LDL-cholesterol, lipoprotein(a) and high-sensitivity low-density lipoprotein cholesterol, lipoprotein(a) and high-sensitivity C-reactive protein are independent predictors of cardiovascular events

Abstract

Background and Aims

Associations of hyperlipidaemia and inflammation with the risk for incident major adverse cardiovascular events (MACEs) were analysed in individuals with and without cholesterol-lowering medication therapy.

Methods

Data from 322,922 participants (55.9% women) aged 38 to 73 years from the UK Biobank were included. Longitudinal associations of low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) [Lp(a)], and high-sensitivity C-reactive protein (Hs-CRP), both individually and in combination, were analysed with the risk for incident MACEs using Cox regression models, stratified by cholesterol-lowering medication use.

Results

During a median follow-up of 13.7 years, 31,295 (9.69%) participants had incident MACEs. The incidence was 8.32% in non-users and 18.6% in users of cholesterol-lowering medication. Higher LDL-C levels were associated with the highest risk for MACEs, followed by Lp(a) and Hs-CRP. One higher standard deviation in LDL-C, Lp(a), and Hs-CRP was associated with a 13%, 8%, and 6% greater risk for MACEs in non-users and 11%, 7%, and 6% in cholesterol-lowering medication users, respectively. When combined, LDL-C, Lp(a), and Hs-CRP demonstrated a synergistic effect. Compared with individuals with all three biomarkers at or below the 75th percentile, those with all three biomarkers above the 75th percentile had a 77% higher risk for incident MACEs among non-users and a 58% higher risk among those on cholesterol-lowering medications.

Conclusions

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.

Structured Graphical Abstract

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Introduction

Many epidemiological studies and pathophysiological findings link hyperlipidaemia to atherosclerosis and increased cardiovascular risk. Furthermore, there is also evidence that hyperlipidaemia may interact with inflammation to further increase this risk.^1–11

Low-density lipoprotein cholesterol (LDL-C) and other apolipoprotein B (apoB)-containing lipoproteins, including lipoprotein(a) [Lp(a)], are directly associated with atherosclerosis.^12,13 Atherogenesis is initiated by the retention and accumulation of these lipoproteins in the arterial intima and triggers an inflammatory response that drives plaque progression and may lead to plaque disruption.⁵

Lp(a) is synthesized in the liver and represents a low-density lipoprotein-like particle where the apoB-100 is covalently bound to an additional apolipoprotein, namely apolipoprotein(a).¹⁴ In addition to being cholesterol-rich, Lp(a) is pro-inflammatory through the oxidized phospholipid load carried by apolipoprotein(a); furthermore, due to the homology of the latter with plasminogen, it may also exert pro-thrombotic effects.^9,15

High-sensitivity C-reactive protein (Hs-CRP) is not a direct cause of cardiovascular disease but serves as a biomarker of systemic low-grade inflammation mediated by cytokines like interleukin-6 and interleukin-1β. These cytokines contribute to the atherosclerotic process by promoting pro-coagulant activity, enhancing monocyte and leucocyte adhesion to vascular endothelial cells, and stimulating the growth of vascular smooth muscle cells.¹⁶

Elevated LDL-C and Lp(a) levels initiate atherosclerosis, promote, gene expression, modulate cytokines and chemoattractants, and facilitate monocyte migration.^17,18 This suggests a synergistic effect with low-grade inflammation in atherosclerosis.^9,17

Several studies^{1–4,6,7,9–11} have analysed the association of LDL-C with Lp(a), LDL-C with Hs-CRP, or Lp(a) with Hs-CRP in participants with or without lipid-lowering therapy on cardiovascular risk, but a recent analysis,¹⁹ including only women examined the overall combined effect of these three biomarkers on the risk for future atherothrombotic events.

We aimed to assess the associations of LDL-C, Lp(a), and the inflammation biomarker Hs-CRP—individually, in pairs, and together—with the risk of major adverse cardiovascular events (MACEs) in men and women, using data from the UK Biobank, stratified by the use of cholesterol-lowering medication.

