Zero cardiovascular risk

[mccoy]

This topics relates to chapter 7 of peter's Attia book 'Outlive', discussed in another thread.

Now, the proposed strategy is to eradicate the main cause of atherosclerosis (hence, cardiovascular disease), by taking back the blood ApoB levels to the physiological levels of babies, specifically, to 20-30 mg/dL. This strategy of course involves the use of cholesterol lowering drugs, like statins and more (typically, two kinds of drugs).

My question:

Would you guys with an already optimal lipids panel (by conventional definitions) contemplate the adoption of Peter's Attia strategy to decrease the atherosclerotic risk to zero, by taking cholesterol lowering drugs?

Can you come up with significant drawbacks or pitfalls to this strategy? Knowing that the potential side-effects of statins can be avoided by choosing other drugs?

 

 

Edited April 22 by mccoy

[Guest]

That's the distribution of causes of death by age group in the US (from the cdc):

Given it's enormous share in causes of death among the (very) old, it seems reasonable to emphasize prevention. It's not just about longevity, but also quality of life - which tends to take a sharp downturn with advanced ASCVD (certainly after your first hearth attack or stroke).

 

The current data-situation supports the notion, that very low levels of APOB-bearing particles will stop the progression of ASCVD - or even reverse it (albeit very slowly). Now how aggressive you'll need to be depends on your personal risk. However, advanced age generally is the most prevalent risk. So there is a point to try to lower "elevated" APOB by medical means if necessary, if you're older than, say, 50. Where "elevated" could mean anything above 60/70 mg/dl.

However, not all drugs are the same. For example ezetimibe/zetia is successful in lowering LDL/APOB - but no study was able to find an effect on mortality. This could be a hint, that there are unaccounted for side effects. That not a new thing: the first fibrates on the market where hailed for lowering LDL. But long-term analysis demonstrated that they increased mortality. And there is indeed a large-scale ex-post cohort analysis in South Korea, that shows increased mortality with ezetimibe,

Long story short: you only should consider LDL-lowering drugs, that are proven to lower all-cause mortality.

Statins - for better or worse - are part of that category. And for the vast majority of people they are the best option, because PCSK9-inhibitors are damn expensive and require a doctors consultation every 14 days. Also one of the 2 inhibitors on the market has somewhat unclear data on all-cause mortality.

[Guest]

To supplement my comment - here are the results of the most recent meta analysis of the effects of ezetimibe and PCSK9 inhibitors:

https://hospitalhealthcare.com/clinical/cardiovascular/meta-analysis-finds-pcsk9-inhibitors-and-ezetimibe-combined-with-statins-reduce-non-fatal-mi-and-stroke-in-high-risk-patients-but-not-death/

and the underlying study in the BMJ:

https://boris.unibe.ch/169782/1/bmj-2021-069116.full.pdf

 

Ezetimibie cannot be universally recommended. The data on mortality (cardiovascular or all-cause) is pretty clear: there is no benefit. Note: this is also true comparing patients taking ezetimibe monotherapy vs. placebo patients taking nothing else - i.e. not even statins. Why is there no benefit? We don't really know, as there hasn't been sufficient collection of data by the drug maker. It could be, that it's simply too weak an effect. Or it could be negative side effects that increase the risk of ASCVD or some other cause of death through some other mechanisms.

PSCK9 inhibitors are a little more complicated. Evolocumab has confusing data on mortality at best. Alirocumab on the other hand got data for a clear benefit on all-cause mortality. As the meta analysis is combining both drugs, the net result is "no benefit" for mortality in their study. Interestingly Peter Attia commented as to injecting Alirocumab.

That leaves statins, fibrates and bile acid sequestrians. Of which statins by far have the best data for effects and least side effects. This is not to say that they don't have side effects. Just that lowering you LDL by 50 mg using statins is much easier and a  much more pleasant experience than trying the same with fibrates and bile acid drugs.

[mccoy]

Thanks Guest for your insights, I spoke with one medical doctor who raised questions about the availability of PCSK9 inhibitors, here they may be available only to those with serious cholesterol problems (probably high Lp(a) by inherited genes). I'm going to ask the local pharmacy because, if this is so, it would be the end of it as a potential general preventive measure in Italy, whatever the literature reports are.

Your comments would constitute a good question to pose to Dr Attia himself, also that article is based on high risk patients, what about a preventive scheme, would the reasoning be more or less valid?

And of course, if we are in the 5% individuals who suffer muscle soreness and elevated liver enzymes from statins, we would have little other choice other than ezetimibe and fibrates.

Edited April 24 by mccoy

[mccoy]

I read the linked article, and it turns out they have separated the group with lower risk. The conclusions seem to rule out the use of cholesterol lowering drugs other than statins even in patients with low risk. A really puzzling issue, why the additional drugs lower non fatal MI and stroke but not the fatal ones, or alternatively introduce other mortality risk factors.

