A previous episode of Sigma Nutrition Radio (episode 321) provided an opportunity to have a real-time discussion about lipids and risk, and in particular to discuss the concept of the ‘lipid triad’ proposed by the show guest, Dave Feldman.
Dave has become one of the most prominent voices in the low-carbohydrate, high-fat (LCHF) community, and Dave is particularly interested in the risk (or lack of) of elevated low-density lipoprotein (LDL), when it is observed in the context of high levels of high-density lipoprotein (HDL), and low triglycerides (TGs). This combination of high LDL, high HDL, and low TGs, is what Dave has termed the ‘lipid triad’.
9/ 8:25 Danny lets me set up and kick off the discussion.
(a) I intro "Atherogenic Dyslipidemia" (⬇️HDL+⬆️TG+⬆️sdLDL)
(b) Many going #LowCarb see the reverse of this, which is what I usually refer to when I say "triad" (⬆️LDL+⬆️HDL+⬇️TG)
— Dave Feldman (@DaveKeto) February 26, 2020
This combination is commonly reported anecdotally from the LCHF community, as a response to going on an LCHF diet. The conversation with Dave in SNR episode #321 provided a lot of food for thought, and in the following written segment we have attempted to take Dave’s case at its highest based on the points made in the podcast, and address key aspects of the argument by reference to the current literature. Previous 'Sigma Statements' on lipids, diet & CVD (available here) give a more general overview of our position. The goal of this article is to zero in on some specific points made in the podcast episode with Dave.
So rather than go into every individual point made in that discussion, this article will focus in on points Dave made in relation to four concepts:
- The ‘Lipid Profile-Centric Model'
- Atherogenic Dyslipidemia and the ‘Lipid Triad’
- Remnant Lipoproteins
More specifically, Feldman makes the following claims:
- LDL-C and ApoB-containing lipoproteins are a part of the process of atherosclerosis but are not necessarily the initial cause.
- In the context of high-HDL/low-TGs, LDL-C has much less association with atherosclerosis.
- Lowering LDL in the context of the Lipid Triad could have downsides in non-ASCVD related risks, such as infection or cancer. Hence he advocates looking to all cause mortality to confirm a net benefit.
- In those with high LDL-C but low remnants, LDL-C would likely associate with less atherosclerosis.
- In the context of low inflammation, elevated LDL may associate much less ASCVD risk.
The ‘Lipid Profile-Centric Model'
Dave proposes what he calls the "lipid profile-centric model" as an alternative the widely-accpepted consensus viewpoint in lipidology and cardiovascular sciences (which Dave labels a "lipoprotein-centric viewpoint"). The proposed model was mentioned in the podcast episode:
Dave Feldman [10:37]: "I think conventional medicine, especially in lipidology has a kind of lipoprotein centric viewpoint which is to say that lipoproteins are themselves pathogenic or in particular at least Apo B containing lipoproteins, LDL particles especially that they themselves at a certain concentration level will drive atherosclerosis. And what I sort of want to put on the table is something that I would call a kind of lipid profile centric model, which is to say that I want to distinguish how much it is that a lipid profile drives the disease especially of atherosclerosis or whether or not it's the disease that drives the lipid profile..."
The first key point to note here is Dave’s suggestion that conventional medicine has a "viewpoint" that ApoB-containing lipoproteins (especially LDL) “at a certain concentration will drive atherosclerosis." This phrasing suggests that the causal role of ApoB (and LDL) in driving atherosclerosis is simply a competing hypothesis, with as much claim to be correct as others. But this is just not the case. Within the lipidology and cardiovascular sciences community, that LDL-C and ApoB-containing lipoproteins drive atherosclerosis is not considered a mere “viewpoint”, but rather an established fact with sufficient proof to deem LDL-C causal.
Conversely, Dave claims that while ApoB-containing lipoproteins and LDL-C are a part of the overall process of atherosclerosis, they are not necessarily the initial cause.
In looking at the issue of causality in a scientific context, "whether the disease drives the lipid profile…”, and whether LDL-C/ApoB are the initial cause, we can look to specific criterion from the 9-criteria Bradford-Hill test for establishing causality. Three of particular relevance here include:
The temporal relationship between high blood cholesterol levels and cardiovascular disease (CVD) is well established in prospective cohort studies indicating that in disease-free participants at baseline, exposure to increasing LDL-C concentrations precedes increased risk of atherosclerotic cardiovascular disease events.
The Prospective Studies Collaboration, (which included 892,337 participants from 61 prospective cohort studies free from cardiovascular disease (CVD) at baseline, a collective 11.6-million person-years at risk during which 33,744 ischaemic heart disease deaths occurred) found a pronounced and linear increase in ischaemic heart disease deaths mortality over time. From a temporality perspective, the association increased with age at-risk, such that the effect of exposure to 1.0mmol/L lower LDL-C in the 40-49yo age bracket was associated with 56% (HR 0.44, 95% CI, 0.42-0.48) lower risk for ischaemic heart disease mortality.
This almost mirrors the evidence from Mendelian randomisation studies on genetic exposure to lifelong lower LDL-C levels, where there is a 54% relative risk reduction of coronary heart disease (95% CI, 0.41-0.52) per each 1.0mmol/L lower long-term exposure to LDL-C was.
Finally, the temporal relationship between exposure to higher LDL-C and atherosclerosis is confirmed by the evidence from Familial Hypercholesterolaemia (FH), which irrespective of the underlying mechanism (i.e., different genetic defects in LDL-receptor function), results in profoundly elevated LDL-C concentrations, early and rapid development of atherosclerosis, and early mortality from coronary artery disease if left untreated.
More particularly from the perspective of whether the process is initiated by LDL-C/ApoB, it is instructive to consider physiological requirements. Both hunter-gatherer humans and non-human primates naturally have very low levels of total cholesterol of <3.1mmol/L [120mg/dL] and consequently LDL-C of often <1.8mmol/L [70mg/dL]. The LDL-receptor becomes saturated at 0.06mmol/L [2.5mg/dL]. This means that the physiological maximum for total circulating LDL-C is around 0.6mmol/L [25mg/dL], i.e., any more than that is surplus to actual cellular requirements. Tissue requirements for cholesterol, for growth and development, are highest in newborn infants and early development: in this critical development phase and period of rapid tissue growth, mean LDL-C levels of 0.7-0.8mmol/L [28-32mg/dL] are sufficient. At thresholds of ~1.8mmol/L [70mg/dL] or under, evidence of atherosclerosis is virtually absent, and under this threshold is where reversal of atheroma has been demonstrated in interventions, indicating reversibility [a key aspect of the Bradford-Hill criteria discussed further, below]. Consequently, there are clear thresholds of circulating LDL-C/ApoB beyond which the process of atherosclerosis is initiated by the retention and accumulation of LDL-C within the arterial intima. It is this initial injury which triggers subsequent responses, including inflammation, oxidation, macrophages phagocytosis, etc. The risk of increasing levels, or the existence of a dose-response, will be discussed next.