Methods

Study population

The UK Biobank

The present study is based on data from the United Kingdom (UK) Biobank,^20–23 an observational large-scale prospective cohort. In total, 502,398 individuals participated in the UK Biobank study. We performed a longitudinal analysis following the baseline examination for the present evaluation. We excluded participants who withdrew informed consent (n = 244) or had previous MACEs (n = 29,107). We also excluded individuals with missing values for Lp(a) (n = 118,210), Hs-CRP (n = 829), LDL-C (n = 659), self-reported cholesterol-lowering medication use (n = 2821), or any of the covariables (n = 27,606) (see Supplementary data online, Figure S1). The final analytical sample comprised 322,922 participants (180,636 women; 55.9%) aged 38 to 73 years at the baseline assessment.

Laboratory measurements

Serum LDL-C levels in mmol/L were directly measured by enzymatic protective selection analysis on a Beckman Coulter AU5800 (Beckman Coulter, UK, Ltd). Serum Lp(a) concentrations, in nmol/L, reflecting the concentration of particles rather than their mass, were measured by immunoturbidimetric analysis on a Beckman Coulter AU5800 (Randox Biosciences, UK). Serum Hs-CRP levels in mg/L were measured by immunoturbidimetric analysis on a Beckman Coulter AU5800 (Beckman Coulter, UK, Ltd). Serum high-density lipoprotein cholesterol (HDL-C) concentrations in mmol/L were measured by enzyme immunoinhibition analysis on a Beckman Coulter AU5800 (Beckman Coulter, UK, Ltd). Serum total cholesterol and triglyceride levels in mmol/L were measured by an enzymatic analysis on a Beckman Coulter AU5800 (Beckman Coulter, UK, Ltd). Remnant cholesterol (RC) concentrations in mmol/L were calculated by subtracting LDL-C and HDL-C from total cholesterol concentrations.^24–26

Major cardiovascular events

The primary outcome of this study was the occurrence of MACEs. Both the time to first MACE and rates of all MACEs were investigated. Our definition of MACEs includes participants with any of the following: fatal and non-fatal myocardial infarction (ICD-10: I21), ischaemic stroke (ICD-10: I63), chronic ischaemic heart disease (ICD-10: I25), and sudden cardiac arrest (ICD-10: I46). It also includes angina pectoris (ICD-10: I20), percutaneous coronary intervention (OPCS-4: K49 or K75), and coronary artery bypass surgery (OPCS-4: K40, K41, or K45).

End of follow-up for each participant was recorded as the date of death, the date of end of follow-up for the assessment centre attended, or the first date of MACE-related hospitalization (for both composite fatal and non-fatal outcomes), whichever came first. The period at risk per participant for incident MACEs began on the next day after the date of their baseline assessment. Participants with any MACE before or at the day of their baseline assessment were excluded from all analyses. Participants were censored at death or loss to follow-up. The number of months between baseline examination and censoring was used as the duration of follow-up.

Statistical analysis

Descriptive data were reported as median (25th and 75th percentile) for continuous variables and as absolute numbers and percentages for categorical variables stratified by the absence or use of self-reported cholesterol-lowering medication.

