TY - JOUR
T1 - Statin-induced LDL cholesterol response and type 2 diabetes
T2 - a bidirectional two-sample Mendelian randomization study
AU - on behalf of the GIST consortium
AU - Smit, Roelof A.J.
AU - Trompet, Stella
AU - Leong, Aaron
AU - Goodarzi, Mark O.
AU - Postmus, Iris
AU - Warren, Helen
AU - Theusch, Elizabeth
AU - Barnes, Michael R.
AU - Arsenault, Benoit J.
AU - Li, Xiaohui
AU - Feng, Qi Ping
AU - Chasman, Daniel I.
AU - Cupples, L. Adrienne
AU - Hitman, Graham A.
AU - Krauss, Ronald M.
AU - Psaty, Bruce M.
AU - Rotter, Jerome I.
AU - Cessie, Saskia le
AU - Stein, C. Michael
AU - Jukema, J. Wouter
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85075930092&partnerID=8YFLogxK
U2 - 10.1038/s41397-019-0125-x
DO - 10.1038/s41397-019-0125-x
M3 - Article
C2 - 31801993
AN - SCOPUS:85075930092
SN - 1470-269X
VL - 20
SP - 462
EP - 470
JO - Pharmacogenomics Journal
JF - Pharmacogenomics Journal
IS - 3
ER -