The biological gradient, or dose-response, is evident in every line of evidence. The prospective studies have indicated a strong relationship between increasing CVD risk with increasing exposure to LDL-C. This relationship is confirmed by meta-analysis of statin intervention studies, where the relative risk per unit increase in LDL-C increases in linear fashion. What the temporal relationship displays is the effect of a cumulative exposure over time; demonstrating LDL-C as the primary causal factor driving the processes of atherosclerosis. In particular, if LDL-C is the primary causal factor, then reversibility should be evident, i.e., does reducing the exposure change the incidence of disease.
This change in disease incidence by reducing the exposure is precisely what is shown, irrespective of the method of reduction. So looking at drug targets, we can consider:
- HMGCR: The target of statins
- NPC1L1: The target of ezetimibe
- PCSK9: The target of PCSK9-inhibitors
Statins reduce the risk of CVD by approximately the same amount per unit reduction in LDL-C that would be predicted from MR studies. The same is true for variants in the NPC1L1 gene, which is the target of the drug, ezetimibe. Per unit reduction in LDL-C, variants in both NPC1L1 and HMGCR have a near identical effect on lower CVD risk. Intervention shows what would be anticipated from genetic predictions; IMPROVE-IT demonstrated that the 20% reduction in risk for vascular events after 6yrs from ezetimibe and the achieved reduction in LDL-C 0.33mml/L (12.5mg/dL) is exactly what would be predicted from the same duration of treatment and same level of LDL-C reduction from statin interventions (18%).
Effect of PCSK9 variants on reduced risk is the exact same as both HMGCR and NPC1L1; again, the implication is that PCSK9-inhibitors and statins should have the same effect on risk of CVD events per unit reduction in LDL-C. This is exactly what interventions show; FOURIER used a PCSK9-inhibitor, reduced LDL-C by 54mg/dL and resulted in a 17% reduction in CVD events after 2-years. This effect size in this duration is exactly what would be expected from a statin intervention achieving the same level in the same duration. Both of these effects have been predicted precisely through MR.
In the above graph from Ference et al., there is a stark difference in the slopes of the two lines: the top line representing genetically lower LDL-C, and the bottom line representing trials in which LDL-C was lowered pharmacologically. The difference in the slopes of the lines showing that the relative risk reduction at a given LDL-C reduction is not as pronounced for drug interventions as it is for the genetic variants causing the lower LDL-C. This is explained by considering the length of exposure to lower LDL-C:
- In drug intervention trials the mean age at the outset is 63 years old; so previous to this, LDL-C was much higher.
- Whilst the genetic variants mean lifelong exposure to lower levels.
Therefore, genetic exposure to lifelong low LDL-C levels is associated with a 3-fold greater reduction in risk than treatment with a statin later in life. Hence why the effect is greater. The clinical benefit of lowering LDL-C seems to be determined by both the absolute reduction in LDL-C and the total duration of exposure to lower LDL-C.
Thus, convincing evidence exists that lowering the exposure reduces the incidence of CVD. In particular, there is no evidence of a threshold to benefit in reducing LDL-C, with levels of <1.29mmol/L (<50mg/dL) demonstrating the most pronounced reductions in risk from statin interventions compared to each incrementally higher category.
The recent FOURIER trial pre-specified for analysis of progressively lower LDL-C levels and clinical outcomes; there was a linear relationship between progressively lower LDL-C and CVD outcomes, with the lowest pre-specified subgroup median of 0.36mmol/L (13.8mg/dL). A quarter of this group achieved on-treatment levels on 0.18mmol/L (6.9mg/dL), with no evidence of adverse effects.
A ‘look under the hood’ in relation to reversibility was provided by the ASTEROID trial, in which high-intensity statin therapy reduced LDL-C from 3.3mmol/L (130mg/dL) to achieved levels of LDL-C 1.5mmol/L (60mg/dL), and reduced atheroma by >50%. Image below compares cross-section at baseline (left) and after 24 months of treatment (right).
The GLAGOV trial similarly demonstrated no threshold to benefit in profound reductions in LDL-C, directly related to the magnitude of coronary atheroma regression. The most important point regarding reversibility is that to achieve regression of coronary atheroma, on the basis of the current evidence, a LDL-C of <1.8mmol/L (<70mgd/dL) is required.
- Temporality: exposure to LDL-C precedes incidence of CVD.
- Biological gradient: increasing levels of the exposure increases incidence of CVD in a dose-dependent manner.
- Reversibility: Lowering LDL-C reduces risk for CVD morality and events in a dose-dependent manner, with no evidence of ceiling thresholds to benefit of lower levels.
LDL-C and ApoB-containing lipoproteins are a part of the process of atherosclerosis but are not necessarily the initial cause.
The totality of evidence supports that the atherogenic lipoproteins, in particular LDL, are in the causal pathway driving - i.e., initiating and progressing - atherosclerosis.
Atherogenic Dyslipidemia and the ‘Lipid Triad’
The ‘atherogenic lipoprotein phenotype’ (ALP) is a well-characterised clustering of cardiometabolic risk factors, in particular low-HDL/high-triglycerides (TGs), and a prevalence of small, dense, LDL particles. The contention Feldman seems to offer in support of the "Lipid Triad" is that, as the ALP is known to be atherogenic, if the reverse is the case (i.e. high-HDL and low-TGs), then perhaps this is protective or at least a much less risk:
Dave Feldman [08:54]: “Atherogenic dyslipidemia is typically characterized by having low levels of HDL cholesterol, high levels of triglycerides which is a measure of fat in the blood, and typically a high preponderance of small LDL particles. Now, what's fascinating is that we find within the low-carb community many people who go on a low-carb diet see an almost exact reverse of that, they tend to see that their HDL cholesterol will go up, their triglycerides will go down, and separately their LDL may also increase…”
The second - and cornerstone aspect of Feldman’s argument - is that there may be potential risk for other non-CVD diseases from proactively lowering LDL-C, in particular increased cancer risk, which is illustrated by this quote:
Dave Feldman: “And that's what I think is a major disconnect that I'm anxious to have this possibility that's being put on the table to be disproven, that if you reduce LDL – or for that matter that when we look at populations that have low LDL and they have higher rates of cancer and it doesn't seem to be just within a few years of the study, but within half a decade, a decade later."