We investigated the associations of LDL-C, Lp(a), and Hs-CRP with incident MACEs using Cox proportional hazard models (with 95% confidence interval [CI]) in participants stratified by the absence or use of self-reported cholesterol-lowering medication adjusted for the baseline assessment of age, sex, body fat mass, body fat-free mass, body height^2.7, systolic blood pressure, glycated haemoglobin, use of self-reported blood pressure and self-reported glucose-lowering medication, smoking status, estimated glomerular filtration rate (eGFR) (Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] cystatin C equation²⁷), ethnicity (defined as White and non-White), and Townsend deprivation index (TDI). To make the regression models comparable, LDL-C, Lp(a), and Hs-CRP were used as standardized variables, with the participants stratified by the absence or use of cholesterol-lowering medication. In the group of participants categorized by no cholesterol-lowering medication use, one standard deviation (SD) corresponded to 0.80 mmol/L for LDL-C, 48.7 nmol/L for Lp(a), and 4.23 mg/L for Hs-CRP. In the group of participants categorized by the use of cholesterol-lowering medication, one SD corresponded to 0.74 mmol/L for LDL-C, 50.9 nmol/L for Lp(a), and 4.38 mg/L for Hs-CRP. In one scenario, we combined the standardized LDL-C, Lp(a), and Hs-CRP in one model. In another scenario, we investigated separately the associations of each biomarker with MACEs. In sensitivity analysis, we investigated the sex-specific associations of LDL-C, Lp(a), and Hs-CRP with incident MACEs in participants stratified by the absence or use of cholesterol-lowering medication with adjustments for the same covariables as the previous models and tested for interaction. Likewise, in sensitivity analysis, we further stratified the groups without or with the use of cholesterol-lowering medication by Hs-CRP levels (<2 or ≥ 2 mg/L) to investigate if the presence of inflammation might have a modulatory effect on the associations of LDL-C and Lp(a) with incident MACEs and also tested for interaction. We included RC in our Cox proportional hazard models for sensitivity analysis that investigated the associations of LDL-C, Lp(a), and Hs-CRP with incident MACEs.

Furthermore, we defined high levels of LDL-C, Lp(a), and Hs-CRP based on the participant’s 75th percentile stratified by the absence or use of cholesterol-lowering medication. In the group of participants categorized by the lack of use of cholesterol-lowering medication, the 75th percentile corresponded to 4.22 mmol/L for LDL-C, 60.8 nmol/L for Lp(a), and 2.66 mg/L for Hs-CRP. In the group of participants categorized by using a cholesterol-lowering medication, the 75th percentile corresponded to 3.27 mmol/L for LDL-C, 63.2 nmol/L for Lp(a), and 2.93 mg/L for Hs-CRP.

Based on these percentiles, we defined categorical variables with the eight following groups: 1. LDL-C, Lp(a) and Hs-CRP ≤ 75th percentile; 2. Hs-CRP and Lp(a) ≤ 75th percentile, and LDL-C > 75th percentile; 3. LDL-C and Hs-CRP ≤ 75th percentile, and Lp(a) > 75th percentile; 4. LDL-C and Lp(a) ≤ 75th percentile, and Hs-CRP > 75th percentile; 5. Hs-CRP ≤ 75th percentile, and LDL-C and Lp(a) > 75th percentile; 6. Lp(a) ≤ 75th percentile, and LDL-C and Hs-CRP > 75th percentile; 7. LDL-C ≤ 75th percentile, and Hs-CRP and Lp(a) > 75th percentile; 8. LDL-C, Lp(a), and Hs-CRP >75th percentile. After using these variables in the Cox regression of participants stratified by the absence or use of cholesterol-lowering medication, we calculated and plotted the cumulative hazard functions for each category adjusted for the baseline assessment of age, sex, body fat mass, body fat-free mass, body height^2.7, systolic blood pressure, glycated haemoglobin, use of blood pressure and glucose-lowering medication, smoking status, eGFR, ethnicity, and TDI. For sensitivity analysis, we calculated a Fine–Gray competing risk model²⁸ adjusted for the same variables as in the main analyses to account for the competing risk for other deaths (excluding fatal myocardial infarction, stroke, chronic ischaemic heart disease, and sudden cardiac arrest) and visualized the results as cumulative incidence function curves of the respective groups of LDL-C, Lp(a), and Hs-CRP.

A two-sided P-value <.05 was considered statistically significant in all analyses. All calculations were performed using Stata 18.5 (Stata Corporation, College Station, TX, USA).

Please see the online data supplement for a more detailed description of the methods.

Results

From our total study sample of 322,922 participants, 280,002 (162,211 women; 57.9%) were not in use, and 42,920 (18,425 women; 42.9%) were using cholesterol-lowering medication (Table 1).

The median duration of follow-up was 13.7 years (25th–75th percentile: 12.8–14.5). During the 4,188,891 person-years of follow-up, from the 322,922 participants, 31,295 (9.69%; 19,161 [61.2%] men and 12,134 [38.8%] women) had incident MACEs. The incidence of MACEs was 8.32% (23,306 from 280,002 participants [13,880 {59.6%} men and 9426 {40.4%} women]) among those not using cholesterol-lowering medication and 18.6% (7989 from 42,920 participants [5281 {66.1%} men and 2708 {33.9%} women]) in those taking this medication.

