The impact of inflammatory and cholesterol risk on cardiovascular events among statin-treated individuals: an observational study using UK Biobank data

Introduction Inflammatory risk, clinically identified by high-sensitivity C-reactive protein (hsCRP) levels ≥2 mg/L, is associated with cardiovascular (CV) events and mortality.1,2 It is unclear how inflammatory risk compares with cholesterol risk, an established CV risk factor, in statin-treated individuals. Purpose To assess CV outcomes and mortality in statin-treated individuals with inflammatory risk, cholesterol risk, both risks, or neither risk, in a real-world setting. Methods This observational cohort study, based on secondary data from the UK Biobank (UKBB), included individuals aged ≥18 years who were already receiving statins and had measurements for hsCRP and low-density lipoprotein cholesterol (LDL-C) at the time of enrolment in the UKBB (index date) between 2006 and 2010. Individuals with hsCRP levels suggestive of acute inflammation (>20 mg/L) or with diagnoses of chronic infection were excluded. Individuals were followed up from the index date until November 2022 or until death, whichever occurred first. The following risk groups were defined: inflammatory risk (hsCRP ≥2 mg/L), cholesterol risk (LDL-C ≥70 mg/dL [1.8 mmol/L]), combined risk (hsCRP ≥2 mg/L and LDL-C ≥70 mg/dL), or neither risk (hsCRP <2 mg/L and LDL-C <70 mg/dL). The primary outcome was 3-point major adverse CV events (3P-MACE; defined as CV-related death, non-fatal myocardial infarction or non-fatal stroke). Secondary outcomes were CV-related death and all-cause mortality. Cox proportional hazard models, adjusted for demographic and clinical factors, were used to evaluate the primary and secondary outcomes for each risk group in the overall cohort, and the primary outcome in a subgroup of individuals with atherosclerotic cardiovascular disease (ASCVD) at the index date. Results The overall cohort comprised 65,793 individuals with a mean age (standard deviation) of 61.9 (6.1) years; 61.1% were men and 94.3% were White. Median hsCRP was 1.43 (quartile [Q]1, Q3: 0.74, 2.85) mg/L and median LDL-C was 104.0 (89.2, 121.0) mg/dL (2.69 [2.31, 3.13] mmol/L). Individuals with inflammatory risk (n=1176) or combined risk (n=23,248) were at significantly greater risk of 3P-MACE (inflammatory risk: adjusted hazard ratio 1.45 [95% confidence interval 1.24–1.70], p<0.001; combined risk: 1.24 [1.10–1.39], p<0.001), compared with those without inflammatory or cholesterol risk (n=2318; Figure). The risk of 3P-MACE in individuals in the cholesterol risk group (n=39,051) was not significantly increased in this statin-treated population (p=0.676). Similar trends were observed for CV and all-cause mortality in the overall cohort, and for 3P-MACE in the subgroup with ASCVD (Table). Conclusions Inflammatory risk, regardless of cholesterol risk, was a significant predictor of CV and mortality outcomes in a statin-treated real-world population in the UK. The cholesterol risk in this population was likely attenuated by background statin therapy.