Lipid levels have opposing effects on risk of diabetes, CAD
medwireNews: Findings from a Mendelian randomisation study suggest that lifelong exposure to increased levels of the major lipid fractions is protective against Type 2 diabetes, even as it raises the risk of coronary artery disease (CAD).
As reported in JAMA Cardiology, Michael Holmes (University of Oxford, UK) and co-researchers assessed genetic and lipid data for 188,577 people, including 63,158 with CAD and 34,840 with diabetes.
They identified 130 single nucleotide polymorphisms (SNPs) with an influence on low-density lipoprotein (LDL) cholesterol levels, explaining 7.9% of its variance. Each one standard deviation (SD; 38 mg/dL) increase in genetically determined LDL cholesterol levels was associated with a significantly increased risk of CAD, but a reduced risk of diabetes, at odds ratio of 1.68 and 0.79, respectively.
These effects, although larger than previously reported, are in line with the slightly increased risk of diabetes among patients taking statins. The authors of an accompanying editorial, Danish Saleheen (University of Pennsylvania, Philadelphia, USA) and colleagues, say that the “totality of evidence” does support LDL cholesterol directly protecting against diabetes.
“This conclusion, extrapolated beyond statins and 3-hydroxy-3-methylglutaryl-CoA reductase, has major implications for PCSK9 inhibitors and other LDL-lowering medicines in development”, they write.
A total of 140 SNPs explained 6.6% of the variance in high-density lipoprotein (HDL) cholesterol levels. Genetically determined HDL cholesterol levels were not significantly associated with CAD, but each SD (16 mg/dL) increase was associated with a reduced diabetes risk, at an odds ratio of 0.83.
Finally, 140 SNPs explained 5.9% of the variance in triglyceride levels. Each SD (89 mg/dL) increase was also associated with a reduced odds ratio of 0.83 for diabetes, but conferred a significantly increased odds ratio of 1.28 for CAD.
The editorialists describe this as the “most counterintuitive” finding, given that it directly contradicts epidemiological studies and other research.
“If true, the implications of this are substantial, including the potential that intervention to reduce [triglyceride] levels could paradoxically increase the risk for [Type 2 diabetes]”, they say.
Saleheen et al note there has been no evidence of this to date, but point out that it took around 20 years before the link between statin treatment and diabetes risk came to light. They therefore stress the importance of monitoring triglyceride-lowering trials for excess cases of diabetes.
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