Use of an Electronic Medical Record to Characterize Cases of Intermediate Statin‐Induced Muscle Toxicity

Abstract

Statin use can be accompanied by a variety of musculoskeletal complaints. We describe the clinical characteristics of case subjects experiencing adverse statin-induced musculoskeletal symptoms within a large, population based cohort in Central Wisconsin. Case status was determined based upon elevated serum creatine kinase (CK) levels and the presence of at least one physician note reflecting an increased index of suspicion for statin intolerance. From the medical records of nearly 2 million unique patients, we identified more than 20,000 potential study subjects (∼1%) having CK data and at least one exposure to a statin drug. Manual screening was completed on 2,227 subjects with CK levels in the upper 10th percentile. Of those screened, 267 met inclusion criteria (12.0% eligibility), and 218 agreed to participate in a retrospective study characterizing the risk determinants of statin-induced muscle toxicity. Three categorical pain variables were graded retrospectively (distribution, location, and severity of pain). The presenting complaints of these case subjects were extremely heterogeneous. The number of subjects with a compelling pain syndrome (diffuse, proximal muscle pain of high intensity) increased at higher serum CK levels; the number of subjects with indeterminate pain variables decreased at higher serum CK levels. The lines reflecting these relationships cross at a CK level of approximately 1,175 U/l, approximately half the threshold level needed to make a clinical diagnosis of “myopathy” (i.e., CK > 10-fold upper limit).

GATM Polymorphism Associated with the Risk for Statin-Induced Myopathy Does Not Replicate in Case-Control Analysis of 715 Dyslipidemic Individuals

“…Notably, a direct comparison of the patient characteristics in our study to the Mangravite et al (2013) study is not possible with the available published data. A few patient characteristics can be found in the original Marshfield (Mareedu et al, 2009) and SEARCH (SEARCH Collaborative Group et al, 2008) publications for the overall patient samples, but the characteristics of the sub-groups used specifically in the Mangravite et al (2013) analysis are unavailable. However some notable differences between our study and the overall Marshfield and SEARCH studies include the statin treatment (our study is the only one to include rosuvastatin) and gender (the SEARCH trial was 83% male).…”

PharmGKB summary

“…There is wide phenotypic variability in the clinical manifestation of muscle toxicity for several orally administered medications such as HMG-CoA reductase inhibitors (statins) [57, 58]. Efforts are being made to standardize the clinical definition of these traits [59], and automated decision support is being deployed in the context of routine clinical practice to identify patients at risk [60].…”

“…Efforts are being made to standardize the clinical definition of these traits [59], and automated decision support is being deployed in the context of routine clinical practice to identify patients at risk [60]. For example, a study of statin-exposed patients identified 2,227 individuals with creatine kinase (CK) levels in the upper 10th percentile from among ~2 million unique patients by scanning electronic medical records [57]. Further exploratory analyses using a pathway-based approach have suggested that variants in multiple members of the RYR gene family may alter patient risk for statin-associated myopathy [61, 62].…”

Does Reduced Creatine Synthesis Protect against Statin Myopathy?

“…Reduced GATM expression should reduce creatine synthesis. Furthermore, the relationship between the GATM differential eQTL locus expression with simvastatin exposure and statin-induced myopathy was examined in two separate population-based cohorts comprising 172 cases of myopathy (Link et al, 2008; Mareedu et al, 2009). Calculation of an odds ratio to quantify the association between presence of the rs9806699 variant and statin myopathy resulted in an overall odds ratio of 0.60 (95% confidence interval = 0.45–0.81) with meta-analysis of these two cohorts, suggesting that reduced GATM expression, and probable reduced creatine synthesis, is associated with a reduced incidence of statin-induced myopathy.…”

“…No prior studies, including several genome-wide association studies (GWAS) (Link et al, 2008; Ruano et al, 2011), have identified the GATM gene as a contributor to statin myopathy. In the study by Mangravite et al (Mangravite et al, 2013), statin myopathy in their cohorts was defined by CK elevations 3–10 times the upper normal limits (Link et al, 2008; Mareedu et al, 2009). But perhaps the rs9806699 variant has indirect effects on CK levels that are independent of myopathy.…”