Individuals using cholesterol-lowering medication were older and had higher body mass index, waist circumference, FM, and FFM. While they had lower total cholesterol, RC, LDL-C, and HDL-C levels, their glycated haemoglobin and triglycerides concentrations were higher. Importantly, Lp(a) and Hs-CRP levels were also higher among the participants using cholesterol-lowering medication. Furthermore, their systolic and diastolic blood pressures were higher, and they were more likely to have a history of hypertension and type 2 diabetes, higher use of blood pressure and glucose-lowering medication, lower eGFR, and a somewhat higher percentage of current smokers. While the cohort was predominantly of White ethnicity, there were a slightly higher proportion of non-White participants and a higher TDI among those taking cholesterol-lowering medication (Table 1).

Associations of standardized LDL-C, Lp(a), and Hs-CRP concentrations with incident MACEs

In multivariable Cox proportional hazard models, increased LDL-C, Lp(a), and Hs-CRP levels revealed significantly higher risk for incident MACEs in both groups with and without cholesterol-lowering medication. Overall, and noteworthy, the results did not change if the three variables were used separately or together in the same model. In both groups of participants, higher LDL-C concentrations indicated the greatest risk for incident MACEs, followed by Lp(a) and Hs-CRP. Specifically, a one higher SD in LDL-C levels was associated with a 13% and an 11% greater chance for incident MACEs in the groups of subjects without and with cholesterol-lowering medication usage. Accordingly, a one higher SD in Lp(a) concentrations was associated with an 8% and a 7% higher chance for incident MACEs in non-users and users of cholesterol-lowering medication groups, respectively. Finally, a one higher SD in Hs-CRP levels was associated with a 6% greater chance for incident MACEs in both groups of those without and with the use of cholesterol-lowering medication (Table 2). In sensitivity sex-specific analysis, we observed an interaction of sex with LDL-C and Lp(a), in participants without cholesterol-lowering medication usage, with a larger effect in men. There was no interaction of sex with Hs-CRP in both groups and with LDL-C and Lp(a) in the cholesterol-lowering medication use group (Figure 1). Noteworthy, lower (<2 mg/L) or higher (≥2 mg/L) Hs-CRP levels did not modify the independent associations of LDL-C and Lp(a) with MACEs in both participants without and with cholesterol-lowering medication (Figure 1). In a sensitivity analysis, we included RC in our Cox proportional hazard models that investigated the associations of LDL-C, Lp(a), and Hs-CRP combined with incident MACEs (Table 3). Specifically, one higher SD in RC levels was associated with a 7% and a 5% greater chance for incident MACEs in the groups of subjects without and with cholesterol-lowering medication usage independent of LDL-C, Lp(a), and Hs-CRP concentrations, respectively. On the other hand, we observed that compared with the separate models, the associations of LDL-C concentrations with incident MACEs were lower in the combined models with all four variables together. In the group of individuals without use of cholesterol-lowering medication, the HR decreased from 1.13 to 1.08, and in the group of individuals using cholesterol-lowering medication the HR decreased from 1.12 to 1.08. Likewise, the HR for RC levels on incident MACEs decreased from 1.11 to 1.07 in individuals not using lipid-lowering medication and from 1.09 to 1.05 in individuals using lipid-lowering medication. There were no changes in the HR of the associations of Lp(a) and Hs-CRP concentrations with incident MACEs if these variables were analysed separately or combined with LDL-C and RC in the same model.

