Coronary Artery Calcification and Lipoprotein (a)

Coronary Artery Calcification and Lipoprotein (a)

by Jeffrey Dach MD

Sam is a 56 year old music conductor at the local symphony. Lately Sam has been having chest pain unrelieved by antacid drugs. His cardiologist did an evaluation showing that Sam has a high calcium score over 400, and elevated Lipoprotein (a), a genetic form of accelerated coronary artery disease.

What is Lipoprotein (a)  Also called Lp(a)?

In people carrying this mutation, Lp(a) is a small protein called the Apo a protein which attaches to the Apo-B protein of the LDL particle. (See left diagram )

Note: The Apo a has a small letter a to differentate from the APO A protein which is attached to the HDL particle. The Apo B protein is attached to the LDL particle, and the Apo a protein in people with this mutation is attached to the Apo B protein by a disulfide bond.

Left Image: courtesy of Berglund, Lars, and Rajasekhar Ramakrishnan. “Lipoprotein (a) an elusive cardiovascular risk factor.” Arteriosclerosis, thrombosis, and vascular biology 24.12 (2004): 2219-2226.
Top Header Image: atheroscloeroitic plaque electron microscopy image courtesy of wikimedia commons. Density dependent scanning electron microscopy image of a carotid plaque showing calcified (orange) collagen layers (green). Magnification = 4.94K

A Plasminogen Lookalike

Lp(a) resembles plasminogen, a protein involved in thrombosis and blood clotting. This means Lp(a) prevents degreadation of fibrin, leading to increased inflammation and intravascular clotting. Atherosclortic plaque material shows an abundance of Lp(a) within it.

Accelerated Arterial and Aortic Valve Calcification

Lp(a) is associated with accelerated deposition of calcium along the walls of the arteries, and accelerated progression of coronary calcium score, and as such, accelerated coronary artery disease. Lp(a) is also associated with calcification of the aortic valve which leads to aortic valvular stenosis, treatable with surgery, an aortic valve replacement. Lp(a) is a genetic form of early and progressive coronary artery disease as well as aortic valvular disease.

Treatment for Lp(a) – Apheresis

Unfortunately Mainstream Cardiology does not currently have an approved treatment for Lp(a).

However, in Germany, there has been  good results with lipoprotein apheresis, originally developed as a treatment for familial hypercholesterolemia.

A recent study of 171 patients with elevated Lp(a) and serious coronary artery diease, showed an 86 percent reduction in major adverse cardiac events using lipoprotein apheresis once a week. Patients had a roughly 60 per cent reduction in serm Lipo(a) levels, and enjouyed a 97 per cent reduction in annual risk for myocardial infarction. In 2023 Dr. Dragana Tomic Naglic in Biomolecules and Biomedicine writes:

LDL apheresis has proven to be an effective therapeutic solution, since literature data and clinical experience suggest that it can reduce Lp(a) plasma levels by up to 60% [73]. Moreover, LDL apheresis has been shown to reduce the risk of major adverse CV events, defined as CV death, coronary bypass surgery, nonfatal myocardial infarction, percutaneous coronary intervention, or stenting, by up to 86%, as well as to reduce the annual risk of myocardial infarction by up to 97%.

Update August 30, 2023: New Drugs for Lp(a):

August 30, 2023 Successful early studies reported for two Lp(a)-lowering therapies cardiology today ByErik Swain

“Muvalaplin is the first oral agent specifically developed to lower Lp(a) levels….Muvalaplin disrupts interaction between ApoA and ApoB and is the first once-daily oral agent developed to specifically lower Lp(a) levels,” Nicholls said during the presentation. “Muvalaplin resulted in dose-dependent lowering of Lp(a) of up to 65% with no discernible effects on plasminogen activity. An ongoing phase 2 study is assessing muvalaplin in patients with elevated Lp(a) levels, and the longer-term impact of muvalaplin on Lp(a) and cardiovascular outcomes will require additional studies….in the 36-week on-treatment results of OCEAN(a)-DOSE, olpasiran 75 mg or greater dosed subcutaneously every 12 weeks reduced Lp(a) concentration by more than 95%.

