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Common non-synonymous substitutions in SLC01B1 predispose to statin intolerance: a population pharmacogenetics study
  1. CC Lang,
  2. L Donnelly,
  3. C Kimber,
  4. A Doney,
  5. AD Morris,
  6. CN Palmer
  1. University of Dundee, Dundee, UK

Abstract

Introduction The most significant side effect of statin therapy is muscle toxicity, ranging from mild myalgic symptoms to severe rhabdomyolysis. Recent whole genome data from 95 clinical trial participants (total trial size 20 000) have identified that common amino acid substitutions in the known statin transporter SLC01B1 are strong determinants of muscle toxicity. We examined how this genotype would influence statin tolerance at a population level in a large population of patients with type 2 diabetes prescribed statins as part of routine clinical care and enrolled in a large population-based cohort of patients with diabetes.

Methods 4340 patients treated with statins identified from the Genetics of Diabetes Audit and Research in Tayside Scotland (Go-DARTS) database were genotyped for rs4149056 (Val174Ala) and rs2306283 (Asp130Asn). Statin intolerance was determined by anonymously linking at a patient-specific level to a comprehensive dispensed prescription and regional biochemistry database. Intolerance was defined as an abnormal creatine kinase (CK; above the upper limit of normal) with no abnormal CK before statin commencement and/or an alanine aminotransferase (ALT) 1.5 times above the upper limit of normal with no abnormal ALT before statin commencement while on statin treatment and evidence of prescribing change (switching to lower dose or discontinuation of statin prescribing).

Results 300 (6.9%) of the treated population were intolerant of statins by these criteria. The tolerant group were defined as individuals with no abnormal CK or ALT measures upon statin treatment, did not display any prescribing changes indicative of intolerance and had been prescribed a statin dose equivalent of more than 10 mg simvastatin. The association of Val174 Ala and Asp130Asn with intolerance was assessed by binary logistic regression. Homozygous ala174 was associated with a 3.13-fold increase in intolerance (95%CI 1.44 to 6.78, p = 0.0038). The homozygous Asp130 was associated with a slightly decreased intolerance as previously reported; however, this did not achieve significance (p = 0.14). ala174 homozygous individuals were also less likely to achieve a target serum low-density lipoprotein cholesterol of 2 mmol/l. Odds ratios for failure 2.27 (95% CI 1.11 to 4.61, p = 0.0242).

Conclusions This real-world study suggests that a genetic variant selected for an extreme phenotype of statin intolerance also has a major impact on common milder statin intolerance and has an impact on prescribing practice.

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