We will address both claims in turn, starting with the contention that in the context of the Lipid Triad, LDL-C confers less risk of atherosclerosis.
The first aspect to clarify is the difference between independent causal risk factors and systems biomarkers. This is fundamental to any analytical process which views a number of biomarkers together:
- Independent risk factor: biomarker in a causal pathway between the exposure and outcome.
- Systems biomarker: biomarker which provides indications of underlying cardio-metabolic processes, but are not causal independently.
Both HDL and triglycerides are appropriately classed as systems biomarkers; neither are causally associated with CVD in themselves. Neither intervention studies or Mendelian randomisation studies suggest a causal role for HDL with regard to CVD, although epidemiological data consistently suggests a protective effect of higher HDL. Triglycerides are a particularly important systems biomarker; high-TG can provide an indicator of increasing remnant cholesterol levels, increased secretion of VLDL, and precipitate remodelling of HDL and LDL. However, independent associations with TGs are no longer evident once adjusted for non-HDL-C (note: non-HDL-C is the cholesterol content of ApoB containing lipoproteins, namely VLDL, VLDL remnants, IDL, Lp(a) and LDL). This was confirmed in a recent analysis of genetic variants in TGs which found that once TGs were adjusted for ApoB, the independent relationship with TGs was no longer evident. Collectively, this demonstrates that it is the levels of atherogenic lipoproteins within the measure of TGs which relates to risk.
While observational studies suggest a protective effect of high-HDL/low-TGs, this effect appears to be most pronounced when LDL-C remains below <3.3mmol/L (<130mg/dL). Feldman's view of the "lipid triad" suggests that in the context of high-HDL/low-TGs, the larger LDL particle size means LDL has a lower atherogenic potential. However, the predominance of LDL-I and LDL-II (i.e., the largest LDL particles) in individuals with low plasma TGs results in rapid clearance of LDL-C from circulation, and is therefore characterised by low LDL-C levels (~2.5mmol/L or 100mg/dL). This is lower by orders of magnitude compared to the levels of LDL-C often anecdotally reported from the LCHF community. The only available data of very high LDL-C concentrations in the context of low-TGs is that in homozygous FH, in which both HDL and TGs are in normal range: the accelerated development of atherosclerosis and coronary artery disease relates to LDL-C. This again indicates the difference between a causal, independent risk factor that is a direct target for treatment (LDL-C) and correlated biomarkers that may report on cardio-metabolic function, but are not independent causal factors themselves.
This discrepancy may be observed in the Framingham Offspring Study, in which CVD risk relative to low HDL-C was stratified by levels of LDL-C and TGs. In this study, the statistically significant protective effect of high HDL-C was no longer evident when LDL-C and TGs exceeded 2.5mmol/L [100mg/dL] and 1.1mmol/L [100mg/dL], respectively. More particularly, comparing high HDL-C and TGs <1.1mmol/L [100mg/dL] with LDL-C levels of either >3.3mmol/L or <3.3mmol/L [130mg/dL], the higher LDL-C level was associated with greater risk. This supports that increasing LDL-C confers an increase in CVD risk, and while the magnitude of risk may be mediated by the levels of related biomarkers, that risk is nonetheless independent of these factors, i.e., risk increases consistent with the biological gradient elucidated above. Thus, while LDL particles do possess varying degrees of atherogenicity, the fact remains that all LDL particles are atherogenic.
In this context, for the ‘lipid profile’ to be true, i.e., for LDL-C to less association with atherosclerosis, it must demonstrate that high LDL-C alone does not increase risk for CVD, independent of its relationship to other correlated biomarkers. Establishing this would mean providing sufficient evidence to rebut the body of evidence supporting LDL-C causality itself, including:
- over 200 prospective cohort studies
- randomised controlled clinical intervention trials with a collective two-million participants
- 20-million person-years of follow-up during which over 150,000 CVD events occurred
- Mendelian randomisation studies on genetic predispositions to elevated or reduced lifelong exposure to LDL-C
- Mechanistic research supporting the underlying pathology
Nonetheless, the second limb of the triad is an important consideration - does lowering LDL-C, while reducing CVD risk, potentially increase risk for other conditions, with particular reference to cancer? The relevant question in this regard is whether low LDL-C - or deliberately lowering LDL-C - is causally related to cancer. The association between low LDL-C levels and increased risk for cancer has been evident in the literature. For example, Alsheikh-Ali et al. conducted a meta-analysis large clinical trials of statins, in which low LDL-C levels in the intervention group achieved through reductions from statin therapy, and low LDL-C levels in the control group receiving no therapy, were both associated with a significantly higher risk of cancer diagnosis. The similar rates in the intervention and control group are critical, as it indicates that lowering LDL-C through statin intervention is not the cause of increased cancer risk. One explanation for the relationship between low LDL-C and cancer is what Rose and Shipley termed the “unsuspected sickness phenomenon”, characterised by an underlying undiagnosed disease, like cancer, lowering cholesterol levels, i.e, it is the metabolic consequence of unsuspected disease. In a case-control study of the Framingham Heart Study Offspring Cohort, LDL-C values were lower in participants with cancer than matched controls at each point of assessment over an average of 18.7yrs prior to diagnosis, indicating that low LDL-C levels predate diagnosis. The question is whether this is an indicator, or causal. Feldman suggested in the podcast that even with elimination of early follow-up, the association persists. However, it is important to note that in most studies, elimination of early follow-up attenuates the results - although the association is not entirely abolished. Thus, the time course of diagnosis relative to incidence of cancer is important. Rose and Shipley found that after exclusion of 2yrs follow-up, the relationship between low cholesterol and cancer was no longer evident. Tornberg et al. examined both cancer incidence and mortality relative to blood cholesterol levels, and found that the relationship between low cholesterol levels and cancer incidence and mortality was strongest with the first 2yrs of follow-up, suggesting a pre-clinical cholesterol-lowering effect of undiagnosed cancer. The inference from this data was that hypocholesterolemia would be most pronounced when measured before the time of death from cancer than before a diagnosis i.e., the relationship reflects a pre-clinical metabolic effect of underlying cancer rather than a causal relationship between lowering cholesterol and cancer incidence.
Benn et al. conducted a Mendelian randomisation study examining whether genetic exposure to lifelong reduced LDL-C levels is causally linked to an increased risk of cancer, and compared these results to prospective data excluding initial 4yrs of follow-up. The Mendelian analysis demonstrated that lifelong lower LDL-C levels were not associated with cancer risk, indicating that low LDL-C per se is not a causal of cancer, however, in the prospective population comparison study lower LDL-C levels were associated with increased risk of cancer. In a recent study with ~half a million participants, time-lag analysis indicated that reverse causation explained some of the associations between lower cholesterol levels and cancer, however, this did not fully account for all of the associations. In addition, lipid-lowering therapies were not analysed.