Heart Book by Jeffrey dach MDArticles with Related Interest:

Heart Book by Jeffrey Dach MD (Left Image)

Plant Based Diet, Health Benefits for Coronary Artery Disease

Calcium Score Determines Who to Treat With Statin Drug

Diabetes, Arterial Calcification and Statin Drugs

LDL-Cholesterol Does Not Cause Coronary Artery Disease

LDL Particle Size and Number, What Gives?

Does Cholesterol Cause Coronary Artery Disease ?

Reverse Heart Disease with Coronary Calcium Score

Low Level Endotoxemia LPS Theory of Coronary Artery Disease

Calcium Score Paradigm Shift in Cardiology

Coronary Calcium Score Benefits of Aged Garlic

Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314
Heart Book by Jeffrey Dach


May 27, 2023 Preventing Chronic Disease “The cholesterol paradox”: a catchy phrase for an idea with no substance  Peter Attia By: Kathryn Birkenbach, Tom Dayspring, Peter Attia
A recent study reported that hypercholesterolemia is associated with reduced mortality, but it falls short of upsetting conventional wisdom

investigators defined patients as hypercholesterolemic if they reported either a pre-existing diagnosis of high cholesterol or active treatment with lipid-lowering medications.

Pooled analyses likewise found that self-reported hypercholesterolemia was associated with lower mortality, with a hazard ratio of 0.71 (95% CI: 0.58-0.84). Contrastingly, self-reported diabetes, smoking, and hypertension were all found to be associated with higher ACM risk across all four groups.

in a subset of 7,744 CAC and CCTA patients who had also undergone serum lipid testing at the time of scanning, patients with the lowest LDL-C levels (<100 mg/dl) also had lowest survival compared to other LDL-C ranges, consistent with the overall inverse relationship between LDL-C and mortality reported by the investigators.

The authors themselves call attention to this problem, noting that it arises when a risk-associated variable (such as hypercholesterolemia) prompts “potent therapeutic interventions which then modify the outcomes” (such as initiation of lipid-lowering medications). That is to say, the patients with the highest LDL-C levels were also the most likely to receive the most aggressive lipid-lowering treatment – and those treatments work. So those who were categorized into the highest LDL-C tertile based on baseline LDL-C values may well have spent most of the follow-up period with LDL-C values in the lowest tertile – completely inverting the meaning of the study results.

Why a recent study hasn’t shaken my faith in statins
A rebuttal of Byrne et al. by Peter Attia

If the treatment duration is short, then the only possible way to detect a significant effect would be to examine studies with a large magnitude in LDL-C reduction. Such data do exist, primarily from trials investigating PCSK9 inhibitors (see for example the FOURIER trial on combined evolocumab and statin treatment), and they show strong causal associations between LDL-lowering treatment and CV events and mortality.

Though LDL-C does provide some approximation of atherogenic risk, either apoB or non-HDL-C would do so more accurately, yet neither of these preferred metrics was included in the analysis conducted by Byrne and her colleagues.

First, as previously stated, Byrne et al. chose to use LDL-C as the relevant variable for mechanistically linking statin efficacy to clinical outcomes, yet LDL-C is not an ideal metric for determining the atherogenic risk. As I’ve discussed numerous times on the podcast and in previous newsletters, the most reliable risk-associated variable is the concentration of apolipoprotein B (apoB), the protein that associates with LDL particles and, to a much lesser extent, very-low-density lipoproteins (VLDLs) and chylomicron remnants. ApoB-containing particle number – not their cholesterol content – is the key determinant of atherogenic risk, and because only a single molecule of apoB associates with each LDL or remnant particle, apoB thus provides a far more accurate estimate of the number of atherogenic particles than cholesterol content, which varies widely across different LDL particles.

November 24, 2019 Preventing Chronic Disease Coronary Artery Calcium Scan by Peter Attia

As noted above, statins are known to increase the calcification of atherosclerotic plaque. Researchers have hypothesized that statins can promote or increase calcification through various actions.