Quote

 

The authors also found that among patients with low to moderate risk of cardiovascular disease, adding either a PCSK9 inhibitor provided no additional benefit over statin therapy alone. In other words, it was only patients with the highest cardiovascular risk who benefited from adding either ezetimibe or a PCSK9 inhibitor to their statin. Similar reductions, again only among high or very high risk individuals and a lack of mortality benefit, were observed in patients intolerant of statins.

The authors concluded that the benefits of adding PCSK9 inhibitors and ezetimibe were limited largely to patients only with a high or very high cardiovascular risk.

 

[mccoy]

I find it useful to report the conclusions in the BMJ paper itself. Actually, in the context of a preventive therapy for those with low risk, the results would deny the use of drugs other than statins.

Quote

All-cause and cardiovascular mortality When used as monotherapy or combined, ezetimibe or PCSK9 inhibitor therapy had no impact on all-cause and cardiovascular mortality (table 3).

Quote

Discussion Principal findings In this network meta-analysis of 83660 individuals receiving maximal statin therapy or intolerant to statin therapy, ezetimibe or PCSK9 inhibitor may reduce non-fatal myocardial infarction and stroke in adults at very high or high cardiovascular risk, but not in those with moderate and low cardiovascular risk. Adding ezetimibe or PCSK9 inhibitor to the background lipid-lowering therapy had no significant effect on all-cause or cardiovascular mortality. Thus, patients with the most significant cardiovascular risk may gain maximum benefits, whereas those with moderate to low cardiovascular risk achieve trivial absolute reductions in non-fatal myocardial infarction and stroke. Similarly, ezetimibe or PCSK9 inhibitors in statin-intolerant patients may reduce myocardial infarction and stroke among patients with very high and high cardiovascular risk. Overall, PCSK9 inhibitors seemed to have the highest absolute reductions in myocardial infarctions and strokes when added to background therapy, followed by ezetimibe.

[mccoy]

I've checked PCSK9 inhibitors at the local pharmacy. It turns out that in Italy they are not in commerce, they are apparently administered only in hospitals to individuals who have had MI, strokes or similar. 

[Ron Put]

As I posted elsewhere, I would take Attia with a large grain of salt, even if I find his shows informative on many topics.

Statins in healthy people may not be a solution, as they tinker with the body's ability to make cholesterol, and we all need that 🙂 There are questions about diminishing brain functionality, as well as potential insulin resistance and other issues, which for healthy people may not be worth the risks.

Was this, for example, posted already?

Long-Term Outcomes of Short-Term Statin Use in Healthy Adults: A Retrospective Cohort Study

"Conclusions: Short-term statin use for primary prevention in this healthy cohort was associated with an increased risk of long-term diabetes and diabetic complications without cardiovascular benefits. Further study using pragmatic studies and prospective observational studies appropriately equipped to eliminate unidentified confounders are urgently needed."

[Saul]

I agree that it's ridiculous for people with good lipid levels to take statins.

  --  Saul

 

[Guest]

@ Saul:

I guess this is hard to come to conclusion about without putting some numbers to it. What is a good lipid level? Conventional wisdom for people in primary prevention would say that anything below 100 mg/dl in LDL-C is "good". However, people like Peter Attia, Tom Dayspring and Allan Sniderman (the latter 2 are very well respected researchers, who almost single handily shaped the modern view on blood lipids over the past 40 years) make a reasonable point, that anyone is at high risk for ASCVD if someone is living long enough.

See the graph from the CDC that I posted earlier.

There is good data out off large randomized placebo controlled clinical trials and genetic cohort studies demonstrating, that APO-B/LDL-C levels substantially below 100mg/dl confer additional benefit for cardiovascular mortality and all-cause mortality. Up to a point where the progress of ASCVD can be virtually stopped.

How to get to those low levels is someones personal journey. But drugs can reasonably play a part in that. It is prudent to be skeptical about a particular drug, of course. Even among the same class of drugs, there can be large variations. Alirocumab has much more convincing data than the other PCSK9-inhibitor on the market - Evolocumab. The first fibrates increased mortality - whereas modern fibrates do the opposite. There was a statin called Lipobay in the early 2000s that had 20-80 times the rate of serious side effects than it's competitors - Bayer Pharma deceived the public about that, got sued for billions and had to pull it from the market. And ezetimibe has no effect on mortality, not even cardiovascular, despite lowering LDL - which can make you question what kind of long-term side effects lurk in the background.

But don't throw out the baby with the bathwater. Modern statins - particularly the high-potency ones Atorvastatin and Rosuvastatin - have long term data showing decreased all-cause mortality. And in proportion to the level of LDL-lowering. We are talking about 5 years of clinical trials and up to 15 years of well collected follow-up data, i.e. 20 years of total observation. So if Alirocumab is not possible to acquire and you prefer to not spend your days and nights on the toilet thanks to bile acid drugs - statins are an option that can be considered.

 

@ Ron Put:

That study is certainly not up to date. Just last year a major review in the UK found, that the diabetes risk of statins is negligible if you compare it with the ASCVD-benefit of statins. That's the reason diabetic patients routinely get statin prescriptions as part of their treatment.