Thus, while Mendelian randomisation and many time-lag studies indicate that the relationship between low cholesterol and cancer is not causal, there are relationships which are observed in other studies. This should be factored into an overall risk:benefit assessment. Our position is that the certainty of evidence for benefit to lipid-lowering clinical trials favours intervention. In support of this position, the Cholesterol Treatment Trialists' [CTT] meta-analysis of individual data including >90,000 patients from 14 trials randomised to statin therapy or a control group, demonstrated that in the 5,103 patients diagnosed with cancer after randomization, there was no evidence that lowering LDL-C by ~1.0mmol/L [~40mg/dL] over 5yrs increased the risk of developing a first cancer. The rate of diagnosis was identical - 6.4% - in both intervention and control groups, yielding a null relative risk comparing the groups of 1.00 [95% CI 0.95–1.06). This result has been bolstered by an updated CTT meta-analysis of 175,000 participants from 27 statin interventions demonstrating no increase in risk for cancer incidence or mortality. Of particular note, there were less cancer cases in participants with lower baseline LDL-C levels prior to the interventions, and lowering LDL-C with intensive therapy from 1.7mmol/L [65mg/dL] to 1.3mmol/L [50mg/dL] was not associated with cancer incidence or mortality. A similar null result in relation to deliberate LDL-C lowering was found for ezetimibe trials including 20,617 randomized patients, in which 313 cancer diagnosis were recorded in the intervention group and 326 among the control group,, yielding a risk ratio of 0.96 [95% CI 0.82-1.12]. Also of importance, Mendelian randomisation has demonstrated no causal effect on cancer mortality resulting from PCSK9 genetic variants.
- In the context of high-HDL/low-TGs, LDL-C has much less association with atherosclerosis.
- Lowering LDL in the context of the Lipid Triad could have downsides in non-ASCVD related risks, such as infection or cancer. Hence one should look to all cause mortality to confirm a net benefit.
- There are inverse relationships between cholesterol levels and cancer incidence evident in case-control and prospective studies;
- The strength of association is attenuated upon exclusion of early follow-up, suggesting pre-clinical cancer explains a degree of the association, but it is not eliminated, indicating a residual association;
- Mendelian randomisation studies indicate that low LDL-C per se is not the causal factor in cancer incidence;
- Deliberate LDL-C lowering through intervention with statins or ezetimibe is not associated with increased cancer risk, compared to controls.
Thus, while the residual associations in observational research warrant further investigation, we submit that the weight of evidence favours lipid-lowering, and the greater evidential certainty of benefit to lowering high LDL-C for CVD risk is bolstered by the lack of evidence from such intervention trials of any increased risk for cancer, when compared to controls.
The context of the ‘Lipid Triad’ acknowledges that the ALP presents a risk for atherosclerosis. Indeed, Feldman directly states:
Dave Feldman [19:58]: “... you probably have a higher preponderance of VLDLs, and that does tend to be associated with atherogenic dyslipidemia... And remnants are, as a profile, definitely highly associated with cardiovascular disease…”
However, this appears to be impossible to reconcile with the contentions supporting the 'Lipid Triad' that high LDL-C is not a risk for atherosclerosis; the broad functional properties of these lipoproteins, diameter size and presence of ApoB, means that to acknowledge that VLDL and/or remnants are atherogenic implicitly acknowledges LDL as such. In fact, recent evidence indicates that the risk is almost identical per unit increase in cholesterol:
The main case Feldman makes in relation to remnants is that in those with high LDL-C, but low remnants, LDL-C may be less of a risk for atherosclerosis. However, as can be seen from the illustration above, the risk for LDL-C mirrors that of remnant cholesterol per unit increases in circulating levels. It is important to note that in this study, the risk for myocardial infarction was evident whether the remnant cholesterol analysis was adjusted for LDL-C levels, or whether the LDL-C analysis was adjusted for remnant cholesterol levels. After this adjustment, however, LDL-C was a better predictor of MI. This indicates an independence of effects for both remnant cholesterol and LDL-C, with the implication that elevated LDL-C alone - without remnant cholesterol - remains a significant risk for heart disease.
What this indicates is that the cholesterol content of ApoB-containing lipoproteins is the common issue, and increasing the cholesterol content of remnants mirrors the risk related to increasing the cholesterol content of LDL on a per-unit basis. In the JUPITER trial, participants achieved a median LDL-C of 1.4mmol/L (55 mg/dL), with low triglyceride of 1.1mmol/L (102mg/dL). However, in the context of very low LDL-C levels, residual risk was driven by the cholesterol content of VLDL, not the TG content. In fact, no association was observed for TG measures, and changing TGs was not associated with risk.
In those with high LDL-C but low remnants, LDL-C would likely associate with less atherosclerosis.
Cumulatively, the data is consistent with the cholesterol content of atherogenic lipoproteins being the primary concern for atherosclerosis.
Importantly, analysis indicating that significant effects of LDL-C are observed after adjustment for remnants suggest that, even in the context of low remnants, elevated LDL-C remains a significant cardiovascular risk.
Dave Feldman [104:40]: “I've really seen a much stronger acknowledgement towards the process of inflammation and its association back with atherosclerosis. And again with full acknowledgment, as I did earlier, that we haven't yet been able to fully elucidate how much LDL particles initiate and progress the disease, but how much they are involved, how much inflammation for that matter and the inflammatory response is involved.”
We do not propose to address the statement that, "we haven't yet been able to fully elucidate how much LDL particles initiate and progress the disease…”, because this is largely addressed above: LDL is in the causal pathway initiating the process of atherosclerosis, and progressing the disease. The progression of disease, and the risk for disease, is strongly mediated by inflammation. High-sensitivity C-reactive protein (hsCRP) is an important systems biomarker, and a strong predictor of CVD risk. It is also a mediator of the clinical benefit associated with LDL-C lowering, and a number of excellent recent trials have elucidated the relationship between magnitude of risk reduction, and achieved levels of LDL-C and hsCRP.
The fundamental claim from Feldman in relation to inflammation and LDL-C is that, in the context of low inflammation, elevated LDL-C may associate much less with CVD risk. There are a number of intervention trials that have examined this relationship, and this literature suggests that for the most significant reductions in CVD risk, achieving both low LDL-C and low hsCRP is optimal.
