Pesky PSCK9 inhibitors (2)

Eric put various links in the comments to the first PSCK9 post leading, eventually, to this study:

Sequence Variations in PCSK9, Low LDL, and Protection against Coronary Heart Disease

which gives us these results:

"Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P = 0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P = 0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P = 0.003)."

and the conclusion:

"These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non–lipid-related cardiovascular risk factors."

Well. There we go. Again.

Soooooo. What is the glaring omission from the study results?

That's correct, there is no body count. Presumably the paper was written by cardiologists and/or lipidologists.

Perhaps we should get a body count.

Lets go to UK Biobank and some folk in Denmark. Here we have

Low LDL Cholesterol by PCSK9 Variation Reduces Cardiovascular Mortality

"In causal, genetic analyses, a 0.5-mmol/l (19.4-mg/dl) lower LDL cholesterol was associated with risk ratios for cardiovascular and all-cause mortality of 0.79 (95% confidence interval [CI]: 0.63 to 0.99; p = 0.04) and 1.02 (95% CI: 0.94 to 1.12; p = 0.63) in the Copenhagen studies, 0.79 (95% CI: 0.58 to 1.08; p = 0.14) and 0.98 (95% CI: 0.87 to 1.10; p = 0.75) in the UK Biobank."

and in conclusion:

"Genetically low LDL cholesterol due to PCSK9 variation was causally associated with low risk of cardiovascular mortality, but not with low all-cause mortality in the general population."

Note, particularly that in the UK Biobank data, there was no significant risk reduction for CVD events in addition to the no, zero, zilch, nil reduction of risk in all cause mortality. None. I'm a subject in UK Biobank.

So why would anyone expect PSCK9 inhibitors, certainly in the UK, to do any better than genetic PSCK9 activity reduction?

Perhaps such people have a drug to sell in a broken paradigm.

Peter