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

Roelof A J Smit^{1

2}, Stella Trompet^{3

4}, Aaron Leong^{5

6}, Mark O Goodarzi^{7

8}, Iris Postmus⁴, Helen Warren^{9

10}, Elizabeth Theusch¹¹, Michael R Barnes^{9

10}, Benoit J Arsenault^{12

13}, Xiaohui Li¹⁴, QiPing Feng^{15

16}, Daniel I Chasman^{6

17}, L Adrienne Cupples^{18

19}, Graham A Hitman²⁰, Ronald M Krauss¹¹, Bruce M Psaty^{21

22}, Jerome I Rotter^{14

23}, Saskia le Cessie^{24

25}, C Michael Stein^{15

16}, J Wouter Jukema^{3

26}; GIST consortium

Affiliations

¹ Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands. r.a.j.smit@lumc.nl.
² Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands. r.a.j.smit@lumc.nl.
³ Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
⁴ Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.
⁵ Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
⁶ Harvard Medical School, Boston, MA, 02115, USA.
⁷ Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁸ Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁹ William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK.
¹⁰ National Institute for Health Research, Barts Cardiovascular Biomedical Research Center, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK.
¹¹ Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA, 94609, USA.
¹² Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada.
¹³ Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada.
¹⁴ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁵ Department of Medicine, Vanderbilt University, Nashville, TN, USA.
¹⁶ Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
¹⁷ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA.
¹⁸ Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
¹⁹ NHLBI Framingham Heart Study, Framingham, MA, 01702, USA.
²⁰ Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
²¹ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, 98101, USA.
²² Kaiser Permanente Washington Health Research Institute, Seattle, WA, 98101, USA.
²³ The Institute for Translational Genomics and Population Sciences, Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
²⁴ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
²⁵ Section of Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
²⁶ Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.

PMID: 31801993
PMCID: PMC7260089
DOI: 10.1038/s41397-019-0125-x

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

Roelof A J Smit et al. Pharmacogenomics J. 2020 Jun.

. 2020 Jun;20(3):462-470.

doi: 10.1038/s41397-019-0125-x. Epub 2019 Dec 5.

Authors

Affiliations

¹ Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands. r.a.j.smit@lumc.nl.
² Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands. r.a.j.smit@lumc.nl.
³ Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
⁴ Section of Gerontology and Geriatrics, Department of Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.
⁵ Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
⁶ Harvard Medical School, Boston, MA, 02115, USA.
⁷ Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁸ Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
⁹ William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK.
¹⁰ National Institute for Health Research, Barts Cardiovascular Biomedical Research Center, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 6BQ, UK.
¹¹ Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA, 94609, USA.
¹² Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada.
¹³ Department of Medicine, Faculty of Medicine, Université Laval, Québec, QC, Canada.
¹⁴ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
¹⁵ Department of Medicine, Vanderbilt University, Nashville, TN, USA.
¹⁶ Department of Pharmacology, Vanderbilt University, Nashville, TN, USA.
¹⁷ Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA.
¹⁸ Department of Biostatistics, Boston University School of Public Health, Boston, MA, 02118, USA.
¹⁹ NHLBI Framingham Heart Study, Framingham, MA, 01702, USA.
²⁰ Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
²¹ Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, 98101, USA.
²² Kaiser Permanente Washington Health Research Institute, Seattle, WA, 98101, USA.
²³ The Institute for Translational Genomics and Population Sciences, Department of Medicine, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
²⁴ Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
²⁵ Section of Medical Statistics, Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
²⁶ Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.

PMID: 31801993
PMCID: PMC7260089
DOI: 10.1038/s41397-019-0125-x

Abstract

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, n_max = 40,914) and DIAGRAM (n_max = 159,208) consortia, we found a positive genetic correlation between LDL-C statin response and T2D using LD score regression (r_genetic = 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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Figures

**Figure 1.**
Overview of two-sample Mendelian randomization (MR) study on the bidirectional association between statin-induced LDL cholesterol response and type 2 diabetes (T2D). Top panel shows direction of statin response to T2D, bottom panel liability to T2D to statin response. Layout of figure based upon the work by Taylor et al. 2016 (PMID 27215954).

**Figure 2.**
Scatter plots of instrument-outcomes (y-axis) against individual instrument-exposure (x-axis) per-allele effects, shown separately for statin response (left panel) and liability of type 2 diabetes instruments (T2D, right panel). The filled dots correspond to the restricted lists of variants (see text), while the full set included all dots. The lines correspond to the inverse-variance weighted combined MR estimator, for the restricted (dashed line) and full set of instruments.

**Figure 3.**
Funnel plots of individual causal effect estimates (Wald ratios) for statin response on type 2 diabetes (T2D, left panel), and liability to T2D on statin response (right panel). The black dots correspond to the restricted lists of variants (see text), while the full set included all dots. The lines correspond to the inverse-variance weighted combined MR estimator, for the restricted (dashed) and full set of instruments.

See this image and copyright information in PMC

References

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

Affiliations

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

Authors

Affiliations

Abstract

Figures

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials