Genetic deficiency of cholesteryl ester transfer protein tied to lower CV risk, higher AMD risk: JAMA
Denmark: Hereditary cholesteryl ester transfer protein (CETP) deficiency is associated with lower cardiovascular risk but an increased risk of age-related macular degeneration, finds a new study conducted by Liv Tybjærg Nordestgaard and team.
The findings of this study were published in the journal JAMA Cardiology on 6th October 2021.
CETP is a hydrophobic glycoprotein that is secreted mainly from the liver and that circulates in plasma, bound mainly to HDL.2 It promotes the redistribution of cholesteryl esters, triglycerides, and, to a lesser extent, phospholipids between plasma lipoproteins.
The long-term clinical advantages and risks associated with hereditary cholesteryl ester transfer protein insufficiency, which mimics pharmaceutical CETP suppression, are unclear, keeping this in mind researchers assessed the relative advantages and disadvantages of hereditary CETP deficiency.
This study looked at two identical prospective cohorts of the Danish general population, including data on 102 607 people gathered between October 10, 1991, and December 7, 2018. The researchers first looked to see if a CETP allele score was linked to morbidity and mortality when scaled to genetically lower levels of non–high-density lipoprotein (HDL) cholesterol (i.e., 17 mg/dL), which corresponded to the reduction seen with anacetrapib vs placebo in the Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial. Second, the researchers looked at how much of the increase in morbidity and death was due to genetically lower levels of non-HDL cholesterol. Finally, the possible long-term clinical benefits and hazards associated with hereditary CETP deficiency were calculated. Higher levels of HDL cholesterol linked with hereditary CETP impairment were also included in the AMD studies.
Key findings include:
- Multivariable adjusted hazard ratios showed that a genetically lower level of non-HDL cholesterol (ie, 17 mg/dL) was associated with a lower risk of cardiovascular mortality (hazard ratio [HR], 0.77), ischemic heart disease (HR, 0.80), myocardial infarction (HR, 0.72), peripheral arterial disease (HR, 0.80), and vascular dementia (HR, 0.38) and an increased risk of AMD (HR, 2.33) but was not associated with all-cause mortality (HR, 0.91), ischemic stroke (HR, 1.05), or Alzheimer disease (HR, 1.25).
- When scaled to a higher level of HDL cholesterol, the increased risk of AMD was even larger.
- A considerable fraction of the lower risk of cardiovascular endpoints was associated with genetically lower levels of non-HDL cholesterol, while the higher risk of AMD was associated with genetically higher levels of HDL cholesterol.
- Per 1 million person-years, the projected 1916 more AMD events associated with genetically higher levels of HDL cholesterol was similar to the 1962 fewer events of cardiovascular mortality and myocardial infarction combined associated with genetically lower levels of non-HDL cholesterol.
In conclusion, this study shows that hereditary CETP impairment, which mimics pharmaceutical CETP suppression, is linked with a decreased absolute risk of cardiovascular mortality, IHD, MI, PAD, and vascular dementia, but an increased absolute risk of AMD of comparable size. This data shows that pharmaceutical CETP inhibition may have a long-term negative effect on AMD.
Nordestgaard LT, Christoffersen M, Lauridsen BK, et al. Long-term Benefits and Harms Associated With Genetic Cholesteryl Ester Transfer Protein Deficiency in the General Population. JAMA Cardiol. Published online October 06, 2021. doi:10.1001/jamacardio.2021.3728