While the beneficial effects of statins on coronary artery plaque progression4 and ASCVD outcomes have been shown, statins increase coronary artery calcification, which is referred to in the literature as the “statin paradox” or the “plaque paradox.” (I always think of the physicist Niels Bohr’s quote when seeing this word: “How wonderful that we have met with a paradox. Now we have some hope of making progress.”) It’s possible that the observation of the plaques getting smaller and more calcified represents a conversion to a more stable plaque that’s less likely to rupture, although there doesn’t seem to be enough data to date to confirm or refute this hypothesis.

For the statin-treated patient, it’s possible that the progression of CAC over time is due to the treatment, and may not necessarily be an indicator of increased risk. This is why it might not make sense to monitor CAC once you’re on therapy. (There is one interesting study to suggest there’s a camp of patients that can benefit from monitoring CAC while on statin therapy that we’ll need to explore another time.)

While the beneficial effects of statins on coronary artery plaque progression4 and ASCVD outcomes have been shown, statins increase coronary artery calcification, which is referred to in the literature as the “statin paradox” or the “plaque paradox.” (I always think of the physicist Niels Bohr’s quote when seeing this word: “How wonderful that we have met with a paradox. Now we have some hope of making progress.”) It’s possible that the observation of the plaques getting smaller and more calcified represents a conversion to a more stable plaque that’s less likely to rupture, although there doesn’t seem to be enough data to date to confirm or refute this hypothesis.

When CAC Tests Are Useful and When They Are Not

When CAC Tests Are Useful and When They Are Not by Peter Attia April 15, 2022

Coronary artery calcium scan — Part 2 Peter Attia Nov 24, 2019

Here’s where it gets complicated once you’re treated with statins. Statin therapy, demonstrated to reduce the clinical manifestation of ASCVD, can lead to an increase in CAC, yet equally potent low-density lipoprotein (LDL) lowering PCSK9i, which also reduce clinical events, do not. Why do two potent LDL lowering drug therapies, specifically statins and PCSK9i, have differing effects on CAC?

As noted above, statins are known to increase the calcification of atherosclerotic plaque.

PCSK9i, conversely, had no effect, up or down, on plaque calcification. One speculative reason why is that PCSK9i are more effective at lowering lipoprotein(a), or Lp(a) for short, than statins, and Lp(a) is positively correlated with calcification and an independent risk factor for aortic valve stenosis and calcification. In some patients, statins may increase Lp(a) concentration which hypothetically may also play a role in statin-induced calcification.

In light of what we’ve been discussing, calcification and CAC scores as a predictor of ASCVD, what are we to make of changes in the calcium content of coronary arteries brought on by statins? Here you have an intervention that has been shown to reduce CV events and yet may increase CAC. This presents a problem for evaluating the efficacy of lipid-lowering therapies using CAC scans. For example, should a statin-treated patient, with a CAC score of 200, whose apolipoprotein B levels, blood pressure, insulin, glucose, and other treatable risk factors have been adequately improved, worry if CAC increases over the course of 10 years?

Joshua Mitchell Study

In a 2018 study, (Joshua Mitchell Study)  investigators identified people without pre-existing ASCVD who got a CAC scan between 2002–2009. They followed these 13,644 patients (mean age of 50; 71% men) for an average of 9.4 years and sought to determine whether CAC can identify patients most likely to benefit from statin treatment.

, patients with a positive CAC benefited over ~10 years by taking a statin, but those with a CAC of zero did not benefit over this period of (relatively short) timeframe.

While the beneficial effects of statins on coronary artery plaque progression and ASCVD outcomes have been shown, statins increase coronary artery calcification, which is referred to in the literature as the “statin paradox” or the “plaque paradox.”

For the statin-treated patient, it’s possible that the progression of CAC over time is due to the treatment, and may not necessarily be an indicator of increased risk. This is why it might not make sense to monitor CAC once you’re on therapy. (There is one interesting study to suggest there’s a camp of patients that can benefit from monitoring CAC while on statin therapy that we’ll need to explore another time.) (Paolo Raggi study)  Raggi, Paolo, Tracy Q. Callister, and Leslee J. Shaw. “Progression of coronary artery calcium and risk of first myocardial infarction in patients receiving cholesterol-lowering therapy.” Arteriosclerosis, thrombosis, and vascular biology 24.7 (2004): 1272-1277.

