Understanding the effects of LDL-C lowering on several diseases

Genetic evidence confirms both the positive and negative associations of low-density lipoprotein cholesterol (LDL-C) reduction with certain metabolic and cardiovascular diseases (CVDs), according to the results of a Mendelian randomization (MR) study in the UK Biobank.

Specifically, no adverse effects are associated with lipid lowering, except for diarrhoea, which is a common side effect of ezetimibe. On the other hand, PCSK9-inhibitor proxy appears to contribute to lower lung capacity as measured by FEV1 and FVC. [https://www.nhs.uk/medicines/ezetimibe/]

In addition, the statin proxy shows an association with higher hippocampal volumes. This relationship potentially suggests benefits for brain health, particularly a reduced risk for dementia. [Alzheimers Dement 2020;16:209-218; J Affect Disord 2011;134:483-487]

“Our biomarker analyses suggested novel associations between the PCSK9-inhibitor proxy and lower lung function (lower FEV1 and lower FVC) and between the statin proxy and higher hippocampal volumes,” said the investigators, led by Prof Elina Hyppönen from the Australian Centre for Precision Health, Clinical & Health Sciences, University of South Australia, Adelaide, Australia.

Hyppönen and her team carried out an MR phenome-wide association study in a total of 337,475 UK Biobank participants to examine the associations between four proposed LDL-C‒lowering genetic risk scores (ie, PCSK9, HMGCR, NPC1L1, and LDLR) and 1,135 disease outcomes. Follow-up MR analyses were also conducted in 52 serum, urine, imaging, and clinical biomarkers.

Inverse-variance weighted MR was used for the main analyses and complementary MR methods (ie, weighted median, weighted mode, MR-Egger, and MR-PRESSO) for the sensitivity analyses. Finally, the investigators accounted for multiple testing with false discovery rate correction (p<2.0x10^-4 for phecodes and p<1.3x10^-2 for biomarkers). [Br J Clin Pharmacol 2023;89:2992-3004]

Disease outcomes

Genetic evidence was found, which suggested a causal relationship between at least one of the four genetic instruments and 10 diseases, including unstable angina, myocardial infarction (MI), angina pectoris, coronary atherosclerosis, other chronic ischaemic heart diseases, hypertensive heart/renal disease, abdominal aortic aneurysm, peripheral vascular disease, hypercholesterolaemia, and diarrhoea.

In biomarker analyses, evidence showed that LDL-C lowering through PCSK9 had an impact on lung function (FEV beta per 1-mg/dL lower LDL-C: ‒1.49, 95 percent confidence interval [CI], ‒2.21 to ‒0.78; FVC: ‒1.42, 95 percent CI, ‒2.29 to ‒0.54) and through HMGCR on hippocampal volume (beta per 1-mg/dL lower LDL C: 6.09, 95 percent CI, 1.74‒10.44).

“Our analyses confirmed the known associations between the LDL-C-lowering effect of statins and a range of metabolic and cardiovascular diseases,” the investigators said.

“There was no evidence for adverse effects of lipid lowering, aside from confirming diarrhoea as a side effect of ezetimibe and suggestion for novel associations between the PCSK9 genetic instrument and lower lung capacity,” they added.

Cardiometabolic effects

Other phenome-wide studies in the past also reported an association between PCSK9-inhibitor lipid-lowering medication and a lower risk of hypercholesterolaemia, hyperlipidaemia, and CVD. [Circ Genom Precis Med 2018;11:e002162; NPJ Genom Med 2019;4:3; Pharmacogenomics J 2020;20:462-470]

The present study confirmed the robust relationships between lower LDL-C and lipid-related metabolic diseases. Such finding was expected since unfavourable lipid profiles have been shown to cause disorders of lipid metabolism, hyperlipidaemia, and hypercholesterolaemia. [https://www.health.harvard.edu/a_to_z/high-cholesterol-hypercholesterolemia-a-to-z]

A recent meta-analysis also confirmed the association between LDL-C and CVD. A reduced LDL-C lowers the risk of CVD by decreasing the atherosclerotic plaque build-up on the artery walls. [Eur Heart J 2017;38:2459-2472; JAMA 2016;316:1289-1297]

“By scaling our estimates to represent a clinically relevant decrease in LDL-C of 20 mg/dL, which is comparable to a low dose of statin medications, our results suggest that LDL-C lowering through these targets may reduce risk of MI by up to 33 percent and peripheral vascular disease by up to 34 percent,” the investigators said. [BMJ 2003;326:1423]

The current analysis identified an increased risk of diarrhoea as the only negative side effect of LDL-C lowering. This effect could be explained by the effect of NPC1L1 protein on LDL-C by preventing the absorption of cholesterol in the gastrointestinal tract. [Curr Med Chem 2016;23:983-999]

Neurological effects

Notably, an association was observed between the HMGCR genetic instrument and a slightly increased hippocampal volume, a known marker of dementia. This finding warrants further research, according to the investigators. [Alzheimers Dement 2020;16:209-218]

“To our knowledge, the association is yet to be reported in human subjects; however, a study performed in mice found that long-term use of simvastatin impaired synaptic plasticity within the hippocampus,” the investigators said. [Alzheimers Dement 2020;16:209-218]

The biomarker MR analyses also revealed an association between PCSK9 and higher volumes of white matter hyperintensity (WMH), but this association did not reach significance after false discovery rate correction. Of note, WMHs are indicators of brain lesions, as well as cognitive impairment, depression, dementia, and stroke. [J Am Heart Assoc 2015;4:001140]

In earlier genetic studies, results showed the harmful effects of LDL-C reduction via PCSK9 on the risks of Alzheimer’s disease and depression. [Int J Neuropsychopharmacol 2018;21:1067-1075; Ann Neurol 2020;87:30-39]

“Given that in the UK Biobank the neuroimaging biomarkers have been collected from a significantly smaller sample size (n≤27,117) than the serum, urine, and clinical markers, we may see an association between PCSK9 and biomarkers of dementia or cognitive impairment as the number of participants in the imaging substudy increases,” according to Hyppönen and colleagues.

“Future studies should aim to further investigate the effects of lipid lowering on lung function and brain volume, particularly in clinical settings,” they said.