Associations of high levels of LDL-C, Lp(a), and Hs-CRP concentrations with incident MACEs

Study participants not taking cholesterol-lowering medication

When compared with the participants in the group of LDL-C, Lp(a), and Hs-CRP ≤ 75th percentile (reference), the fully adjusted hazard ratio (HR) for incident MACEs, was 1.24 (95% CI: 1.19 to 1.29) for the group with LDL-C > 75th percentile; 1.17 (95% CI: 1.12 to 1.22) for the group with Lp(a) > 75th percentile; 1.20 (95% CI: 1.15 to 1.25) for the group with Hs-CRP > 75th percentile; 1.47 (95% CI: 1.39 to 1.56) for the group with LDL-C and Lp(a) > 75th percentile; 1.45 (95% CI: 1.37 to 1.52) for the group with LDL-C and Hs-CRP > 75th percentile; 1.42 (95% CI: 1.34 to 1.50) for the group with Lp(a) and Hs-CRP > 75th percentile; and 1.77 (95% CI: 1.65 to 1.91) for the group of LDL-C, Lp(a) and Hs-CRP > 75th percentile (Figures 2A and 3). The crude number of incident MACEs in the group of no cholesterol-lowering medication use is shown in Figure 3. In sensitivity analysis, accounting for the competing risk for other deaths, the results of the Fine-Gray model showed only minor differences in comparison to the main results (see Supplementary data online, Figures S2A and S3).

Study participants using cholesterol-lowering medication

When compared with the participants in the group of LDL-C, Lp(a), and Hs-CRP ≤ 75th percentile (reference), the fully adjusted HR for incident MACEs, was 1.15 (95% CI: 1.07 to 1.24) for the group with LDL-C > 75th percentile; 1.11 (95% CI: 1.03 to 1.19) for the group with Lp(a) > 75th percentile; 1.17 (95% CI: 1.10 to 1.25) for the group with Hs-CRP > 75th percentile; 1.47 (95% CI: 1.33 to 1.63) for the group with LDL-C and Lp(a) > 75th percentile; 1.39 (95% CI: 1.26 to 1.54) for the group with LDL-C and Hs-CRP > 75th percentile; 1.33 (95% CI: 1.20 to 1.48) for the group with Lp(a) and Hs-CRP > 75th percentile; and 1.58 (95% CI: 1.38 to 1.82) for the group of LDL-C, Lp(a) and Hs-CRP > 75th percentile (Figures 2B and 3). The crude number of incident MACEs in the group of cholesterol-lowering medication use is shown in Figure 3. In sensitivity analysis, accounting for the competing risk for other deaths, the results of the Fine–Gray model showed only minor differences in comparison to the main results (see Supplementary data online, Figures S2B and S3).

Discussion

In our analyses of 322,922 participants of a large-scale cohort study without prior MACEs, we found that hyperlipidaemia (elevated LDL-C and Lp[a]) and low-grade inflammation (Hs-CRP) are independent predictors of future atherothrombotic events. The risk was related to the serum levels of these biomarkers rather than to the use or not of cholesterol-lowering medication. LDL-C was the strongest predictor, followed by Lp(a) and Hs-CRP. When these factors were combined, they had a synergistic effect on the risk for incident MACEs (Structured Graphical Abstract). Besides that, lower (<2 mg/L) or higher (≥2 mg/L) Hs-CRP levels did not modify the independent associations of LDL-C and Lp(a) with MACEs in both the groups without and with cholesterol-lowering medication. We decided to include RC in a sensitivity analysis following previous studies^25,26,29 that showed that RC (the cholesterol carried in triglyceride-rich lipoproteins) might be considered as a significant causal risk factor for atherosclerosis. Although RC was shown to be independent of LDL-C, Lp(a), and Hs-CRP as a predictor for incident MACEs in our analyses, including RC alongside LDL-C resulted in a reduction of the associations of LDL-C and RC with incident MACEs in groups using or not cholesterol-lowering medication.

Notably, while in participants without cholesterol-lowering medication the group with all three variables above the 75th percentile showed a significant higher risk for incident MACEs than all the other groups, in the cholesterol-lowering medication, the presence of LDL-C accompanied by Lp(a) or Hs-CRP, above the 75th percentile, already showed the highest risk for incident MACEs that was not statistically different than the group with all three variables.

In the group without cholesterol-lowering medication use, the adjusted residual risk for incident MACEs increased from around 7% when all three variables were below or equal to the 75th percentile to around 12.5% in the group with all three variables above the 75th percentile, which corresponded to a 77% greater risk. The presence of one of the variables paralleled a 17% to 24% higher risk, while the presence of two of the variables corresponded to a 42% to 47% greater risk.

