medwireNews: A meta-analysis published in JAMA shows that mutations linked to reduced low-density lipoprotein (LDL) cholesterol levels are associated with an increased risk of diabetes.
Nicholas Wareham (University of Cambridge, UK) and team found that LDL cholesterol-lowering mutations located in and around the NPC1L1 gene, which encodes the molecular target of ezetimibe, conferred a reduced risk of coronary artery disease (CAD), but raised the carriers’ diabetes risk.
Each genetically predicted 1 mmol/L reduction in LDL cholesterol was associated with a 2.42-fold increased likelihood of having diabetes, based on data from 50,775 Type 2 diabetes patients and 270,269 controls, primarily from the EPIC–InterAct study, the UK Biobank study and DIAGRAM.
This equated to an additional 5.3 incident cases per 1000 person–years, say the researchers. But at the same time, these LDL cholesterol-lowering mutations reduced the risk of CAD, with each 1 mmol/L reduction being associated with a 39% lower risk among 60,801 CAD patients and 123,504 controls.
Wareham and team also looked at other lipid-lowering drug targets, finding that each 1 mmol/L reduction in LDL cholesterol conferred by mutations linked to the statin target HMGCR was associated with a 1.39-fold increased diabetes risk and a 38% decreased CAD risk, consistent with outcomes in patients treated with statins.
And the team also found a 1.19-fold increased diabetes risk associated with LDL cholesterol-lowering mutations linked to PCSK9, along with a 40% CAD risk reduction, suggesting that treatment with PCSK9 inhibitors could also result in an elevated diabetes risk.
But the researchers advise a cautious interpretation, given the relatively low statistical significance (p=0.03) and multiple comparisons.
Of note, whereas the magnitude of reduction in CAD risk conferred by genetically determined LDL cholesterol reduction was the same regardless of the gene involved, the increase in diabetes risk varied, “which would be consistent with the mediation of their associations by different mechanisms.”
This, “in turn might suggest that the adverse consequences of lipid-lowering agents on diabetes risk could be specific to a particular drug target”, write Wareham et al.
“This may have clinical implications for the future of lipid-lowering therapy in the context of the increasing number of approved drugs acting on different molecular targets”, they say, noting that doctors could choose lipid-lowering drugs based partly on patients’ personal risk of diabetes.
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