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.

Keywords: Cardiovascular mortality; Cholesterol-lowering medication; High-sensitivity C-reactive protein; Hyperlipidemia; Lipoprotein(a); Low-density lipoprotein cholesterol; Residual risk.

Structured Graphical Abstract

Figure 1

Crude number of individuals/events (%) and adjusted* hazard ratios (HR) (95% confidence interval [CI]) of the associations of standardized low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) [Lp(a)], and high-sensitivity C-reactive protein (Hs-CRP) with incident major adverse cardiovascular events (MACEs)** stratified by the absence or use of cholesterol-lowering medication, sex, and high-sensitivity C-reactive protein (Hs-CRP) levels (n = 322,922). * Cox proportional hazard models adjusted for the baseline assessment 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, estimated glomerular filtration rate, ethnicity, and Townsend deprivation index. ** Incident major adverse cardiovascular events (MACEs) = fatal and non-fatal myocardial infarction (ICD-10: I21), stroke (ICD-10: I63), chronic ischaemic heart disease (ICD-10: I25), and sudden cardiac arrest (ICD-10: I46); also, angina pectoris (ICD-10: I20), percutaneous coronary intervention (OPCS-4: K49 or K75) and coronary artery bypass surgery (OPCS-4: K40, K41, or K45). *** SD, standard deviation. No cholesterol-lowering medication: one SD corresponded to 0.80 mmol/L LDL-C, 48.7 nmol/L Lp(a), and 4.23 mg/L Hs-CRP. Cholesterol-lowering medication: one SD corresponded to 0.74 mmol/L LDL-C, 50.9 nmol/L Lp(a), and 4.38 mg/L CRP

Figure 2

Cumulative hazard function curves* of incident major adverse cardiovascular events (MACEs)** of the participants with different levels of low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) [Lp(a)], and high-sensitivity C-reactive protein (Hs-CRP) levels, categorized by below or equal the 75th percentile*** or above the 75th percentile, stratified by the absence (A) (n = 280,002) or use (B) (n = 42,920) of cholesterol-lowering medication. * Cox proportional hazard models adjusted for the baseline assessment 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, estimated glomerular filtration rate, ethnicity, and Townsend deprivation index. ** Incident major adverse cardiovascular events (MACEs) = fatal and non-fatal myocardial infarction (ICD-10: I21), stroke (ICD-10: I63), chronic ischaemic heart disease (ICD-10: I25), and sudden cardiac arrest (ICD-10: I46); also, angina pectoris (ICD-10: I20), percutaneous coronary intervention (OPCS-4: K49 or K75), and coronary artery bypass surgery (OPCS-4: K40, K41, or K45). *** No 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. *** 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

Figure 3

Crude number of individuals/events (%) and adjusted* hazard ratios (HR) (95% confidence interval [CI]) of incident major adverse cardiovascular events (MACEs)** of the participants with different levels of low-density lipoprotein cholesterol (LDL-C), lipoprotein(a) [Lp(a)], and high-sensitivity C-reactive protein (Hs-CRP) levels, categorized by below or equal the 75th percentile*** or above the 75th percentile, stratified by the absence or use of cholesterol-lowering medication (n = 322,922). * Cox proportional hazard models adjusted for the baseline assessment 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, estimated glomerular filtration rate, ethnicity, and Townsend deprivation index. ** Incident major adverse cardiovascular events (MACEs) = fatal and non-fatal myocardial infarction (ICD-10: I21), stroke (ICD-10: I63), chronic ischaemic heart disease (ICD-10: I25), and sudden cardiac arrest (ICD-10: I46); also, angina pectoris (ICD-10: I20), percutaneous coronary intervention (OPCS-4: K49 or K75), and coronary artery bypass surgery (OPCS-4: K40, K41, or K45). *** No 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. *** 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