In the SHARP trial, reductions in LDL-C reduced CVD risk independent of whether baseline levels of hsCRP were >3mg/L or <3mg/L. In FOURIER, treatment with a PCSK9-inhibitor reduced CVD risk independent of baseline hsCRP, in participants stratified by baseline hsCRP <1mg/L, 1-3mg/L, and >3mg/L, respectively. However, the greatest clinical benefit was observed in those participants with highest baseline hsCRP levels, and the greatest reduction in risk was observed in patients with both the lowest LDL-C and hsCRP levels. JUPITER recruited participants with baseline LDL-C of <3.3mmol/L (<130mg/dL) and hsCRP 2mg/L, however, although there was some degree of improvement in inflammatory markers, the magnitude of CVD risk reduction related to achieving LDL-C levels of <1.8mmol/L (<70mg/dL). This suggests a threshold effect by which residual risk from either inflammation or LDL-C may persist.
This is precisely what was shown in both PROVE-IT and IMPROVE-IT, where the greatest magnitude of effect in reducing CVD risk was derived from achieving both an LDL-C <1.8mmol/L (<70mg/dL) and hsCRP <2mg/L. Of critical importance is the fact that there is no evidence that elevated LDL-C with low hsCRP is not a risk, i.e., that (as suggested by many in the LCHF community) LDL-C is only potentially atherogenic in the context of high inflammation. This is clearly not the case in the evidence from well-conducted, large, intervention studies. Where LDL-C remains >70mg/dL but hsCRP is <2mg/L, there remains ‘residual cholesterol risk’ that is equivalent to if <70mg/dL but hsCRP is <2mg/L.
This is demonstrated in the figure on the right, below: the yellow and orange lines [which run parallel] indicate the relative risk reduction of vascular event in participants in IMPROVE-IT who achieved either an LDL-C level of <70mg/dL or hsCRP level of <2mg/L, but not both [which is represented by the red line]. Although the relative risks overlapped, there was 17% [HR 0.83, 95% CI 0.75-0.91] reduction in risk from lowering only LDL-C to <70mg/dL compared to an 11% reduction [HR 0.89, 95% CI 0.79-0.99] in risk from lowering only hsCRP to <2mg/L. This indicates that even in the context of low inflammation, elevated LDL-C confers a significantly higher risk compared to lower LDL-C levels.
An important factor in the trials mentioned above - SHARP, FOURIER, JUPITER, PROVE-IT, IMPROVE-IT - is that these were not direct tests of the effects of lowering inflammation; hsCRP was an additional measure in the context of lipid-lowering therapy. The first trial to specifically address inflammation reductions with change in lipoproteins was the recent CANTOS trial, where patients in secondary prevention on lipid-lowering therapy and achieved LDL-C in the 1.8mmol/L (70mg/dL) range, were assigned to an anti-inflammatory drug or placebo. Profound reductions in hsCRP, without altering any lipid parameter, led to a significant 25% reduction in CVD risk; the effect mirrors that observed in FOURIER, which used a PSCK9-inhibitor to achieve further reductions in LDL-C.
In the context of low inflammation, elevated LDL may associate much less ASCVD risk.
Cumulatively, these data indicate that the risk associated with LDL-C persists independent of inflammation.
However, inflammation is a strong mediating factor in the progression of atherosclerosis, and hsCRP is an important systems biomarker, particularly for identifying residual risk where LDL-C is low (<1.8mmol/L (<70mg/dL)), but hsCRP remains elevated >2mg/L. However, where hsCRP is <2mg/L but LDL-C remains elevated, the risk relates to the concretely established causal role of LDL-C in driving atherosclerosis.
- On review of some of the claims made in SNR #321, and subsequent follow-up review of the literature, we find no compelling evidence to support that in the context of high-HDL/low-TGs, very high LDL-C is not a risk factor.
- We are in agreement with the European Atherosclerosis Society, that the scientific criteria for established causality has been convincingly discharged in the relation to LDL-C, which is in the causal of pathway of atherosclerosis.
- In this context, LDL-C is an independent causal risk factor that is a target for treatment.
- This is in contrast with TGs and hsCRP, which are important systems biomarkers, but not causal factors.
- In particular, both TGs and hsCRP may be additional targets for treatment in the context of residual risk after LDL-C lowering to current target levels.
- While we acknowledge that high HDL appears to be protective in epidemiological data, the absence of evidence from intervention studies and lack of causal relationship evident in Mendelian randomisation studies do not support emphasis on independent effects of HDL in itself. Indeed, over-reliance on high HDL-C in the context of high LDL-C may be a misnomer for risk management.
This was a great summary of the current data. In regards to the claims about FH patients, it is of interest to note that not all FH patients develop CVD. I was recently made aware of this study: https://www.ahajournals.org/doi/10.1161/JAHA.114.001236
The first sentence of the Discussion section states that “No significant differences were noted in all‐cause mortality between the FH patients and the general Norwegian population except for a significantly lower SMR in the age group 70 to 79 years.”
This analysis seems to show a clear increase in CVD related death among younger FH patients but significantly reduced mortality among those FH patients that did not die young. What are your thoughts on this paper?
Thanks Zack! With regard to the registry study, the time period is largely within the statin era. Information on lipid-lowering therapy was only available for 68/113 deaths recorded, and of that 60 were on statins. We would infer that a majority of the cohort were on statins, hence no difference in overall mortality vs. the general population. With the young vs. old discrepancy, this is most likely attributable to survivorship bias.
Thanks. Though it is still of interest to know what is different about these long-lived individuals, especially since the mean LDL concentration among statin-treated patients was ~5mmol/L, which would still be considered high.
So what does one do? If ideal LDL-C is 70mg/dL or less, that would mean really cutting out fat. In my experience, fats of any type will increase LDL. So should one be vegan low fat or very low fat omnivore?
Cutting out fat completely is not necessary, nor recommended. The evidence is strong that saturated fat has the greatest influence on LDL-C levels, and substituting in PUFA in place of some of that saturated fat leads to reductions in LDL-C and therefore risk.
The recommendation is to have total saturated fat intake less than 10% of calories. This of course can be acheived whilst still consuming a moderate or even high total dietary fat intake.
Some individuals may be best served by being even more restrictive on saturated fat intake, for example those who have ApoE4 alleles. There is a significant diet x genotype interaction with those who are carriers of E4, with such people achieving significantly greater decreases in cholesterol and apoB when SFA is replaced with low GI carbohydrate on a lower fat diet. So this would be an example of a group who could benefit from lower total fat intakes, and certainly lower SFA intake.
