Determining propensity for sub-optimal low-density lipoprotein cholesterol response to statins and future risk of cardiovascular disease.

Background: Variability in low-density lipoprotein cholesterol (LDL-C) response to statins is underappreciated. We characterised patients by their statin response (SR), baseline risk of cardiovascular disease (CVD) and 10-year CVD outcomes.
Methods and Results: A multivariable model was developed using 183,213 United Kingdom (UK) patients without CVD to predict probability of sub-optimal SR, defined by guidelines as <40% reduction in LDL-C. We externally validated the model in a Hong Kong (HK) cohort (n = 170,904). Patients were stratified into four groups by predicted SR and 10-year CVD risk score: [SR1] optimal SR & low risk; [SR2] sub-optimal SR & low risk; [SR3] optimal SR & high risk; [SR4] sub-optimal SR & high risk; and 10-year hazard ratios (HR) determined for first major adverse cardiovascular event (MACE). Our SR model included 12 characteristics, with an area under the curve of 0.70 (95% confidence interval [CI] 0.70-0.71; UK) and 0.68 (95% CI 0.67-0.68; HK). HRs for MACE in predicted sub-optimal SR with low CVD risk groups (SR2 to SR1) were 1.39 (95% CI 1.35-1.43, p<0.001; UK) and 1.14 (95% CI 1.11-1.17, p<0.001; HK). In both cohorts, patients with predicted sub-optimal SR with high CVD risk (SR4 to SR3) had elevated risk of MACE (UK HR 1.36, 95% CI 1.32-1.40, p<0.001: HK HR 1.25, 95% CI 1.21-1.28, p<0.001).
Conclusions: Patients with sub-optimal response to statins experienced significantly more MACE, regardless of baseline CVD risk. To enhance cholesterol management for primary prevention, statin response should be considered alongside risk assessment.
Competing Interests: NQ is a member of the most recent NICE Familial Hypercholesterolaemia & Lipid Modification Guideline Development Groups (CG71 & CG181). SW, IW are members of the Clinical Practice Research Datalink (CPRD) Independent Scientific Advisory Committee (ISAC). RKA currently holds an NIHR-SPCR funded studentship (2018-2021). SW reports honorarium from AMGEN and is also an employee of Janssen. KM holds the CW Malpethorpe Fellowship Award and reports personal fees from IQVIA Ltd have been received outside the submitted work. JB is supported by the Hong Kong Research Grants Council as a recipient of the Hong Kong PhD Fellowship Scheme. EC and IW report grants from Amgen. The remaining authors have no competing interests. This does not alter our adherence to PLOS ONE policies on sharing data and materials.