The cholesterol-lowering medication group, characterized by older individuals and more cardiovascular risk factors such as hypertension and type 2 diabetes, exhibited a lower increase in the risk for incident MACEs between the clusters compared with the group without cholesterol-lowering medication use, though there was higher residual risk in all groups. Consequently, the adjusted residual risk for incident MACEs rose from around 14% when all three variables were at or below the 75th percentile to just over 22% in the group with all three variables above the 75th percentile, indicating a 58% greater risk. The presence of one variable was associated with an 11% to 17% higher risk, while having two variables resulted in a 33% to 47% greater risk.

In summary, the associations of LDL-C, Lp(a), and Hs-CRP with incident MACEs were influenced by their levels, regardless of cholesterol-lowering medication use. Individuals with elevated levels of LDL-C, Lp(a), and Hs-CRP faced the highest risk of incident MACEs, while those with low concentrations of all three biomarkers experienced the lowest risk.

In the context of the published literature

A recent analysis from the Women’s Health Study, involving 27,939 female health professionals in the United States, similarly found that increasing quintiles of baseline LDL-C, Lp(a), and Hs-CRP levels predicted a 30-year risk for MACEs.¹⁹ Each biomarker was independently associated with future MACEs risk, and the risk was additive when multiple biomarkers were elevated, with the highest risk occurring when all were simultaneously increased. In contrast to our findings, which identified LDL-C as the strongest predictor for incident MACEs, followed by Lp(a) and Hs-CRP, the earlier analysis found Hs-CRP to be a stronger predictor than the other two biomarkers.¹⁹ This difference may be due to their use of categorical data, whereas we used continuous data in part of our study. In a sensitivity analysis, we stratified the variables in our sample by quintiles, as the analysis from the Women’s Health Study. Our findings showed that among those using cholesterol-lowering medication, Hs-CRP exhibited the highest risk for incident MACEs (+30%; when the fifth quintile was compared with the first quintile), followed by LDL-C (+28%) and Lp(a) (+18%). Conversely, in the group of non-users of cholesterol-lowering medication, LDL-C (+38%) maintained the strongest risk, closely followed by Hs-CRP (+37%) and Lp(a) (+23%). While at the baseline examination few participants were receiving statin therapy in the Women’s Health Study, it became progressively more common over time (principally after year 15). At the end of the follow-up (by year 30) a total of 57.5% of the participants were in use of cholesterol-lowering therapy. Nonetheless, both studies demonstrate that a combined measure of LDL-C, Lp(a), and Hs-CRP can predict future cardiovascular events over 16 (our analysis) and 30-year follow-up in individuals without prior MACEs. In comparison to the aforementioned study, our results offer significant additional insights. Among other factors, we included both sexes, specifically compared the HRs for incident MACEs for each biomarker and across all biomarker pairs, and examined the effect of lipid-lowering therapy medication.

A recent collaborative analysis of three randomized trials involving 31,245 patients also found that Hs-CRP was a stronger predictor of MACEs, cardiovascular death, and all-cause death than LDL-C.⁷ This analysis focused on moderate hypertriglyceridaemia patients with a high prevalence of cardiovascular disease and type 2 diabetes receiving statin therapy. While our study was based on a large-scale observational prospective cohort, the previous analysis was conducted on patients participating in trials aimed at triglyceride reduction, where all participants received intensive guideline-directed medical therapy.⁷ Additionally, we considered glycated haemoglobin levels and the use of glucose-lowering medications among our participants, factors known to influence the associations between cholesterol, inflammation, and MACEs,⁸ which may further explain the differences between the findings of the two studies.