Also those with heart disease or at high-risk, then a LDL-C goal of < 70 mg/dL is appropriate. For others who are not at high-risk, then a LDL-C of < 100 mg/dL is deemed to be fine. Additionally, on an individual basis, there may be even more fine-tuned risk assessment of looking at ApoB levels, rather than LDL-C alone. Which is something people can discuss with their doctor.
Great Summary!. My most recent overall numbers are not that bad, TG (93) HDL (88) & VLDL (15). However, My LDL numbers do not look so great (207) ouch.. I will see my cardiologist this week, waiting for what she recommends.
There was actually a response by Dave to this article here: https://cholesterolcode.com/a-dialog-on-the-lipid-triad-with-sigma-nutrition-radio/. I have to say that after being in the situation of having very high LDL, HDL and very low TG and doing research on it, the arguments don’t strike me as very convincing that LDL is causal. I’m not saying that it’s in fact not causal, only that the research doesn’t seem to be conclusive and yet the confidence in researchers seems unjustifiably high.
As I won’t take any gambles with my health, I will look into lowering LDL while staying on Keto (replacing SFA with MUFA for example). In the meantime I’m very much looking forward to this study: https://www.youtube.com/watch?v=vCy1ZdeUCyU which will be the first one to actually study this.
What exactly about the arguments are not ‘convincing’ to you? Bear in mind the entire cardiovascular sciences and lipodology communities are virtually unanimous on this issue [barring a few outlier naysayers, which is common to every field], and the body of evidence supporting causality encompasses every line of scientific inquiry available [epidemiology, interventions, genetics, pathology], all of which converge to the same conclusions. It’s the most conclusive body of evidence in biological sciences, which does not mean there are not nuances and stones left to unturn; the latter was all expressely addressed in the second EAS Consensus Statement led by Jan Borén. Your personal decision with your diet sounds prudent. The study you’re referring to will certainly be interesting! But it won’t have a control group, and isn’t an intervention per se. Hopefully the study contains true ‘LMHR’ types with LDL levels >300mg/dL, absent which I’m afraid with only one year there is too much room for a ‘false negative’, given atheroma progression is a cumulative, lifespan exposure.
Because I find it also plausible that high LDL is merely an indicator for other diseases like Dave is saying. Unfortunately almost all people in every western country these days have pretty unhealthy diets and lifestyles. (only 12% of US adults are metabolically healthy: https://pubmed.ncbi.nlm.nih.gov/30484738/). If we only study unhealthy people, it says nothing about the actually healthy ones.
‘I’m afraid with only one year there is too much room for a ‘false negative’ – yes they specifically addressed this in the video. It’s true this is obviously a limitation, but they are using very advanced technology for the measurements which apparently should already be useful after one year. In general though this is of course just a first pilot study with hopefully more to follow.
So the whole point of the totality of evidence is that it is evident that high LDL is not merely that indicator. When LDL-C remains <80mg/dL, atherosclerosis does not progress. This is line with non-human primate data. You're quite right that there is therefore something about modern lifestyles that brings LDL into ranges at which atherosclerosis can progress, but the pathology data shows this progression can start in the second decade of life years before any onset of disease. That is to say, LDL-C levels above a particular threhsold are themselves sufficient to drive atherosclerosis. This process is a cumulative, integrated exposure over the course of the lifespan, which is why CHD does not usually manifest until later in life.
Dave focused almost entirely on the atherogenic lipoprotein phenotype, as if no one else sees it. On the contrary, this phenotype is a widely acknowledged and recognised deleterious profile of dyslipidemia. But it is also understand why this phenotype emerges, and its relationship with metabolic disease. Within the scientific consensus, there is less emphasis now on particle size than perhaps 5yrs ago, due to the recognition that the primary factor is the "cholesterol payload" within the artery wall, i.e., larger particles carry more cholesterol, smaller carry less. Ultimate effect is relatively equivocal net cholesterol deposition.
I've spoken with Spencer Nadolsky about the study, his involvement is a positive and they have a reputable physician doing the CCTA scans who has worked on other interventions with plaque as an outcome.
‘LDL-C levels above a particular threshold are themselves sufficient to drive atherosclerosis.’ – but wait, how do you know that it’s the LDL-C actually causing this? As you said, it could just be something in modern lifestyle bringing this up. This something might cause LDL-C to go up, but also causing many other bad effects which in combination lead to speeding up CHD.
I guess where my bias comes from is not really believing that something that is so evolutionarily consistent would have such negative effects. Even fasting, which most people would consider very healthy, will raise LDL-C. The counter argument to that would be that the negative effect would show simply way too late for evolution to have an effect, but that leads me to my next point.
If you ask me directly, do I think LDL has an effect on CHD or not, I would say yes probably it does have some effect. But it’s probably a rather small effect for otherwise healthy individuals as in it’s necessary for CHD, but not sufficient. And someone with low inflammation, low TG and high HDL probably doesn’t have to worry about it as much and can still live a healthy life up to 100. I will further try to get tests for oxidized LDL and LDL-P as those will probably be very useful in further assessing risk.
That is not quite what I said; it is the LDL-C that is causing (i.e., initiating and driving) atherosclerosis. What I said in relation to modern lifestyles was that there likely a range of factors getting LDL-C to these higher levels, diet, etc.
LDL-C is not “evolutionarily consistent”. This term gets thrown around in the realm of pure speculation. What is evolutionarily consistent about LDL-C? What evidence do you have the LDL-C would have been around modern levels in evolutionary periods? Loren Cordain himself was involved in research which indicated optimal LDL-C levels are a range of 50-70mg/dL, and this is a range consistent with unacculturated (i.e., ‘hunter-gatherer) human populations, neonatal humans, non-human primates, and other mammals, none of which develop atherosclerosis (this paper sets this out nicely: https://www.sciencedirect.com/science/article/pii/S0735109704007168?via%3Dihub)
Usually, “evolutionarily consistent” means ‘cholesterol is natural in the body’, or something to that effect. No one disputes that. This is why LDL-C at low levels is not atherogenic. The lifestage in which cholesterol requirements are maximal is infancy, and these requirements are met with as little as 28-32mg/dL. In fact, the LDL-receptor itself becomes saturated around 6mg/dL circulating cholesterol. If anything is evolutionarily consistent, it is that LDL-C levels <80mg/dL are optimal, as under this threshold atherosclerosis does not develop.
