#2972

Yes. That’s what they did in the landmark Systolic Blood Pressure Intervention Trial (SPRINT) to show that intensive blood pressure control reduces cardiovascular morbidity and mortality. You want to see if there’s a tradeoff between intensive control (whether BP or LDL) and other adverse events. Actually, there are ongoing or planned trials doing just that:

We’ll only get the results in a few years, unfortunately. So I guess it’s up to anyone to decide whether they want to choose the intensive control now (and potentially re-evaluate their choice later if the trials conclude that intensive control is detrimental) or choose the “conventional control” and similarly re-evaluate their decision later as we gather more data on intensive control.

(for whatever reason, all the above trials are done in China, South Korea and Japan: are Westerners not interested in this?!)

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#2973

67% achieved an LDL of 40 mg/dl or lower in the Evolocumab trial.

And the Alirocumab trial did use that approach to target an LDL of 25 to 50 mg/dl but above 15 mg/dl:

Among patients assigned to the alirocumab group, protocol-specified dose-adjustment algorithms14 were used to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter) and to avoid sustained levels below 15 mg per deciliter (details can be found in the Additional Information on the Methods and Results section and in Figs.

https://www.nejm.org/doi/full/10.1056/nejmoa1801174

So we already have that data. And a post hoc analysis of Alirocumab did detect a decrease in all-cause mortality. What do you think of this?

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#2974

No misunderstanding: I didn’t think you were trying to use these interventions to lower apoB. You are objecting that “we don’t have very good long-term intervention study data for all cause mortality data or side effects for lowering apo b to very low levels with current pharmaceuticals,” and I’m pointing out that e don’t have any long-term intervention study data for all cause mortality data or side effects for nearly any of the other things you’re suggesting as alternative ways to hold off CVD. With the exception of an EVOO-rich Mediterranean diet, all we have for these other things is epidemiology and short-term intervention studies with surrogate outcomes instead of deaths or CVD events. And again, in the case of K2, the even the surrogate outcome trials have almost to a one failed.

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#2975

I’ve only skimmed through the article and I may have misunderstood it (please correct me if I’m wrong) but I don’t think we have that data, at least based on this paper. Precisely because the people in the trial “had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter)” and they were given a placebo. So per Figure 1, the placebo group started at ~90 mg/dL and ended at 103 mg/dL:

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So of course the group treated to have LDL below 70 did better! What we want, to be able to conclude on <70 vs <55 mg/dL as a target, is for the second group not to receive the placebo but to reach the <70 target. Also, note that the group treated with alirocumab did not reach the <50 target. Especially the plain line was barely under 70. That line includes “premature discontinuation of the trial regimen”: why did these people quit? Because of side effects? If we had a trial of intensive control, the intensive control arm would HAVE to be below <50, using additional interventions (ezetimibe, bempedoic acid, changing statins to rosuvastatin, etc.). It’s only then that we can conclude on the potential benefits and tradeoffs of intensive LDL control.

This trial just shows that people at very high risk (previous acute coronary syndrome) who use alirocumab and don’t stop using it do better than their peers who only use statins and have LDL around 100 mg/dL. Not really a big learning, is it?

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#2976

Thanks, but I don’t understand why we need a clinical trial where the control group has LDL of <70 mg/dl and an active group <50 mg/dl. Why can’t you just compare achieved LDL levels and see the risk on events, etc?

See this study:

There is a consistent relative risk reduction in major vascular events per change in LDL-C in patient populations starting as low as a median of 1.6 mmol/L (63 mg/dL) and achieving levels as low as a median of 0.5 mmol/L (21 mg/dL), with no observed offsetting adverse effects.

If you combine it with median achieved LDL below 50 studies, the post-hoc regression of plaques studies, it suggest to me we do have enough data. The linear relationship between achieved LDL and RR reduction continues to even lower levels.

