Higher levels of LDL cholesterol, HDL cholesterol, and triglycerides over a lifetime are protective against type 2 diabetes, a Mendelian randomization study has shown.
The study also bolstered established evidence that LDL cholesterol and triglycerides boost the risk of coronary artery disease (CAD) but showed no contribution of HDL cholesterol to that risk.
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Investigators sought to shed light on the role of the most commonly measured lipid fractions – LDL cholesterol, HDL cholesterol, and triglycerides – in the development of CAD and diabetes, particularly the observed link between statin therapy and an increased risk of diabetes.
Because genotype is not modifiable by disease, a genetic instrument can be used as an model for an exposure, and “Mendelian randomization generates unbiased, unconfounded effect estimates that are sometimes taken as evidence of a causal role,” Jon White, PhD, of University College London and his coinvestigators explained.
They used data from three genome-wide association studies involving 188,577 persons with blood lipid measures, 63,158 CAD cases, and 34,840 diabetes cases. All involved only people of European ancestry. Summary-level data for lipids were from the Global Lipids Genetics Consortium (Nat Genet. 2013;45[11]:1274-83), diabetes data came from the Diabetes Genetics Replication and Meta-analysis (Nat Genet. 2012;44[9]:981-90), and CAD data were from the Coronary Artery Disease Genome-wide Replication and Meta-analysis plus Coronary Artery Disease Genetics (Nat Genet. 2013;45[1]:25-33). From these, the investigators constructed genetic instruments comprised of single-nucleotide polymorphisms (SNPs) and conducted Mendelian randomizations designed to adjust for the SNPs’ possible associations with other traits, or pleiotropy.
The results showed that two lipid fractions were associated with reduced risk for type 2 diabetes and one had no discernible effect. LDL cholesterol showed the strongest association: An increase of 1 standard deviation, equivalent to 38 mg/dL, was tied to a 21% reduction in risk (odds ratio, 0.79) of diabetes. For HDL, a 1-SD rise of 16 mg/DL in HDL was associated with a 17% lower risk (OR, 0.83). A 1-SD rise of triglycerides, 89 mg/dL, also reduced risk by 17% (OR, 0.83), but there were statistical inconsistencies between analyses.
The associations between 1-SD increases and CAD were consistent with conventional wisdom: For LDL cholesterol, CAD risk rose by 68%; for triglycerides, the increase was 28%; and for HDL cholesterol, the risk was slightly reduced by 5% but was not statistically significant (JAMA Cardiol. 2016 Aug 3. doi: 10.1001/jamacardio.2016.1884).
These results can help to identify the potential effects of lipid-modifying drugs, yet “although all three lipids were associated with reduced risk of diabetes, it does not necessarily follow that lowering of LDL cholesterol or triglyceride levels through use of drugs that target specific proteins (eg, PCSK9) will alter the risk of diabetes,” Dr. White and his colleagues wrote. Large-scale genetic and clinical trials are needed to determine such dysglycemic associations.
This study was conducted by the Clinical Trial Service Unit of the University of Oxford through a grant by Merck Sharp & Dohme, with additional funding from numerous academic and research institutions. The funding sources had no role in the design or conduct of the study. Two of the investigators had ties to pharmaceutical companies.