Byrne, Paula, et al. “Evaluating the association between low-density lipoprotein cholesterol reduction and relative and absolute effects of statin treatment: a systematic review and meta-analysis.” JAMA internal medicine (2022).
Question What is the association between statin-induced reductions in low-density lipoprotein cholesterol (LDL-C) levels and the absolute and relative reductions in individual clinical outcomes, such as all-cause mortality, myocardial infarction, or stroke?

Findings In this meta-analysis of 21 randomized clinical trials in primary and secondary prevention that examined the efficacy of statins in reducing total mortality and cardiovascular outcomes, there was significant heterogeneity but also reductions in the absolute risk of 0.8% for all-cause mortality, 1.3% for myocardial infarction, and 0.4% for stroke in those randomized to treatment with statins compared with control, with relative risk reductions of 9%, 29%, and 14%, respectively. A meta-regression was inconclusive regarding the association between the magnitude of statin-induced LDL-C reduction and all-cause mortality, myocardial infarction, or stroke.

Meaning The study results suggest that the absolute benefits of statins are modest, may not be strongly mediated through the degree of LDL-C reduction, and should be communicated to patients as part of informed clinical decision-making as well as to inform clinical guidelines and policy.

Main Outcomes and Measures Primary outcome: all-cause mortality. Secondary outcomes: myocardial infarction, stroke.

Findings Twenty-one trials were included in the analysis. Meta-analyses showed reductions in the absolute risk of 0.8% (95% CI, 0.4%-1.2%) for all-cause mortality, 1.3% (95% CI, 0.9%-1.7%) for myocardial infarction, and 0.4% (95% CI, 0.2%-0.6%) for stroke in those randomized to treatment with statins, with associated relative risk reductions of 9% (95% CI, 5%-14%), 29% (95% CI, 22%-34%), and 14% (95% CI, 5%-22%) respectively. A meta-regression exploring the potential mediating association of the magnitude of statin-induced LDL-C reduction with outcomes was inconclusive.

Conclusions and Relevance The results of this meta-analysis suggest that the absolute risk reductions of treatment with statins in terms of all-cause mortality, myocardial infarction, and stroke are modest compared with the relative risk reductions, and the presence of significant heterogeneity reduces the certainty of the evidence. A conclusive association between absolute reductions in LDL-C levels and individual clinical outcomes was not established, and these findings underscore the importance of discussing absolute risk reductions when making informed clinical decisions with individual patients.

Rozanski, Alan, et al. “Association between hypercholesterolemia and mortality risk among patients referred for cardiac imaging test: Evidence of a “cholesterol paradox?”.” Progress in Cardiovascular Diseases 74 (2022): 60-69.

By contrast, hypercholesterolemia was associated with decreased rather than increased mortality (pooled hazard ratio[95% CI]: 0.71[0.58-0.84]). Analysis of serum lipids among 7744 patients undergoing CAC or CCTA scanning revealed an inverse relationship between LDL cholesterol and mortality.

Conclusions: Among a broad spectrum of patients referred for a variety of cardiac tests and ranging from low to high clinical risk, hypercholesterolemia was not associated with increased mortality risk.

Mitchell, Joshua D., et al. “Impact of statins on cardiovascular outcomes following coronary artery calcium scoring.” Journal of the American College of Cardiology 72.25 (2018): 3233-3242.

