Abstract
AimsA genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366: T > C: Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility to muscle-related symptoms. We examined the association of this variant with statin intolerance ascertained from electronic medical records in the GoDARTS study.Methods and resultsIn the GoDARTS cohort, the LILRB5 Asp247 variant was associated with statin intolerance (SI) phenotypes; one defined as having raised CK and being non-adherent to therapy [odds ratio (OR) 1.81; 95% confidence interval (CI): 1.34–2.45] and the other as being intolerant to the lowest approved dose of a statin before being switched to two or more other statins (OR 1.36; 95% CI: 1.07–1.73). Those homozygous for Asp247 had increased odds of developing both definitions of intolerance. Importantly the second definition did not rely on CK elevations. These results were replicated in adjudicated cases of statin-induced myopathy in the PREDICTION-ADR consortium (OR1.48; 95% CI: 1.05–2.10) and for the development of myalgia in the JUPITER randomized clinical trial of rosuvastatin (OR1.35, 95% CI: 1.10–1.68). A meta-analysis across the studies showed a consistent association between Asp247Gly and outcomes associated with SI (OR1.34; 95% CI: 1.16–1.54).ConclusionThis study presents a novel immunogenetic factor associated with statin intolerance, an important risk factor for cardiovascular outcomes. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a potential role for the immune system in their development. We identify a genetic group that is more likely to be intolerant to their statins.
Highlights
Statins are first choice lipid-modifying medications for prevention and management of cardiovascular diseases (CVD).[1,2] The UK is one of the largest users of statins worldwide,[3] and with revised NICE guidelines approximately 12 million UK individuals will be prescribed statins.[4,5] While statins are generally well tolerated, neurological,[6] gastrointestinal, or muscle-based[7,8] adverse drug reactions are reported
Baseline characteristics of general statin intolerance and low dose intolerance Covariates associated with statin use or with the development of adverse drug reactions (ADR) were tested
Covariates associated with general statin intolerance (GSI) included younger age at start and longer duration of therapy, female gender, lower incidence of simvastatin use at the start and end of therapy, lower starting and ending dose, the use of interacting co-medications and, by phenotype definition, creatine phosphokinase (CK) levels at time of diagnosis
Summary
Statins are first choice lipid-modifying medications for prevention and management of cardiovascular diseases (CVD).[1,2] The UK is one of the largest users of statins worldwide,[3] and with revised NICE guidelines approximately 12 million UK individuals will be prescribed statins.[4,5] While statins are generally well tolerated, neurological,[6] gastrointestinal, or muscle-based[7,8] adverse drug reactions are reported. Adverse reactions to statins are likely to manifest as muscle aches (myalgia) along with elevated creatine phosphokinase (CK). Adherence to statin treatment is often negatively impacted in response to adverse reactions.[9,10] The inability to adhere to statin treatment, whether due to statin-induced myalgia or more general forms of statin intolerance result in poor on-statin outcomes.[11] examining risk factors predisposing to statin intolerance is crucial from a public health perspective
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