a)-associated risk for incident CAD was modified by IL-6, with lower associated risk observed in the setting of lower inflammatory biomarker levels,” wrote the researchers. “These findings identify IL-6 as a biomarker of inflammatory risk that may modify Lp(a)-associated CAD risk.”

Managed Care Implications

As investigational Lp(a)-lowering therapies and IL-6-targeted treatments advance through late-stage clinical development, these findings may inform future research evaluating whether inflammatory biomarkers can improve risk stratification beyond Lp(a) concentrations alone. If confirmed in prospective clinical trials, IL-6 or related inflammatory markers could eventually help identify patients most likely to benefit from targeted therapies.

Although NLR is inexpensive and routinely available from complete blood counts, its role in Lp(a)-based risk stratification remains uncertain because the observed interaction did not remain statistically significant after correction for multiple comparisons. Additional studies will be needed before inflammatory biomarkers can be incorporated into treatment algorithms or coverage decisions.

The findings build on the 2022 European Atherosclerosis Society consensus statement, which concluded that elevated Lp(a) is a causal, genetically determined risk factor for both atherosclerotic cardiovascular disease and aortic valve stenosis.² The consensus recommends measuring Lp(a) at least once during adulthood to identify individuals with inherited elevations and emphasizes aggressive management of other modifiable cardiovascular risk factors because no Lp(a)-specific therapies have yet received regulatory approval. It also notes that emerging ribonucelic acid-targeted therapies may eventually allow more personalized treatment strategies for patients with markedly elevated Lp(a).

References

1. Mohammadnia N, Li L, Ezzat D, et al. Lipoprotein(a), inflammation, and risk of coronary artery disease and aortic valve stenosis. JAMA Cardiol. Published online June 24, 2026. doi:10.1001/jamacardio.2026.1852
2. Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J. 2022;43(39):3925-3946. doi:10.1093/eurheartj/ehac361