Exactly. My LDL-C range of 141 to 179 with a zero on my Cornary Calcium scan.
LDL-C the last 2 Blood checks April was 179 and July 141. Above recommended, but arteries are fine, so my physician is accepting it.
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The biggest issue with this study is that 30% of the rapamycin group were on statins which may have contributed to the favorable results. Doctors will be quick to add statins so it will be difficult to have a study without that variable.
Regardless, all of the measured lipids increased in the rapamycin group even with statins, and yet the number of cardiovascular events werenât increased. Certainly suggests a protective effect from rapa.
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Weâve seen the association of low LDL and increased mortality in several population studies. Now a study reveals that in the very elderly with a heart attack, the mortality rate increases very significantly post MI in the lowest LDL group.
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In the previous study, another issue might be that they are comparing Rapa with some other drug that stops rejection, right? So the other drug may cause more heart disease.
In our case weâre comparing Rapa with nothing at all.
They didnât mention this in the discussion, so I could be wrong.
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But this has all the potential confounders that are seen in all the other non-experimental, correlational studies involving LDL and mortality. Basically this study is saying that sick old people with high levels of inflammation (CRP) and low LDL (and being frail/sick/undernourished already lowers LDL) is associated with higher mortality. Yes, it definitively is, but how could we infer from this study that lower LDL causes increased mortality?
To reiterate once again, we already know that pharmacologically lowering LDL, even to extremely low levels, does not increase mortality and in fact lowers it substantially when it comes to heart disease. And these are prospective experimental studies where LDL is specifically modulated. This blows any correlational/observational study out of the water, IMO. If higher or even mid-range LDL were âoptimalâ, youâd see higher mortality across the board when you dramatically cut LDL with meds.
Again, not saying that inflammation isnât important (it is!) and I agree itâs very possible rapamycin gives some substantial protection. I just think itâs a huge and potentially deadly mistake to ignore LDL or suggest itâs a bad idea to keep it low.
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We canât just keep saying that itâs the underlying disease thatâs causing the low LDL levels when all of the subjects have the same disease. They all had myocardial infarctions and yet it was the ones with the low LDLâs that had the higher mortality rates.
In the population studies, each incremental increase in LDL gave lower mortality rates with the sweet spot at 140-160. Why not at 90?
The studies showing benefits of LDL lowering with statins are complicated because statins lower inflammation and have even recently been shown to inhibit mTOR.
This issue deserves a more careful look rather than just dismissing it, especially now when the mantra is â the lower the better â.
Theyâre the âoldest oldâ, so yes they all had heart attacks and they are also likely frail, often undernourished and with all kinds of other medical problems. The sicker they are, the lower LDL is likely to be, which in turn skews the data.
According to the âlow LDL is badâ hypothesis, we should see increased mortality with PCSK9 inhibitors, which are highly selective in their effects on LDL (decrease ApoB without off-target effects on inflammation, etc). I certainly havenât seen anything to suggest this.
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If youâre theory were correct that the disease is causing the LDL reduction, then all of the participants with the same disease, namely CAD and a heart attack, should have had low LDLâs. But only some of them did, and that group had the worst prognosis.
Furthermore, the more selective PCSK9 inhibitors didnât reduce all cause or even cardiovascular mortality rates.
Weâre talking averages/means/medians here. The sick/frail elderly with low LDL and high CRP skew the data in the direction of higher mortality. I donât see this as evidence that low LDL somehow caused their heart attacks.
âFurthermore, the more selective PCSK9 inhibitors didnât reduce all cause or even cardiovascular mortality rates.â
The two PCSK9 inhibitors approved for use in the USA decrease cardiac events and mortality, per the most recent Cochrane meta-analysis below. Important to note that the minimum length of trials was only 6+ months (!!!). Arterial plaque takes decades to build up, so positive effects on vascular disease should only get more substantial over time.
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So that study that you posted showed an absolute risk reduction of 1%!
They concluded â evidence in low-to-medium risk settings is Minimal â.
When assessing benefits/ risks:
â This suggests careful consideration of Alternative lipid lowering treatments before prescribing PCSK9 inhibitors â.
Hardly a ringing endorsement.
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I agree with you.
The amount of evidence that lower LDL-C is good is frankly stupendous compared to the opposite, in the number of studies, length of studies, size of the cohort, quality, etc.
LDL is simply not something I am willing to ignore just because I am taking rapamycin.
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Speaking of which:
Thatâs encouraging, but itâs taken 40 years to identify cognitive impairment with statins. Regardless, we both agree that in a high risk group such as that , the benefits exceed the risks.
Weâre talking about the typical low to medium risk person with an elevated LDL from rapamycin. Thereâs no evidence for a significant total mortality risk reduction in that setting from interventions. Medications almost always have significant side effects that show up sooner or later and serve to surprise us. The benefit/ risk doesnât work in that setting.
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Absolute risk reduction of 1% over a relatively short period of time, relative risk reduction much larger, and thatâs on top of statins, and the effect size is likely to increase over time.
The thing is, that previously âlow to moderate riskâ person could become âhigh riskâ over years/decades because now his LDL is high. Maybe rapamycin will prevent the LDL from causing plaque buildup at whatever dosing regimen is being used, maybe it wonât. Rather than put my faith in rapa with limited evidence, seems prudent to safely lower that elevated LDL now.
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Absolute risk reduction is more informative than relative risk.
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You have no idea that the low risk person will become high risk. It depends on a whole host of other variables. Youâre ignoring diet, exercise, family history, diabetes, obesity,stress, sleep, inflammation, and hypertension, while saying that the person with an elevated LDL, whatever that number may be, will become high risk for heart disease.
In my humble opinion thatâs a vast oversimplification of a complex disease.
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On another note. Yet another variable in the atherosclerosis picture is virally induced atherosclerosis via immunosenescence. But what can we do about it? Regardless, this infectious hypothesis is gaining steam.
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Itâs useful if the goal is to psychologically minimize the effect of a particular intervention. If I had a 5% chance each year of a heart attack and intervention X reduced risk by 20% relative/1% absolute but when I was considering the treatment I only saw the 1% absolute risk in isolation, I might be mistakenly convinced that the treatment is worthless when in fact it might reduce risk to a similar degree as increased exercise, weight loss, etc.
Yes Iâm ignoring all those other things because the topic is rapamycin and LDL, not exercise/stress/sleep/diet/hypertension. I said if you raise LDL w/rapamycin, it could raise that person into a higher risk category and over years/decades result in plaque buildup and vascular events. Safely knocking down that LDL has no downside IMO.
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