In line with our results, a meta-analysis with 29,069 participants from seven randomized, cardiovascular prevention placebo-controlled statin trials (5751 events, 19.8%) demonstrated that, in both subjects on placebo and on statin treatment, higher Lp(a) concentrations were linearly associated with cardiovascular risk independently of LDL-C concentrations.¹

Also in line with our results, the Copenhagen General Population Study (CGPS) with 68,090 participants (median follow-up 8.1 years) concluded that Lp(a) concentrations were associated with the risk of incident atherosclerotic cardiovascular disease (5104 events, 7.50%) or aortic valve stenosis (1220 events, 1.79%) regardless of Hs-CRP levels.⁹ Moreover, a recent study¹⁰ with 357,220 participants (median follow-up 11 years, 37,575 events, 10.5%) of the UK Biobank cohort, without previous cardiovascular events, and 34,020 participants (median follow-up 2 years, 2412 events, 7.09%) of the aggregated data from the FOURIER and SAVOR trials, with previous cardiovascular events, showed that higher levels of Lp(a) were associated with incident cardiovascular events in both primary and secondary prevention populations irrespective of baseline Hs-CRP concentrations.

A recent study of 71,678 participants from 8 European cohorts (BiomarCaRE project) partially aligns with our findings.¹¹ Among individuals without coronary heart disease (65,661 participants, median follow-up of 9.8 years, 5% event rate), Lp(a) levels were linked to incident coronary events, independent of Hs-CRP levels. However, in those with existing coronary heart disease (6017 participants, median follow-up of 13.8 years, 22.8% event rate), Lp(a) was associated with recurrent events only when Hs-CRP levels were ≥ 2 mg/L.¹¹ These results advocate that classifying cohorts into primary vs secondary preventive groups, according to previous cardiovascular disease events, might not be the best method for determining the risk of Lp(a)-associated incident cardiovascular disease events in high-risk individuals.

A previous study²⁵ with 87,192 individuals from the Copenhagen General Population Study, aged 20 to 69 years at baseline, and followed for 13 years showed that participants with RC ≥ 1 mmol/L had a 120% higher chance for incident death from cardiovascular disease. Another study²⁶ with 3806 individuals with type 2 diabetes, also from the Copenhagen General Population Study with a follow-up around 15 years, showed that 20% of atherosclerotic cardiovascular diseases (ASCVD), characterized as incident peripheral artery disease, myocardial infarction, and ischaemic stroke, were related to RC, regardless of statin use. While our results showed that LDL-C and RC were associated with a higher risk for incident MACEs, that study did not find an association of LDL-C with incident ASCVD. A possible explanation, cited in that study might be related to the effective use of lipid-lowering medication for the treatment of individuals with elevated levels of LDL-C.

Clinical implications

The key to preventing atherosclerotic disease and its complications is to maintain a healthy lifestyle, including a balanced diet, regular physical activity, avoiding tobacco and alcohol, and preventing obesity and its related conditions, such as hypertension and type 2 diabetes. On the other hand, early assessment of LDL-C, Lp(a), and Hs-CRP levels can help identify individuals who may benefit from early and more intensive pharmacologic support for long-term atherosclerosis protection.

Our results suggest that targeting both hyperlipidaemia [via LDL-C and Lp(a)] and systemic low-grade inflammation (via Hs-CRP levels) is essential to reduce the risk for incident MACEs. The concentrations and combined effects of these three variables are key determinants of risk, indicating that a ‘triple therapy’ approach—combining aggressive lipid-lowering and anti-inflammatory treatments—could become the future standard of care for atherosclerotic disease. Ultimately, the best strategy to prevent cardiovascular disease is to reduce risk factors today, as waiting until tomorrow may be too late.³⁰

In the end, it is imperative to emphasize that our study is not about whether a specific biomarker is better but about the importance of using them to identify individuals at risk and the benefit of lipid-lowering therapy. Currently, cholesterol-lowering medications such as statins, ezetimibe, pro-protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, small interfering ribonucleic acid (siRNA), and bempedoic acid have all improved cardiovascular outcomes in randomized controlled trials.⁵ Similarly, anti-inflammatory therapy with canakinumab or colchicine also showed decreased risk for cardiovascular outcomes in randomized controlled trials, even without any reduction in LDL-C.⁷ While several promising trials are currently investigating Lp(a)-lowering medications, such as antisense oligonucleotide therapy (ISIS-APO(a)Rx), these studies are still ongoing and have yet to provide results on their effects on cardiovascular outcomes.^9,31

Nevertheless, as we used observational data, our findings cannot be used to conclude that the use of medication to reduce LDL-C, Lp(a), and systemic low-grade inflammation, individually or combined, will decrease the risk for incident MACEs. Randomized clinical trials will be necessary to examine the feasibility and effectiveness of this approach before it can be adopted in clinical practice.