Ravnskov, Uffe, et al. “LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature.” Expert review of clinical pharmacology 11.10 (2018): 959-970. LDL-C does not cause cardiovascular disease Ravnskov Uffe Expert rev clin pharm 2018

Ravnskov, Uffe, et al. “Serious flaws in targeting LDL-C reduction in the management of cardiovascular disease in familial hypercholesterolemia.” Expert Review of Clinical Pharmacology 14.3 (2021): 405-406.
Recently, Polychronopoulos and Tziomalos reviewed research on the use of inclisiran and bempedoic
acid in the management of cardiovascular disease (CVD) risk in people with familial hypercholesterolemia
(FH). Their treatment recommendations were based on the general premise that high LDLcholesterol
(LDL-C) is inherently atherogenic, and that low levels of LDL-C need to be achieved to
reduce CVD risk in FH individuals. However, their perspective on LDL-C is flawed at two levels of
analysis: 1) They ignored the extensive literature demonstrating that CVD is not caused by high LDL-C;
and 2) they failed to consider CVD treatment strategies that take into account the extensive literature
that has shown that coagulation factors are more closely related to coronary events in FH than is LDL-C.
In the following, we have briefly addressed each of these flaws in their review.

DuBroff, Robert, Aseem Malhotra, and Michel de Lorgeril. “Hit or miss: the new cholesterol targets.” BMJ evidence-based medicine 26.6 (2021): 271-278.

Drug treatment to reduce cholesterol to new target levels is now recommended in four moderate to high-risk patient populations: patients who have already sustained a cardiovascular event, adult diabetic patients, individuals with low density lipoprotein cholesterol levels ≥190 mg/dL and individuals with an estimated 10-year cardiovascular risk ≥7.5%. Achieving these cholesterol target levels did not confer any additional benefit in a systematic review of 35 randomised controlled trials. Recommending cholesterol lowering treatment based on estimated
cardiovascular risk fails to identify many high-risk patients and may lead to unnecessary treatment of low-risk individuals. The negative results
of numerous cholesterol lowering randomised controlled trials call into question the validity of using low density lipoprotein cholesterol
as a surrogate target for the prevention of cardiovascular disease.

Limitations of LDL-C as a treatment target Because of the putative role of LDL-C in the pathogenesis of ASCVD, it seems intuitive and logical to target LDL-C to prevent cardiovascular disease. Indeed, there is much evidence to support this approach. However, decades of RCTs of LDL-C
reduction have failed to demonstrate a consistent benefit.19 Conspicuous by its absence in the AHA/ACC guidelines is any endorsement of niacin
or cholesteryl ester transfer protein (CETP) inhibitors, agents with
a proven track record of reducing LDL-C but failing to consistently
save lives or prevent cardiovascular disease.20 21 To validate
the theory that reducing LDL-C reduces the risk of cardiovascular
disease (the lipid hypothesis), LDL-C lowering interventions must
be efficacious. Considering that dozens of RCTs of LDL-C reduction
have failed to demonstrate a consistent benefit, we should question the validity of this theory.22

In this analysis over three-quarters of the cholesterol lowering trials reported no mortality benefit and nearly half reported no cardiovascular
benefit at all.

The widely held theory that there is a linear relationship
between the degree of LDL-C reduction and the degree of cardiovascular
risk reduction is undermined by the fact that some RCTs with very modest reductions of LDL-C reported cardiovascular benefits while others with much greater degrees of LDL-C reduction did not (MEGA, ALLIANCE, SEAS, ODYSSEY FH 1 and 2, SPIRE 1 and 2).5–9 2

This lack of exposure–response relationship is illustrated in figure 3 where the scatter plot and the calculated correlation coefficient (R) suggest there is no correlation between the percent reduction in LDL-C and the absolute risk reduction in cardiovascular events.

Moreover, consider that the Minnesota Coronary Experiment, a 4-year long RCT of a low-fat diet involving 9423 subjects, actually reported an increase in mortality and cardiovascular events despite a 13% reduction in total cholesterol. 24

What is clear is the lack of clarity of these issues. In most
fields of science the existence of contradictory evidence usually
leads to a paradigm shift or modification of the theory in question,
but in this case the contradictory evidence has been largely
ignored simply because it doesn’t fit the prevailing paradigm.25 26

