People with certain LDL cholesterol-lowering gene variants who are treated for their cholesterol with statins and other drugs may be prone to adverse metabolic consequences, a new research suggests.
The new study, published in JAMA, shows that a number of genetic variants linked to cholesterol-related biological processes – many of which are mediated by cholesterol-lowering treatment like statins – are associated with an increased type 2 diabetes risk.
Other available drugs used to reduce LDL cholesterol that carry the same risk include ezetimibe (marketed as Zetia or Ezetrol), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.
This indicates that the specific mechanism used to reduce blood cholesterol may be important for the influence on diabetes risk, and the choice of a lipid-lowering treatment.
The lead author of the study, Dr Luca A. Lotta, of the University of Cambridge, has stressed, however, that this does not mean recommendations to take statins or other cholesterol-lowering drugs should change, if they are warranted.
The study means that we should closely monitor the metabolic consequences of taking these drugs.
The researchers did a meta-analysis of genetic association studies conducted on half a million adults to obtain these results.
The studies included more than 50,000 individuals with type 2 diabetes and 270,000 controls, as well as nearly 61,000 with coronary artery disease (CAD) and about 123,000 controls.
Researchers found that variants in the Niemann-Pick C1-Like 1 (NPC1L1) gene, which mediates cholesterol transport across the small intestinal barrier, were linked to greater type 2 diabetes risk (a 2.4 risk ratio, specifically), but a lower risk of CAD.
NPC1L1 is the molecular target of the LDL-C cholesterol-lowering drug, ezetimibe, which lowers blood cholesterol by inhibiting intestinal cholesterol absorption.
Previous research has shown that silencing NPC1L1 has beneficial effects on components of the metabolic syndromen, such as insulin resistance, in addition to atherosclerosis. So an adverse metabolic risk profile may be the consequence of gene variants leading to an overexpression of NPC1L1.
Another LCL-C-lowering genetic variant of the gene PCSK9, which encodes the target of PCSK9 inhibitors, was also detected as a driver of higher type 2 diabetes risk.
These results can be considered surprising, given that diabetes and heart disease share several risk factors that tend to affect the risk of these two diseases in a consistent direction (e.g. smoking, higher body mass index (BMI), lack of physical inactivity).
Overall, the effect of LDL-C- lowering drugs on increased risk of diabetes appears to be specific to particular genes targeted by these drugs.
According to the researchers, this could inform the choice of a lipid-lowering therapy over another for patients, especially those that are already at high risk for type 2 diabetes.

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