Having genetically low LDL cholesterol due to proprotein convertase subtilisin/kexin 9 (PCSK9) was associated with a reduced risk for cardiovascular and all-cause mortality in the general population, according to data presented Tuesday at Scientific Sessions.
“The results suggest that more prolonged reductions in LDL cholesterol with, for example, PCSK9 inhibitors, might eventually translate into a reduction in both cardiovascular and all-cause mortality,” said Marianne Benn, MD, PhD. “However, randomized clinical intervention trials of PCSK9 inhibitors with long follow-up are needed to document such effects.”
According to Benn, associate professor and chief physician in the Department of Clinical Biochemistry at Rigshospitalet, a function of Copenhagen University Hospital in Denmark, PCSK9 degrades LDL receptors and lowers the amount of LDL cholesterol that can be removed by the liver. Genetic variation in the PCSK9 gene reducing protein function (similar to PCSK9 inhibition) increases the number of LDL receptors and lowers LDL cholesterol.
In this study, Benn and colleagues tested whether genetically low LDL due to PCSK9 was causally associated with reduced cardiovascular and all-cause mortality in the general population. They genotyped for PCSK9 R46L (rs11591147), R237W (rs148195424), I474V (rs562556) and E670G (rs505151) in 109,566 individuals from the Copenhagen General Population study and the Copenhagen City Heart Study. With a median follow-up of 8.6 years and more than 1 million person years, they observed 2,261 cardiovascular deaths and 14,651 deaths from any cause.
Results of the study revealed that genetically low LDL cholesterol due to PCSK9 variation (corresponding to pharmacologic inhibition of PCSK9 by alirocumab or evolocumab) was causally associated with low risk of cardiovascular mortality. Specifically, an increasing number of weighted PCSK9 alleles were associated with stepwise lower LDL cholesterol of up to 0.61 mmol/L (P for trend <.001), and with lower cardiovascular (P=.0002) and all-cause mortality (P=.045).
“Mortality data on low LDL cholesterol via PCSK9 has not been reported before,” Benn said. “There is only one study which has shown that lowering LDL cholesterol as primary prevention reduces mortality.”
The researchers conducted causal genetic analyses and found a 1 mmol/L lower LDL cholesterol was associated with significantly reduced risk for cardiovascular death (risk ratio=0.33; 95 percent CI, 0.19-0.58; P<.001) and all-cause mortality (risk ratio=0.72; 95 percent CI, 0.60-0.88; P=.001).