What to do now Cardiovascular disease continues to be the leading cause of death worldwide. Between 2002 and 2013 statin use in the US nearly doubled, cholesterol levels are falling, yet cardiovascular deaths
appear to be on the rise.30 31 In Sweden, recent widespread and
increasing utilisation of statins did not correlate with any significant
reduction in acute myocardial infarction or mortality, while
in Belgium a very modest reduction in cardiovascular events was
reported between 1999 and 2005, but primarily in elderly individuals
not taking statins.32 33 These population studies suggest that,
despite the widespread use of statins, there has been no accompanying
decline in the risk of cardiovascular events or cardiovascular
mortality. In fact, there is some evidence that statin usage
may lead to unhealthy behaviours that may actually increase the
risk of cardiovascular disease.34 35 The evidence presented in this
analysis adds to the chorus that challenges our current approach
to cardiovascular disease prevention through targeted reductions
of LDL-C.

Given the lack of clarity on how best to prevent cardiovascular
disease, we encourage informed decision-making.


Maihofer, Adam X., et al. “Associations between Serum Levels of Cholesterol and Survival to Age 90 in Postmenopausal Women.” Journal of the American Geriatrics Society 68.2 (2020): 288-296.

Objectives: Although elevated lipid levels predict increased risk of coronary heart disease and death in middle-aged women and men, evidence is mixed if lipid levels measured in later life predict survival to very old ages. We examined lipid levels and survival to age 90 with or without intact mobility in a large cohort of older women.

Design: Prospective cohort.

Setting: Laboratory collection at a Women’s Health Initiative (WHI) center and longitudinal follow-up via mail.

Participants: Women aged 68 to 81 years at baseline.

Measurements: Serum high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol were collected at baseline. Participant survival status and self-reported mobility was compared across lipid levels.

Results: HDL and LDL levels were not associated with survival to age 90 after adjustment for cardiovascular risk factors (HDL: quartile (Q) 2: odds ratio [OR] = 1.14 [95% confidence interval [CI] = .94-1.38]; Q3 OR = 1.08 [95% CI = .88-1.33]; Q4 OR = 1.09 [95% CI = .88-1.35]; LDL: Q2 OR = 1.07 [95% CI = .88-1.31]; Q3 OR = 1.27 [95% CI = 1.04-1.55]; Q4 OR = 1.07 [95% CI = .88-1.31]). Similarly, no associations were observed between HDL and LDL levels and survival to age 90 with mobility disability. High HDL was not associated with survival to age 90 with intact mobility after adjustment for other cardiovascular risk factors. Compared with the lowest LDL quartile, the three upper LDL quartiles were associated with greater odds of survival to age 90 with intact mobility (LDL: Q2 OR = 1.31 [95% CI = .99-1.74]; Q3 OR = 1.43 [95% CI = 1.07-1.92]; Q4 OR = 1.35 [95% CI = 1.01-1.80]; P = .05).

Conclusion: Neither higher HDL nor lower LDL levels predicted survival to age 90, but higher LDL predicted healthy survival. These findings suggest the need for reevaluation of healthy LDL levels in older women. J Am Geriatr Soc 68:288-296, 2020.

Ding, Mozhu, et al. “The association of apolipoproteins with later-life all-cause and cardiovascular mortality: a population-based study stratified by age.” Scientific Reports 11.1 (2021): 24440.

In the age-specific analysis, we found that high TC (≥ 7.25 mmol/L) at age 39–59 years was associated with a higher all-cause mortality, but high TC at age 60–79 and ≥ 80 years was associated with a lower mortality. A similar age difference was also found for the association between LDL-C and mortality. Previous evidence on the association between cholesterols and mortality among older adults is conflicting, though most studies support no association or an inverse association5,6,18–23. The reason behind such a paradoxical association is not entirely clear.

We also found that the lowest TC and LDL-C levels were associated with higher mortality in all the age groups. Cholesterol is important for many body functions including brain metabolism and intracellular transport, and very low cholesterol could increase the susceptibility to cancer, hemorrhagic stroke, or fatal diseases with infectious origins, such as respiratory and gastrointestinal diseases25–27.

