Tuesday, July 07, 2020

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

"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.



karl said...

I saw the non significant increase in 'deaths from any cause' in the 2017 NEJM paper -
'Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease'

When the nurse was recommending Evolocumab to me - I pointed out the increase in deaths - all I got was a confused look.

As I get older, I've realized that medical interventions, if not mechanical, are mostly sketchy. People want miracle cures - and there are people standing by to sell them something.
They are handing out benzodiazepine prescriptions at a record rate to deal with CoVid-19 Anxiety. Benzos were supposed to be safer than the old barbiturates - but the addiction rate is non trivial and I think the number of people getting permanent harm(increase seizure tenancies) is greatly under reported. People want pill cures - want to believe in easy medical interventions, but the public has no understanding of how sketchy the medical business is.

I am amazed at how sold the public is that the 'health experts' know what they are doing with the lock-down. Hard to know with precision, but my first glance at 'excess death' numbers makes me think that the lock down could be causing deaths at a rate about 1/2 of the virus - and this is short term. Total deaths from the lock-down would be very hard to measure - probably toxic to anyone who would publish on the topic. ( I've spoken to MD's that are afraid to say what they think about CoVid ). I've spoken to friends and host-students that are experiencing major anxiety from the CoVid hysteria seeking my advise. I could be wrong, but I think these policies are doing net harm.

Peter said...

It's strange what people will believe, oddly enough the cardiologists seem strangest with their weird certainty that lipids cause heart disease. Incredible.

Hee hee, just deleted a rant about our current government here in the UK. Boris the Executioner!


cavenewt said...

@karl "As I get older, I've realized that medical interventions, if not mechanical, are mostly sketchy. People want miracle cures - and there are people standing by to sell them something."

"Sketchy" is a pretty tame description. The more I learn about biology, with its intricately interconnected myriad of negative feedback loops, and where many if not most chemical substances serve multiple purposes, the more I picture it as a huge machine comprised of millions of gears; the idea that you can insert a monkey wrench in any one spot without causing some sort of trouble elsewhere in the mechanism is breathtakingly hubristic.

Modern medicine engages in a certain amount of magical thinking. For example, that you can take a pill for a specific purpose and it will magically target that single purpose, even if the medication is being prescribed off label for something it wasn't originally meant for. Years ago I started developing essential tremor in one hand. I mentioned it to my GP, who offhandedly prescribed propranolol, saying it often helps. This is a *heart* medication. My heart is absolutely fine just the way it is, thank you. Needless to say, I didn't fill the prescription.

Passthecream said...

Cavenewt -- nice imagery. Here's a small working model of it:

https://youtu.be/Bp4tGTNNi1I. The square gear is a nice touch.

Magical Thinking, same thing as Cargo Cult mentality I think. I was earlier pondering how Westerners are certainly no more sophisticated than some of the traditional people you find in New Guinea, maybe less. Nothing much has changed in human nature for thousands of years.

Bob said...

cavenewt said, "Modern medicine engages in a certain amount of magical thinking."

Yes, just like "ancient folks" with their shamans, witch doctors, and "magic potions". In our current age, we're a bit more enlightened than our ancestors but more easily subject to hubris about it.

It is said, "A little knowledge is a dangerous thing." I expect we'll remain in the "little knowledge" stage for quite a long time.

karl said...

I think it is beyond 'cargo cult' - there is some straight up corruption of science, but I think the public is part of the problem.

We want to be sold hope - want to blindly trust our doctor so we don't have to deal with our mortality. Part of the lockdown hype is from this - no one is supposed to die. We want to be sold some cure even if it isn't rational. The public does not want to think their is any doubt about the mainstream treatments.

Now they have figured out how to shape the perception of reality by ghosting dissenting voices like Nobel laureate Michael Levitt or Oxford university's Professor Sunetra Gupta(an epidemiologist). ( I first found Sunetra's take of the subject in 'Hindustien Times' - extremely close to what I was thinking - she might be underestimating the health costs of lockdown if anything. ) You can find them - but you really have to want to find them - pretty much invisible in the USA.

So how many voices that are skeptical of the LDL mantra have been ghosted - "for the public's own good"..

Unknown said...

Here's another nail in the coffin, disguised as a new lease of life -

statins in over-75 veterans, from non-randomised large study with propensity scores.

As advertised -
"In sensitivity analysis, HRs plotted at 2-year intervals following the index date indicated that statin use was significantly associated with lower mortality within the first three 2-year intervals. For all-cause mortality, HRs at years 2, 4, and 6 were 0.68 (95% CI, 0.66-0.69), 0.79 (95% CI, 0.77-0.81), and 0.87 (95% CI, 0.84-0.91), with a similar pattern for cardiovascular death (eTable 2 in the Supplement). Results were unchanged when veterans who died in the first 150 days (n = 4213) were included (HR, 0.75 [95% CI, 0.74 to 0.76] for all-cause mortality and 0.80 [95% CI, 0.78 to 0.82] for cardiovascular mortality)"

The only problem is - look at that shrinking HR gap - they also had a fourth 2-year interval. Some people in the study had been taking the statin for 8 years.
We can only find the HRs for this group in the supplement: in eTable 2. Hazard Ratios for Mortality and CV Outcomes for 2-8 Years After Index Date

ACM: 8 years HR 1.03 (0.84-1.24)
CVDM: 8 years HR 1.25 (0.89-1.74)

Diminishing returns indeed, so much for "lifetime exposure to LDL". I would say that longer duration of statin use favours statin discontinuation in this age group.
Sure it's non-significant, but the authors don't even mention it or discuss what it might mean.

Peter said...

Hi Unknown,

Yes, I looked at the title and thought how statins were miraculously associated with protection against Alzheimers, Parkinson’s, cancer etc. Until you test them in an intervention trial, where they worsen such diseases. The eight year figures are marvellous (unless you take a statin). I guess they study was just lucky that p stayed above 0.05. Few more years for that one…


It’s that eternal dichotomy between stupidity and malice. I’m an innocent bloke and tend to go with stupidity for most of the explanation but you only have to look at the treatment of people like Tim Noakes to realise malice is rampant and no one needs malice if their data show them to be correct.


cavenewt said...

@Passthecream—thanks for the geary video. It really tickles my timepiece fetish.

Eric said...

I had no doubt that genetically low LDL would confer no total mortality benefit, in fact I'm surprised it isn't worse.

However, it seems like those are two distinct mutations (a different one in black folks than in white) rather than random, so if they have survived in 2-3% of the population, they probably did confer an advantage. Which?

Also, the data do seem to confer an advantage in CVD and might actually somewhat redeem the lipid hypothesis. Is there any way to understand this? The whole causal chain of LDL and plaque formation has been thoroughly disproven, so why all of a sudden is there a decrease in folks with this mutation if they do not happen to live in the UK??

altavista said...

According to Petro, we got everything wrong :) CVD? Wrong Diabetes? Wrong Cancer? Wrong

Surely we got something right, Peter. We've been spending $5-$10 trillions a year for decades, you're saying all we got right is aspirin, metformin and hydroxychloroquine? These are all 50 years old and cost $0.1/pill.
and were discovered for something else to begin with :)

Passthecream said...

Alta Vista --- not even that