Statin-induced LDL cholesterol response and type 2 diabetes: a bidirectional two-sample Mendelian randomization study

Research output: Contribution to journalArticle


  • on behalf of the GIST consortium

External Institution(s)

  • Leiden University
  • Harvard University
  • Cedars-Sinai Medical Center
  • Queen Mary University of London
  • Université Laval
  • University of California at Los Angeles
  • Vanderbilt University
  • Boston University
  • National Institutes of Health
  • Children's Hospital Oakland Research Institute
  • University of Washington
  • Kaiser Permanente


Original languageEnglish (US)
Pages (from-to)462-470
Number of pages9
JournalPharmacogenomics Journal
Issue number3
StatusPublished - Jun 1 2020


It remains unclear whether the increased risk of new-onset type 2 diabetes (T2D) seen in statin users is due to low LDL-C concentrations, or due to the statin-induced proportional change in LDL-C. In addition, genetic instruments have not been proposed before to examine whether liability to T2D might cause greater proportional statin-induced LDL-C lowering. Using summary-level statistics from the Genomic Investigation of Statin Therapy (GIST, nmax = 40,914) and DIAGRAM (nmax = 159,208) consortia, we found a positive genetic correlation between LDL-C statin response and T2D using LD score regression (rgenetic = 0.36, s.e. = 0.13). However, mendelian randomization analyses did not provide support for statin response having a causal effect on T2D risk (OR 1.00 (95% CI: 0.97, 1.03) per 10% increase in statin response), nor that liability to T2D has a causal effect on statin-induced LDL-C response (0.20% increase in response (95% CI: −0.40, 0.80) per doubling of odds of liability to T2D). Although we found no evidence to suggest that proportional statin response influences T2D risk, a definitive assessment should be made in populations comprised exclusively of statin users, as the presence of nonstatin users in the DIAGRAM dataset may have substantially diluted our effect estimate.

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