Taken together, our findings suggest that, for people who survived to advanced ages, a high cholesterol, triglyceride, and apolipoprotein profile starts to lose some of its ability to confer a higher mortality. High TC at ages younger than 60 was associated with higher mortality, while high TC at older ages was associated with a lower mortality. On the other hand, low ApoA-I was associated with higher all-cause and cardiovascular mortality, regardless of age of lipid measurement, and high ApoB/ApoA-1 ratio was associated with higher all-cause mortality in ages up to 80 and cardiovascular mortality in all ages. Our findings indicate the potential relevance of apolipoprotein measures in terms of survival in both young and older individuals, as well as the importance of age-specific analyses in the evaluation of lipid profiles and health outcomes.

Orkaby, Ariela R. “The highs and lows of cholesterol: A paradox of healthy aging?.” Journal of the American Geriatrics Society 68.2 (2020): 236-237.
The presented studies suggest that cholesterol levels in late life are not associated with mortality. However, neither study examined the role of cholesterol-lowering medications on cholesterol levels over time and the potential added benefit of reducing cholesterol in those at risk of CVD and related con-ditions such as dementia and frailty.

Rozing, Maarten Pieter, and Rudi GJ Westendorp. “Altered cardiovascular risk pattern of LDL cholesterol in older adults.” Current opinion in lipidology.
Purpose of review: Elevated serum low-density lipoprotein cholesterol (LDL-C) levels at middle-age constitute a strong risk factor for later cardiovascular events. In older populations, however, LDL-C levels are no longer predictive of cardiovascular mortality or may even seem protective. Whether the altered risk pattern of LDL-C in old age reflects a causal mechanism or is due to confounding and bias is subject to debate. In this review, we briefly discuss the possible explanations for the altered risk pattern of LDL-C observed in old age.
Recent findings: Using examples from the recent literature we illustrate how LDL-C levels ‘lose’ their predictive value as a cardiovascular risk factor in old age. We review three potential explanations for the changed cardiovascular risk pattern of LDL-C in older populations: survivorship bias, reverse causation, and effect modification.
Summary: The absent or protective effect of LDL-C on cardiovascular mortality in older populations found in observational studies might be explained by survivorship bias, reverse causation, and effect modification. However, this does not necessarily preclude the possibility that (specific) cholesterol-lowering treatment could decrease the risk of morbidity and mortality. Placebo-controlled trials may importantly add to our understanding of who may benefit from lipid-lowering therapy or statins at an older age.

Kim, Seung Hee, and Ki Young Son. “Association of Lipoprotein Cholesterol With Future Cardiovascular Disease and Mortality in Older Adults: A Korean Nationwide Longitudinal Study.” (2020).

Dyslipidemia is an independent health risk of cardiovascular disease (CVD), a leading cause of mortality in older adults. Despite their importance, there have been few reports on the association between
lipoprotein cholesterol and future CVD and cardiovascular (CV) mortality among elderly Asians. This longitudinal study investigated the correlations in an elderly Korean population by using a large
nationwide sample.
Among participants in the cohort database of the Korean National Health Insurance Service who completed the National Screening Program, a total of 62,604 adults aged 65 years or older (32,584 men and 30,020 women) were included. High-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) values were categorized by quartiles. Cox proportional hazard models were used to assess the association between the quartiles of lipoprotein cholesterol and CV events or CV mortality.
Results   The mean follow-up period was 3.3 years. The incidence rates of ischemic heart disease and ischemic brain disease were 0.97 and 0.61 per 1,000 person-years, while the mortality rates from these diseases
were 0.22 and 0.34 per 1,000 person-years, respectively. In a fully adjusted model, high HDL-C and LDL-C levels were not associated with the total CV events and CV mortality; however, high LDL-C levels were
signicantly associated with a lower incidence of ischemic brain disease. Furthermore, diabetic patients with high LDL-C were more likely to have higher CV mortality, whereas non-smokers with high LDL-C were
less likely to be at risk of CV events.

Neither high LDL-C nor HDL-C was significantly associated with future CV mortality in older adults aged ≥65 years. Older adults with diabetes were signicantly associated with a higher risk of CV mortality in high LDL-C levels.


