New study shows cardiovascular risk rises mainly when IL-6 is also elevated, highlighting a potential role for combined biomarker testing.
Increased lipoprotein(a) may only signify an increased cardiovascular risk when inflammation is also high, a new UK Biobank study has found.
The study involved 34,092 individuals free from atherosclerotic cardiovascular disease (ASCVD) at baseline, followed up for a median of 13.6 years.
Associations between Lp(a) and cardiovascular risk were found to be non-significant among individuals with lower interleukin-6, an upstream cytokine and inflammatory biomarker.
Among those with IL-6 above the median, elevated Lp(a) was associated with increased major adverse cardiovascular events (MACE) risk (HR 1.17) compared to those below median Lp(a), which did not show an association.
The study follows previous reports that routine Lp(a) testing could prevent 60 heart attacks, 13 strokes and 26 early deaths per 10,000 people. This earlier research, reported by The Medical Republic last year, also used UK Biobank data.
For the 10,000 randomly selected people aged 40–69, modelling suggested one-off Lp(a) testing would have reclassified one in five as high-risk for cardiovascular disease, prompting earlier intervention and potentially preventing poorer outcomes.
This more recent study from a different team of researchers, published in Atherosclerosis, sheds more light on Lp(a) as a biomarker of CVD risk.
The median Lp(a) level was 21.4nmol/L and the median IL-6 level was −0.03NPX. Those above the IL-6 median were more likely to be older, have a higher BMI, smoke and have higher rates of diabetes and hypertension compared with individuals with below median IL-6.
When Lp(a) was analysed as a continuous variable, each unit increase in log-transformed Lp(a) was associated with a higher risk of MACE among individuals with IL-6 levels above the median (HR 1.07).
On the absolute scale, 10-year MACE incidence was similar between low and high Lp(a) in individuals with low IL-6 (4.49% vs 4.42%), but higher in those with elevated IL-6 (8.26% vs 9.16%).
Even applying a clinical threshold for Lp(a) (≥125 nmol/L) yielded similar results; higher Lp(a) remained associated with increased MACE risk only in those with elevated IL-6. These results were mirrored by an additional eight-year landmark analysis, restricted to participants who remained event-free.
Interestingly, sex-stratified analyses showed no association between Lp(a) and MACE in females, while males with elevated Lp(a) and IL-6 had an HR of 1.23, with no association observed at lower IL-6 levels.
Researchers also looked at coronary artery disease (CAD) and ischaemic stroke (IS) separately for an association with Lp(a) and IL-6. Throughout follow-up, 3166 individuals experienced a MACE; 2717 a CAD event and 577 an IS event.
For CAD, elevated Lp(a) was associated with increased risk among individuals with IL-6 levels above the median (HR 1.18) but not among those with lower IL-6 (HR 0.98). In contrast, no significant associations between Lp(a) and IS were observed in either IL-6 stratum.
Related
Both Lp(a) and inflammation are established causal risk factors for atherosclerotic CVD, authors explained. Lp(a) carries oxidized phospholipids, which promote vascular inflammation through innate immune pathways such as downstream IL-6 signalling. These processes drive endothelial activation, leukocyte recruitment and plaque inflammation, which are amplified when IL-6 levels are elevated.
IL-6 also has direct pro-atherothrombotic effects, increasing cytokine release, tissue factor expression and procoagulant activity in endothelial cells. Together, these effects may enhance the harmful impact of Lp(a), promoting plaque instability and thrombosis.
Although IL-6 can increase Lp(a) production in the liver, the very weak correlation between circulating IL-6 and Lp(a) in this cohort (ρ = 0.02) suggested to researchers that they are not simply co-regulated and instead, that IL-6 influences how harmful Lp(a) is rather than how much is present.
“Our data indicate that IL-6 measurement could help identify individuals more likely to achieve the greatest risk reduction from Lp(a)-targeted treatments,” authors wrote, stating that Lp(a)-lowering drugs are currently approaching clinical availability.
“In the interim, patients with both elevated Lp(a) and IL-6 may warrant closer surveillance and more intensive management of modifiable risk factors.”