1 Like
#2977

Thanks for all of this color @scta123 and @L_H

I think we know have heard each other and for my part I’m content in agreeing they there still is some agreement and some disagreement and just see what new data comes out in the months and years ahead of us.

Just to be clear that I’m not just following Attia, rather a “lower is better” view that seems to be something that more and more experts are believing in - even if I agree that the slow moving guidelines are not there (yet?).

For instance, top Prof at a very conservative institution:

“The lower the LDL, the better,” says Professor Eugene Braunwald, MD, distinguished Hersey Professor of Medicine at Harvard Medical School, faculty dean for academic programs at Mass General Brigham and cardiovascular medicine specialist at Brigham and Women’s Hospital. “You can’t have too low an LDL." (quote from recent feature in MIT Technology Review)

And

· Cholesterol: the race to the bottom (Cholesterol: the race to the bottom | European Heart Journal | Oxford Academic)

· Chasing LDL cholesterol to the bottom—PCSK9 in perspective (www.nature.com/articles/s44161-022-00085-x)

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#2978

We need an RCT because that’s the only way to have a definite answer. I guess that’s why the national guidelines haven’t been lowered yet, contrary to hypertension.

Because if we look at the achieved LDL levels then in the alirocumab trial it’s 66 mg/dL vs 103 mg/dL. And of course 66 is better than 103. We want the same trial but with at the end let’s say 50 vs 66. And see whether people on 50 do better, including on side effects, not only the primary end point of MACE.

Because otherwise in all meta analyses the people who have higher LDL are those who have higher risk, so no wonder they do worse! You do a trial where you give the same dose to everyone, let’s say 5 mg rosuvastatin, yes of course the guy who ends up at 50 mg/dL does better than the guy at 70 mg/dL post treatment (the AUC of the first one over the course of their life before the trial must be so smaller as well). And they both do better than the guy who stops the treatment because of side effects and is at 100 mg/dL. But what if you give ezetimibe to the guy at 70 mg/dL to bring him to 50? And what if you switch the statin intolerant one to PCSK9i and/or something else to bring them to 50? That’s what we want to see.

I assume that “lower is better” is probably the good conclusion, but in the absence of an RCT between the two strategies, I’m not sure clinical practice will change.

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#2979

Re the approach to decision making.

For me the main goal is mark risks of stroke and hear attach in 3-6 decades from now…

… for that I don’t think we’ll ever get a RCT

So we have to use the whole Medicine 3.0 and triangulate between what data and what mechanistic data we have in totally and just make the best calls we can and then be ready to adapt along the way as new data comes out (even if that data will never be perfect).

The difference for me when it comes to (a) cardiovascular disease and to some extent (b) metabolic disease vs eg (c) cancer, (d) neurodegenerative disease, and (e) longevity is that we understand the mechanisms in (a) (and to some extent in (b)) much better than in (c) to (e).

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#2980

I agree with you.

By the way, the latest European guidelines (from 2019) have the following targets: “<1.4 mmol/L (55 mg/dL) in very high-risk groups, <1.8 mmol/L (<70 mg/dL) in high-risk groups, a goal of <2.6 mmol/L (<100 mg/dL) in moderate-risk groups and a goal of <3.0 mmol/L (<116 mg/dL) in low-risk groups”. They’ll update them next year. Will be interesting to see if they lower the thresholds for all groups. (Or they could change the definition of "low-risk group?) I don’t know when the 2018 American guidelines will be updated.

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#2981
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#2982

I am proud to be enhanced.

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#2983

I’m surprised that at the end (9:08), he says about bempedoic acid: “it’s possible that this type of therapy will eventually replace statins”. Indeed, it seems that it reduces apoB and LDL by only 20–25% and that it might not have effect on MACE and mortality:

On the other hand, “Statins have the most consistent evidence for the prevention of cardiovascular complications with a relative risk reduction of about 25% for MACE and 10% to 15% for mortality.” So… did I miss something? Why is he so bullish on BA?