The types of effect modification you're describing has been extensively studied, this is the thing. Elevated LDL-C still drives the processes of atherosclerosis independent of inflammation, of triglycerides, remnants, etc. Those factors are effect modifiers, so they modulate the extent of the risk posed by LDL-C, but do not themselves invalidate the underlying pathology. So compare someone with isolated high LDL-C and then high LDL-C plus inflammtion, other dyslipidemia, insulin resistance, and sure the latter is far more of a risk profile than the former. But what is being split here is risk profile, the latter being a higher risk does not invalidate the risk posed by isolated LDL-C alone, it just may take longer for this to manifest as overt disease (6th and 7th decades of life).
With “evolutionarily consistent” I simply refer to the fact that my own diet and lifestyle is evolutionarily consistent (well, as much as possible these days), and yet I see a higher LDL-C. That the average LDL is lower for current times hunter-gatherers is no contradiction here, because it seems to be only a certain group of people who have this effect which tend to be very lean and active. Also current times hunter-gatherers have quite a different diet compared to times when mega fauna was still around.
‘LDL-C still drives the processes of atherosclerosis independent of inflammation, of triglycerides, remnants’ – well how would we know this? Do you have a study where they looked at people living an evolutionarily consistent, healthy life or are they all studying regular people in Western countries?
On what basis do you think living in an “evolutionary consistent” way (whatever that exactly means) would allow someone to have elevated LDL-C (or ApoB) and *not* develop atherosclerosis?
Given the overwhelming evidence for LDL’s causal role in atherosclerosis, what aspect of “evolutionary consistent” living would make this not be the case?
@Danny Lemon As I understand it ApoB is necessary but not sufficient for atherosclerosis. So assuming there are further factors required for atherosclerosis that don’t exist in very healthy individuals. Obviously nobody lives a perfect life and the takeaway still would be trying to lower ApoB as much as possible given an individual’s context.
Would you agree?
Very interesting read, but for me, I won’t take any gambles with my health, I will look into lowering LDL while staying on Keto
Yeah that’s very prudent. Someone can eat a ketogenic diet and be healthy; they just need to make sure their LDL isn’t elevated. If it is, then simply swapping out some saturated fat for some unsaturated fat (particularly polyunsaturated fat), and ensuring fibre is high, will help. If that still doesn’t resolve the issue, then medication should certainly be discussed with their doctor.
This is indeed a great discussion, well done as it is quite critical to the masses! I too feel the same as Marcus as I sense the LDL-C is reacting to the cause or its particles are being damaged promoting the Liver to make more .. which unfortunately appears to be a long term chronic exposure to the western diet and may well require a long time to reverse, I would tender that Omega-6, HFCS and overeating are more causal 😉 Indeed what about damaged particles not being re-absorbed by the Liver and Statins only pulling healthy particles out. I have read so much literature in the last 2 years after being given the Low Fat directive 10 years ago with a CAC of 370 and it only made matters worse x 3, I followed all the advice including Fish Oils(which I now question) except Statins which I reacted badly to, my Liver enzymes skyrocketed which can’t be healthy, yet avoiding Sugar alone reduced my GGT from 250 to 40 in 5 years .. I see no reason for me to continue the Low Fat diet and why would anyone recommend it given my result 10 years later. Since starting a LCMF diet, I have tested all of my markers including Genetics and they all look fantastic now except LDL-C, which remains between 4-5mmol fasted, my Lipid Substrate is Type A. Why would something so native to and highly regulated by our Body be damaging regardless of volume unless the metabolics were broken. I suggest we should be focusing on our Endothelium and what’s damaged this as causal .. all Study’s thus far continue to miss the key elements of the issue including your reference above pointing the finger at LDL-C as Causal, yet it makes no mention of the diet and its Omega-6 or simple Carbs content .. I welcome of course all constructive viewpoints which is why I think this discussion is awesome! I appreciate any and all insights at this stage but cannot agree that the medical and scientific communities are aligned, nor do they prove in my mind that said results are explicitly driven by LDL-C and as David suggests .. we need the Study’s to be more inclusive of the western diet elements that may well be the catalysts for LDL-C reaction, driven by our Liver. I trust we will not become a species dependent upon Statins for breakfast! 😉 Thanks!
A few points I would submit for your consideration:
1) Avoiding high LDL-C doesn’t mean you need to eat a low-fat diet. From diet, high SFA intake is going to most strongly drive LDL-C increases in people. So why not consider a moderate or high-fat diet, but just with lower SFA?
2) You suggest omega-6 is causal. This has literally zero evidence to support it. This claim comes from people pointing to mechanistic speculation, while they ignore the mountains of data showing LDL/ApoB is in the causal pathway of atherosclerosis. Why have you concluded omega-6 is causal?
3) Thinking that elevated LDL-C is not a problem because it is “native” is a naturalistic fallacy, and a really poor basis to come to conclusions about diet and health.
4) If you haven’t done so already, and if you’re interested in more evidence to support our position, we have 3 written statements on the site that might be useful. The first one is here: https://sigmanutrition.com/lipids/
Thanks for reading and for the comment!
Thanks Danny for responding,
I agree keeping SFA to a minimum may assist me in managing LDL-C, complimented with healthier fats.
I have seen several videos and science articles pointing the finger at Omega-6(Veg Oils), I’m certain you will find them, for example; https://openheart.bmj.com/content/5/2/e000898
I believe it is both Processed Omega-6 and Sugars, particularly excess Fructose that are the catalysts.
I’m still confused as to whether your stating LDL-C particle count is the issue(Causal) or whether it is the state of said particles(oxLDL), please clarify this?
As per Dr Paul Mason’s description of the Lipid Substrate values, one would like to believe there is substance in this leading to a means of determining whether damage is occurring, but are you suggesting elevated LDL is causal regardless of the damage factor?
Are you stating there is scientific evidence that healthy LDL particles are still atherosclerotic .., or that volume is key.
I also understand Statins do not remove oxLDL, only healthy LDL and that CoQ10 is inhibited, yet this is a major dependent of our Body’s function and protection, potentially increasing the residual ratio of bad to good LDL.
Without explaining why one’s Liver would maintain this native function regardless of not consuming SFA, confining it to a naturalistic fallacy is difficult 😉
I will certainly review the statements and evidence as recommended.
I find this response fascinating to consider, and a great example fo the confusion that quacks in this space have created. So, for example, in response to the overwhelming evidence on LDL being in the causal pathway for atherosclerosis, you stated that you didn’t feel this was strong enough to be considered causal. Rather, in your view omega-6 oils seemed to have better evidence for causality. Yet, when asked for the supporting evidence, you provided two links:
1) a viewpoint/opinion piece that discusses a hypothesis based on mechanistic speculation. In other words, zero evidence that humans eating omega-6 FA drives atherosclerosis. In addition, the author on the paper (Di Nicolantonio) has zero credibility. We’ve discussed his quackery in episode 400 if you’re interested.
