Many patients initiating statin therapy show sub-optimal LDL-c lowering, resulting in higher CVD risk

Sub-optimal cholesterol response to initiation of statins and future risk of cardiovascular disease

Literature - Akyea RK, Kai J, Qureshi N et al. - Heart 2019;0:1–7. doi:10.1136/heartjnl-2018-314253

Introduction and methods

Guidelines recommend LDL-c level reduction targets to reduce CVD [1,2], which are based on a meta-analysis of cholesterol treatment trials of data of patients in whom statin therapy reduced CVD events [3]. Individuals using statins show both individual biological and genetic variability in LDL-c response [4], as well as in adherence [5]. It is, however, uncertain whether this variability in LDL-c response also exists among patients in the general population starting statin treatment for primary prevention of CVD. This study therefore assessed variability in LDL-c response in primary care patients initiated on statin treatment and their impact on future CVD events.

This large, prospective open population cohort study used data from the UK Clinical Practice Research Datalink (CPRD) of primary care electronic health records, which are linked to hospitalization and mortality databases The patients in the CPRD database are broadly representative of the general population with regard to age, sex and ethnicity. Primary care patients (n=183.213) included in this cohort initiated statin treatment between Sept 1990 and June 2016. Eligible participants (n= 165.411) had ≥2 recorded LDL-c measurements (≥1 within 12 months before statin initiation and ≥1 within 24 months after statin initiation), and were free of CVD events before initiating statin treatment. Patients with a recorded CVD event within 24 months of treatment were excluded from the analysis, because the full effect of cholesterol lowering on CVD risk has been described to be achieved after the first two years of statin therapy [6].

Sub-optimal LDL-c response was defined as <40% reduction in untreated baseline LDL-c levels within 24 months, according to current NICE Cardiovascular Disease Guidelines [1]. Study outcome was CVD events, defined as coronary heart disease (CHD), stroke/transient ischemic attack (TIA), peripheral vascular disease (PVD), or CVD-related mortality. Median follow-up was 6.2 years.

Main results

  • Sub-optimal LDL-c response within 24 months after the initiation of statin treatment was seen in 51.2% (84609 out of 165411) of participants.
  • More patients with a sub-optimal response were prescribed lower potency statins than those showing a good response to treatment (29.2% vs. 18.2%).

Incidence of CVD events

  • During 1.077.299 person-years (PY) of follow-up, 12.142 CVD events were recorded in sub-optimal responders and 10.656 in optimal responders, yielding CVD event rates of 22.6 and 19.7 per 1000 PY, respectively.
  • Incident CVD events were seen significantly more often in sub-optimal responders, compared to optimal responders (crude HR: 1.17, 95%CI: 1.13-1.20, P<0.001), which remained similar after adjustments for age and baseline untreated LDL-c (HR: 1.22, 95%CI: 1.19-1.25, P<0.001).

Incidence of constituent CVD outcomes

  • After adjustments for age and baseline untreated LDL-c, sub-optimal responders had significantly higher risk of CAD (HR: 1.30, 95%CI: 1.25-1.34), stroke/TIA (HR: 1.15, 95%CI: 1.08-1.22), PVD (HR: 1.16, 95%CI: 1.08-1.25) and CVD-related mortality (HR: 1.25, 95%CI: 1.13-1.38), compared to optimal responders.
  • In both sub-optimal and optimal responders, a unit reduction of 1 mmol/L LDL-c was linked to a significant decrease in any CVD (OR: 0.94, 95%CI: 0.91-0.98 and OR: 0.87, 95%CI: 0.84-0.90, respectively).


In this large prospective primary care patient cohort, more than half of patients initiated on statin therapy did not show optimal LDL-c lowering at 24 months after starting treatment. These sub-optimal responders had significantly higher risk of future CVD events (CAD, stroke/TIA, PVD), compared to those with optimal LDL-c response. Patient adherence was not assessed in this study, nor was information provided on whether statin therapy was up- or down-titrated.


1. 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.

2. Stone NJ, Robinson JG, Lichtenstein AH, et al. ACC /AHA Guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. A report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation 2013;2014:S1–45.

3. 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

4. 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.

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.

6. Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? BMJ 1994;308:367–72.

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