Study limitations

Our study has several limitations. First, the self-reported medication use and the diagnosis of MACEs based on classification codes in the UK Biobank may be prone to selection bias and misclassification. Second, unlike LDL-C and Lp(a), which are direct pathogenic agents, Hs-CRP is an indirect inflammation biomarker and may not fully capture cardiovascular risk. Third, the UK Biobank may have a healthy volunteer bias, potentially affecting the results.³² Fourth, the study may be affected by regression dilution bias, as biomarkers were assessed only once at baseline. Lastly, despite adjusting for many confounders, we cannot exclude the influence of unmeasured or unknown factors. However, our study has significant strengths, including its sizeable population-based design, long follow-up period, comprehensive data on health outcomes, and the availability of multiple metabolic risk factors for adjustment.

Conclusions

Our findings showed that hyperlipidaemia, marked by elevated LDL-C and Lp(a) levels, and inflammation, indicated by high Hs-CRP levels, were each independently associated with a higher risk for incident atherothrombotic events. When combined (in pairs or all three), those biomarkers had a synergistic effect, significantly increasing the risk. This heightened risk was linked to the serum concentrations of these biomarkers rather than the use of cholesterol-lowering medication.

Supplementary data

Supplementary data are available at European Heart Journal online.

Declarations

Disclosure of Interest

S.K. has received honoraria related to consulting, research and or speaker activities from: AstraZeneca, Daiichi-Sankyo, Sanofi-aventis, Novartis Pharma GmbH, and SOBI. N.R.T.D. receives a research support scholarship from State of São Paulo Research Foundation (FAPESP 2020/03529-6 and 2022/03738-0); National Institute of Science and Technology of Complete Fluids (INCTFCx/FAPESP 2014/50983-3); and the Coordination of Improvement of Higher Education Personnel (CAPES 88887.609440/2021-00, 88887.646449/2021-0, and 88887.659109/2021-0). R.D.S. receives a research support scholarship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) grant # 30377103771/2023-2, was a member of the steering committee of PROMINENT and has received honoraria related to consulting, research, and or speaker activities from Aché, Amryt, Amgen, Daiichi-Sankyo, Esperion, Eli-Lilly, Ionis, Kowa, Libbs, MSD, Novo-Nordisk, Novartis, PTC Therapeutics, Sanofi/Regeneron, Ultragenyx, and Torrent. S.B.F. has received a research support from German Centre for Cardiovascular Research (DZHK) and has received honoraria related to consulting, research, and or speaker activities from AstraZeneca, Bayer, Novartis, and Pfizer. C.T. has received honoraria related to consulting, research, and or speaker activities from Medtronic, Microport, Philips, Biotronik, Innova, and Shockwave. E.S-T. has received honoraria related to consulting, research, and or speaker activities from Novartis, Amgen, Sanofi, and Sobi. All other authors have no conflict of interest to declare.

Data Availability

The UK Biobank is a controlled-access dataset and the trial data from this analysis cannot be shared, as consistent with the original consent.

Funding

This analysis was funded by the University Medicine Greifswald. UK Biobank was established by the Wellcome Trust, Medical Research Council, Department of Health, Scottish government, and Northwest Regional Development Agency. It has also had funding from the Welsh assembly government and the British Heart Foundation.

Ethical Approval

UK Biobank’s scientific protocol and operational procedures were reviewed and approved on 17th June 2011by the North West Multi-Centre Research Ethics Committee (reference: 11/NW/0382) and extended on 13th May 2016 [reference: 16/NW/0274] and on 18th June 2021(reference: 21/NW/0157) in the UK. All participants gave written informed consent before enrolment in the study which was conducted in accordance with the principles of the Declaration of Helsinki.

Pre-registered Clinical Trial Number

Not applicable.

References

Author notes