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Statin-induced LDL cholesterol response and type 2 diabetes: a bidirectional two-sample Mendelian randomization
Roelof A J Smit1,2, Stella Trompet3,4, Aaron Leong5,6
1Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands. r.a.j.smit@lumc.nl.
The Pharmacogenomics Journal
|December 6, 2019
Summary
This study investigated if statins increase type 2 diabetes risk due to lower LDL-C or proportional LDL-C changes. Genetic analysis found no causal link between statin response and type 2 diabetes risk.
Area of Science:
- Genetics and Cardiovascular Disease
- Metabolic Disorders Research
- Pharmacogenomics
Background:
- Statin use is associated with an increased risk of new-onset type 2 diabetes (T2D).
- The underlying mechanism remains unclear, with debate on whether low LDL-C levels or the proportional LDL-C reduction induced by statins drives this risk.
- Previous genetic studies have not explored if T2D susceptibility influences statin efficacy in lowering LDL-C.
Purpose of the Study:
- To investigate the causal relationship between statin-induced LDL-C response and T2D risk.
- To examine if genetic liability to T2D affects the proportional LDL-C lowering response to statins.
- To utilize genetic association data from large consortia to address these questions.
Main Methods:
- Utilized summary-level statistics from the Genomic Investigation of Statin Therapy (GIST) and DIAGRAM consortia.
- Employed LD score regression to assess genetic correlation between LDL-C statin response and T2D.
- Conducted Mendelian randomization analyses to infer causal effects in both directions.
Main Results:
- A positive genetic correlation (r=0.36) was observed between LDL-C statin response and T2D.
- Mendelian randomization did not support a causal effect of statin response on T2D risk (OR 1.00 per 10% increase).
- No evidence was found for a causal effect of T2D liability on statin-induced LDL-C response (0.20% increase per doubling of odds).
Conclusions:
- Current genetic evidence does not support a causal role for proportional statin response in influencing T2D risk.
- The study highlights potential dilution of effect estimates due to the inclusion of non-statin users in the DIAGRAM dataset.
- Further investigation in exclusive statin-user cohorts is recommended for a definitive assessment.
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