2) a paper on oxidation products, that yet again tells us precisely zero when it comes to the question of ‘does higher omega-6 content of the diet increase ASCVD risk in humans’.
So, I find it odd that these two papers are sufficient for you to feel omega-6 is causal, yet the evidence on LDL is still met with skepticism.
Onto your question of “is there scientific evidence that healthy LDL particles are still atherosclerotic?”. So yes, it is the high concentration of ApoB-containing lipoproteins (LDL, IDL, VLDL, Lp(a)) that increases risk. All of these particles of atherogenic. They can become oxidized after getting into the endothelium, so concluding that only oxLDL in circulation is a problem is incorrect.
I don’t think Paul Mason is a credible source of information on this topic.
I think if you’re looking for experts in this field look to people like Chris Packard, Brian Ference, Bruce Griffin, Samia Mora, Tom Dayspring, etc., rather than the likes of Di Nicolantonio and Mason.
One of the things that puzzles my brain is the fact that saturated fatty acids cannot oxidize. So, lowering or raising saturated fatty acid intake does not affect oxidation of LDL particles. For oxidation of LDL particles to occur on a scale that causes damage, intake of linoleic acid molecules has to become so high that it overwhelms antioxidant resources the body uses to control their action. https://academic.oup.com/advances/article/12/3/647/6164876?login=false
This is a misunderstanding. High SFA intake can increase total number of LDL (and other atherogenic) particles. A high burden of atherogenic lipoproteins can increase the likelihood of them penetrating the arterial wall and the process of atherosclerosis starting.
LDL particles can become modified after getting into the intima. So looking to dietary fats and oxidation is a distraction.
Your final sentence is simply without any good evidence to support it. The opinion piece you link to is highly speculative, and largely flawed unfortunately.
Hi Danny, for added context re oxLDL and my endeavour to confirm if it is indeed LDL or “Damaged” LDL that we should be concerned about.
I of course appreciate if you have higher LDL then the risk potential is higher, however if the damage is avoided then should we remain so focused on reducing otherwise healthy LDL ..
This study demonstrates that serum ox-LDL levels predict 10-year progression of subclinical atherosclerosis. Moreover, this effect is independent of the cholesterol content, the number, and the size of LDL particles.
Hi Danny, again thanks for your responses, I suggested that processed Omega-6 was one of many Western Diet catalysts impacting our endothelials which is where the trouble begins in conjunction with HFCS etc, unless I have misunderstood(probably ..;-)).
I appreciate your confirmation that it is indeed the “native” particle volume that poses the greater risk(which I would have thought our bodies would know how to regulate natively except for the enormity of the dietary problem in modern societies today ..) and it isn’t the case that such papers convince me of anything, PubMed is also saturated with such articles, so on the contrary I find it so confusing that both the medical and scientific communities cannot agree on this.
To a Patient’s ears it would seem we have evolved to depend on Statins, unless we can mitigate via natural methods and avoid fake food .. 😒
Personally I am still not convinced on Statins, especially when I see the impact on my Liver, CoQ10 and muscles .., moreso the risk for long term complications. I have found Robert Lustig and Ben Bikman to be convincing as they go into the details and try to articulate the logic.
I have a significant amount of 2 year trial and error blood stats which are now favourable due to diet augmentation, the LDL remains in question but what is obvious to me is that it takes a few years to see the results, the LCMF or Med Diets work best for me.
Thank you for the advice and clarifications, I will investigate further the causes of endothelial degradation in the context of high particle saturation as well, but my hopes are that in avoiding fake foods, added sugars and veg oils, I may arrest my condition.
I trust my patient view has expanded the discussion a bit further for the layman.
Here’s some of the links I found particularly informative;
“Brown and Goldstein identified receptors in macrophages that could bind and endocytose modified (acetylated or oxidized) but not native LDL”
This is in support of my understanding thus far regarding particle damage as opposed to volume, the Endothelial disfunction is obviously a key precursor, so I’m focusing on what causes this as there are plenty of people out there with high particle counts and no CVD.
This was also a very interesting interview where Dave was also mentioned.
Thanks for the comments and continuing to engage. Unfortunately, my answer will be very similar to the previous one…
1) The links you provide are virtually meaningless for the question we are discussing. Not to mention the larger claim of omega-6 being more of a causal driver of atherosclerosis than LDL. I really need to emphasize how you are ignoring a large body of evidence that demonstrates causality of elevated ApoB in atherosclerosis, in favor of unsupported hypotheses, typically spouted by quacks.
2) The sources you reference are not credible at all. And so, with regret, I will not be watching the YouTube link to the CarnivoreMD. I’m very aware of his position. And as I’ve mentioned, it’s totally incorrect.
Your previous comment mentioned “Personally I am still not convinced on statins”. I’m not sure what you mean by convinced by them. The data is overwhelming. There are people who experience side effects, hence why alternative options can be provided (different types or statins, or moving to other drugs like ezetimibe or PCSK9i). But the idea that they don’t work is just wrong.
I wish you the best on your journey, but I do fear that you are consuming content from the wrong sources, who have led you to some really erroneous conclusions. I understand their narratives sound informed and that they “make sense”, but these are fringe positions, bordering on malpractice in some cases, that are just not a good reflection of the evidence base.
@Danny I was following your discussion here with Lukas, interesting responses. My only question to you would be if you could provide evidence for this statement: ‘They can become oxidized after getting into the endothelium, so concluding that only oxLDL in circulation is a problem is incorrect.’. How do we know this?
And just a small update from my side, I finally managed to get Lp(a) particle count and ApoB test (had to travel to USA to get this). The good news was that my Lp(a) particle count was lower than expected from Lp(a) mg/dl test. The bad news was ApoB was indeed high. I’ll be going on a statin soon.
Great news on the Lp(a) front! And it’s positive that you’re taking steps to lower ApoB.
For discussion of the development of arterial plaques, and how modification can take place after lipoproteins penetrate the arterial wall, work going back to the early 90s already noted how this could occur.
This is a good paper for context: https://jamanetwork.com/journals/jama/article-abstract/384363
From that: “However, further studies showed that the fatty streak lesion, which antedates the fibrous plaque, actually develops under a structurally intact endothelial surface.” As presented in that paper, elevated intimal LDL can precede oxidation.
Another nice overview paper from around that time, stating: “Lipoproteins may be trapped in the intima by matrix components and then modified.”, is from Stary et al: https://www.ahajournals.org/doi/10.1161/01.CIR.89.5.2462
Many other sources, but these are the couple that first came to mind.