Understanding the causes and consequences of low statin adherence: evidence from UK Biobank primary care data

Statins are prescribed to lower LDL cholesterol. Clinical guidelines recommend 30-50% reduction within 3 months, yet many patients do not achieve this. We investigated predictors of LDL-c reduction, treatment adherence, and adverse clinical outcomes in a sample of UK Biobank participants.

We analysed 76,000 UK Biobank participants prescribed atorvastatin or simvastatin in primary care: 41,000 had LDL-c measurements before statin initiation (median = 16 days prior, IQR = 28) and within a year of starting treatment (median = 89 days, IQR = 125). Adherence was defined as the "proportion of days covered" (PDC). We estimated associations between PDC within 1 year of statin initiation, genetic factors, post-treatment LDL-c reduction, and clinical adverse outcomes. For 13,000 patients with ≥ 3 LDL-c measures, we used inverse probability of treatment weighting methods to estimate the effect of sustained adherence intervention on LDL-c reduction longitudinally.

LDL-c reduction following statin initiation was predicted by time until the 1st measurement (up to 26% greater reduction if returned ≤ 3 months vs > 3 months), PDC (up to 38% reduction when PDC > 95% [high] vs. 15% when PDC < 50% [low]), and the pharmacogenetic variant SLCO1B1*5 (lowest reduction in CC-allele: 37% versus TT-allele: 39.5%). Longitudinal causal modelling showed that the most recent PDC measure exerted the largest influence on overall LDL-c reduction, followed by the initial PDC. Genetic predictors of reduced PDC included liability to schizophrenia (Coef_{top 20%} - 1.94, 95%CI - 2.69 to - 1.19), while genetic liability to cardiovascular diseases increased PDC (Coef_{top 20%}1.30, 95%CI 0.55 to 2.05). High PDC was associated with increased risk of incident iron deficiency anaemia (HR 1.30, 95%CI 1.09-1.54) and cataract (HR 1.20, 95%CI 1.07-1.34), and decreased risk of incident coronary heart disease (HR 0.78, 95%CI 0.73-0.84).

We identify substantial variability in the time to first on-treatment LDL-c measurements and also in adherence to statin medication, highlighting a gap between NHS guidelines, LDL-c monitoring, and statin adherence. We show its subsequent impact on long-term health, demonstrating the potential effect of targeted interventions to improve adherence. We identify important predictors of reduced statin effectiveness, including pharmacogenetic variants, polygenic scores, but most of all, adherence. Tailored statin therapy strategies with patient education on statin indication and adherence could optimize treatment efficacy, safety, and long-term clinical outcomes.