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#2984

Probably because BA is a targeted drug that reduces LDL and does not cause myopathy. For those that are statin intolerant, like myself, it’s the only real choice that doesn’t break the bank. So, I pair it with Ezetemibe for better effect.

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#2985

That’s as would be expected: we only have a limited number of very short-term trials on BA, some of them not powered for hard outcomes and none of them powered for total mortality. Their formal Phase 3 CVD outcomes trial demonstrated that MACE risk was "significantly lower with bempedoic acid than with placebo (819 patients [11.7%] vs. 927 [13.3%]; hazard ratio, 0.87; 95% confidence interval [CI], 0.79 to 0.96; P = 0.004), as were the incidences of a composite of death from cardiovascular causes, nonfatal stroke, or nonfatal myocardial infarction (575 [8.2%] vs. 663 [9.5%]; hazard ratio, 0.85; 95% CI, 0.76 to 0.96; P = 0.006); fatal or nonfatal myocardial infarction (261 [3.7%] vs. 334 [4.8%]; hazard ratio, 0.77; 95% CI, 0.66 to 0.91; P = 0.002); and coronary revascularization (435 [6.2%] vs. 529 [7.6%]; hazard ratio, 0.81; 95% CI, 0.72 to 0.92; P = 0.001). "

Some of the metas you cite don’t even include their Phase 3 hard outcome trial, so unsurprisingly they don’t find an effect on hard outcomes. In others it’s diluted. It’s not clear how many patient-years are reflected in the umbrella systematic review on statins you cited, but e.g. the Cholesterol Treatment Trialists’ (CTT) Collaborators meta-analysis of statins in low-risk patients had 134,537 people in it with a median follow-up of 4·8 years, versus a “total of 3956 patients and follow-ups of four to 52 weeks” in the 2022 BA meta you cite.

This is the nature of diseases of aging: it takes a long time and a lot of people to demonstrate reductions in total mortality, in substantial part because of competing risks. As Attia often emphasizes (and others in this thread have done), you are never going to get the kind of trial we want to prove the use of these drugs for their best potential (true primary prevention people not at high 10-year risk): you have to go from the data we have and the understanding of the causal relationship between exposure AUC and the pathogenesis of the disease.

Attia’s specific enthusiasm is because of the lack of myopathy and lack or dramatically lower risk of diabetes compared to statins.

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#2986

@adssx have you seen the paper(s) that @AnUser has shared in the past on how all cause mortality is not often part of the design of trials and why it generally should not be - because they would need to be orders of magnitudes larger and longer.

The math is counter intuitive so you have to give it some reading and reflection to internalize it.

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#2987

(it’s not Attia but Brad Stanfield) So you think that bempedoic acid could replace statins as the first line treatment for mild high LDL because of the lower side effects, despite the lower efficiency vs statins? But why bempedoic acid specifically and not PCSK9i?

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#2988

Haven’t seen them. Would love to read them. But besides all cause mortality, bempedoic acid is not impressive just in terms of LDL reduction so again, I don’t get why Brad Stanfield seems so excited about it (unless he meant all non-statin therapies?).

#2989

Think it’s this one

Should a Reduction in All-Cause Mortality Be the Goal When Assessing Preventive Medical Therapies?

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.116.023359

I’m not sure what Brad is saying, I hardly ever find it valuable to watch his stuff. And def would not expect him to be deep and provide new perspective on cardiovascular disease.

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#2990

PCSK9i is injectable so it’s a different in a significant way imo.

Since you care about hepatoselectivity I think, I think a similar reason is why bempedoic acid might be seen as a replacement. The selectivity for action in liver should minimize possible side effects like on brain cholesterol levels. If you add ezetimibe which is similar as in Nexlizet, it isn’t that large of a difference between it and a statin. Combined with PCSK9 inhibitor like Attia does and apoB is most likely in optimal levels.

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#2991

Yes, I can’t wait to have more data on ezetimibe + bempedoic acid to start using them!

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