Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease
By Heather Nelson Cortes, PhD and Kevin C Maki, PhD
Cardiovascular disease (CVD) continues to be the leading cause of death around the world and it is directly associated with blood levels of low-density lipoprotein cholesterol (LDL-C).1,2 In many clinical trials and in clinical practice, statins have been shown to be effective for lowering LDL-C, in both primary and secondary prevention, and to reduce the risk of future CVD events.3-6 The multi-society American College of Cardiology and American Heart Association guidelines for cholesterol management suggest that an adequate LDL-C lowering response with an intermediate-intensity statin is ≥30% and is ≥50% with higher-intensity statins.5 The National Institute for Health and Care Excellence (NICE) guidelines defined sub-optimal responders as patients on treatment with statins for primary prevention of CVD who fail to achieve >40% reduction in LDL-C within the 24 months of statin initiation.6
Previous studies have identified individual biological and genetic variability of LDL-C response to statin therapy, as well as variation in treatment adherence, yet there is a paucity of literature on the variation of LDL-C response to statins in the general population.7,8 To address this issue, Akyea et al. examined the change in LDL-C and future risk of CVD in primary care patients over 24 months in response to initiation of statin therapy.9
This prospective cohort included 165,411 primary care patients, who were free of CVD at the initiation of statin therapy. The data were collected from the UK Clinical Practice Research Datalink (CPRD), which is considered representative of the general population in the UK in terms of age, sex, and ethnicity. Over half (51.2%, n=84,609) of patients had a sub-optimal LDL-C response to statin therapy within 24 months. During the 1,077,299 person-years of follow-up (median follow-up 6.2 years) there were 22,798 CVD events. Of these CVD events 12,142 were reported among the sub-optimal responders and 10,656 among the optimal responders (as defined by NICE). The rates of CVD in the sub-optimal and optimal responders were 22.6 and 19.7/1000 person-years, respectively.
Compared to optimal responders, sub-optimal responders had a hazard ratio (HR) for incident CVD of 1.17 (95% CI 1.13-1.20). After adjusting for age and baseline untreated LDL-C, the sub-optimal vs. optimal responders had a HR of 1.22 (95% CI 1.19-1.25). Consideration of competing risks (e.g., patients transferring out of the practice, death) led to a lower HR for sub-optimal responders of 1.13 (95% CI 1.10-1.16) and an adjusted HR of 1.19 (95% CI 1.16-1.23). It is worth noting that in this cohort, a higher proportion of patients with sub-optimal responses were prescribed lower potency statins than those with an optimal response.
Comment. Overall the results show that over half of the patients in this general population cohort did not achieve >40% LDL-C reduction over 24 months with statin therapy. Patients with suboptimal LDL-C responses were at higher risk for future CVD events. These findings further support the view that “lower is better” for LDL-C and suggest that patients with a suboptimal response to statin therapy should be identified and evaluated for possible additional intervention, which might include intensification of lifestyle therapies, counseling regarding adherence to the prescribed statin regimen, dose escalation, switching to a higher-potency statin, or adjunctive pharmacotherapy such as ezetimibe or a proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor.
- Nichols M, Townsend N, Scarborough P, et al. Cardiovascular disease in Europe 2014: epidemiological update. Eur Heart J. 2014;35:2950–9.
- Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380:581–90.
- Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ. 2003;326:1423.
- Cholesterol Treatment Trialists’ (CTT) collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 2010;376:1670–81.
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. J Am Coll Cardiol. 2018;Epub ahead of print.
- National Institute for Health and Care Excellence. Cardiovascular disease: risk assessment and reduction, including lipid modification. London: National Institute for Health and Care Excellence, 2016.
- Mega JL, Morrow DA, Brown A, et al. Identification of genetic variants associated with response to statin therapy. Arterioscler Thromb Vasc Biol. 2009;29:1310–5.
- Mann DM, Woodward M, Muntner P, et al. Predictors of nonadherence to statins: a systematic review and meta-analysis. Ann Pharmacother. 2010;44:1410–21.
- Akyea RK, Kai J, QUreshi N, Iyen B, Weng SF. Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease. Heart. 2019;Epub ahead of print.