DARWIN EU® - Association between genetic polymorphisms of interest and risk of myopathy among statin users

Study type

• Study topic:
  Human medicinal product
• Study topic, other:
  pharmacogenetics
• Study type:
  Non-interventional study
• Scope of the study:
  Other

  Safety study (incl. comparative)
• If ‘other’, further details on the scope of the study:
  To estimate the association between SLCO1B1 (and additionally ABCG2) genetic variants and the risk of statin-associated myopathy
• Data collection methods:
  Secondary use of data

Non-interventional study

• Non-interventional study design:
  Cohort

Study drug and medical condition

• Medicinal product name, other:
  Statins
• Anatomical Therapeutic Chemical (ATC) code:
  (C10AA05) atorvastatin

  atorvastatin

  (C10AA01) simvastatin

  simvastatin

  (C10AA07) rosuvastatin

  rosuvastatin

  (C10AA04) fluvastatin

  fluvastatin

  (C10AA03) pravastatin

  pravastatin
• Medical condition to be studied:
  Myopathy

Population studied

• Short description of the study population:
  The source population will comprise of all incident statin users during the study period.
• Age groups:
  • Adult and elderly population (≥18 years)

Study design details

• Study design:
  New User Cohorts
• Main study objective:
  Primary objectives; 1a - To estimate the risk of myopathy in new users of atorvastatin (any dose) according to genotype status; 1b - To estimate the risk of myopathy in new users of lower-dose atorvastatin according to genotype status; 1c - To estimate the risk of myopathy in new users of higher-dose atorvastatin according to genotype status; ; Secondary objectives; 2a - To estimate the risk of myopathy in new users of simvastatin (separately for any dose, lower-dose and higher-dose) according to genotype status; 2b - To estimate the risk of myopathy in new users of rosuvastatin (separately for any dose, lower-dose and higher-dose) according to genotype status if feasible (See Section 8.7 "Study Size" for more details on how to determine if this analysis is feasible) ; 2c - To estimate the risk of myopathy in new users of fluvastatin (separately for any dose, lower-dose and higher-dose) according to genotype status if feasible (See Section 8.7 "Study Size" for more details on how to determine if this analysis is feasible) ; 2d - To estimate the risk of myopathy in new users of pravastatin (separately for any dose, lower-dose and higher-dose) according to genotype status if feasible (See Section 8.7 "Study Size" for more details on how to determine if this analysis is feasible).
• Setting:
  This study will be conducted using two prospective Biobank cohorts with primarily collected genetic data linked to routinely collected electronic health records in two European countries. Except for the genetic information, all other data have been previously mapped to the OMOP CDM to allow for federated analytics, and DARWIN EU data quality controls have been completed during onboarding to the network. ; 1. UK Biobank (UKBB), United Kingdom; 2. Estonian Biobank (EBB), Estonia
• Outcomes:
  1. Myopathy (primary) ; 2. Myositis (secondary) ; 3. Myalgia (secondary)
• Summary results:
  This large, federated, population-based cohort study was initiated in response to regulatory interest in the role of OATP1B1 in atorvastatin-associated myopathy. Real-world evidence reported in this study may support existing clinical knowledge on the benefits of candidate genetic testing for SLCO1B1 (rs4149056, rs2306283) and ABCG2 (rs2231142) to reduce SAMS, especially when prescribing simvastatin. However, the non-significant results highlight that these genotype-statin-dose combinations may still warrant attention, and we recommend future studies with additional Biobanks, more precise phenotyping with biomarker data, together with more comprehensive characteristics of multiple genetic variations (e.g., polygenic models or allele combinations).