Diamond, David M., Benjamin T. Bikman, and Paul Mason. “Statin therapy is not warranted for a person with high LDL-cholesterol on a low-carbohydrate diet.” Current Opinion in Endocrinology & Diabetes and Obesity 29.5 (2022): 497-511.
Purpose of review Although there is an extensive literature on the efficacy of the low carbohydrate diet (LCD) for weight loss and in the management of type 2 diabetes, concerns have been raised that the LCD may increase cardiovascular disease (CVD) risk by increasing the level of low-density lipoprotein cholesterol (LDL-C). We have assessed the value of LDL-C as a CVD risk factor, as well as effects of the LCD on other CVD risk factors. We have also reviewed findings that provide guidance as to whether statin therapy would be beneficial for individuals with high LDL-C on an LCD.
Recent findings Multiple longitudinal trials have demonstrated the safety and effectiveness of the LCD, while also providing evidence of improvements in the most reliable CVD risk factors. Recent findings have also confirmed how ineffective LDL-C is in predicting CVD risk.
Summary Extensive research has demonstrated the efficacy of the LCD to improve the most robust CVD risk factors, such as hyperglycemia, hypertension, and atherogenic dyslipidemia. Our review of the literature indicates that statin therapy for both primary and secondary prevention of CVD is not warranted for individuals on an LCD with elevated LDL-C who have achieved a low triglyceride/HDL ratio.


FEMINO, Raimondo, et al. “PCSK9 inhibition, LDL and lipopolysaccharides: a complex and “dangerous” relationship.” International Angiology 40.3 (2021): 248-60.

Literature concerning the causative factors of atherosclerotic cardiovascular disease shows complex and sometimes contrasting evidence. Most guidelines suggest a strategy aimed at lowering circulating low density lipoproteins (LDL) and ApoB lipoprotein levels. The use of statins and of cholesteryl ester transfer protein inhibitors has led to a number of controversial outcomes, generating a certain degree of concern about the real efficacy and especially safety of these drugs. Literature data show that the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors results in a dramatic reduction of various markers of lipid metabolism (namely LDL); however, several critical scientific papers have questioned the value, the need and especially the safety of these innovative drugs. LDL are a protective factor against lipopolysaccharides and other microbial derivatives. Similarly, these gram-negative bacteria-derived compounds have been identified as probable culprits of cardiovascular atherogenesis; moreover, lipopolysaccharides increase hepatic synthesis of PCSK9, as defense mechanism. This enzyme modulates LDL receptors level in the liver, as well as in other organs, such as adrenal gland and reproductive organs. Hence, PCSK9 inhibition may influence glucocorticoid secretion and fertility. Lastly, the consequent reduction of circulating LDL may relevantly hindrance immune system and favor lipopolysaccharides diffusion.

Both alirocumab and evolocumab did not decrease the risk of all cause
mortality, whereas evolocumab seemed to increase mortality risk (OR=1.12; 95% CI: 1.00-1.25).110

. A very recent paper found the lowest all-cause mortality risk for a LDL level of 140 mg/dl among 108,243 individuals aged 20-100. More in detail, the hazard ratio for all-cause mortality was 1.25 with LDL
concentration below 70 mg/dL and lower (1.15) with LDL
figures above 189 mg/dL. Hence, the authors highlighted a clear U-shaped relationship between LDL figure and all cause mortality, which reinforces the need of a thorough reappraisal of lipid-lowering strategy, especially in terms of general health, beyond CVD issues.18

In conclusion, the emerging evidence about the microbial/
inflammatory origin of most chronic degenerative diseases,
atherosclerosis included, is inducing a reappraisal of
conventional treatments. Hence, the increase in total cholesterol,
LDL and PCSK9 are more recently considered defensive
responses against the microbial pathomechanism.
Consequently, the inhibition of cholesterol synthesis, or
the strategy aimed at lowering LDL levels, including the
use of PCSK9 inhibitors, could result inappropriate, especially
if not combined with a targeted microbial regulation.

To date, this strategy has not succeeded in curbing the inflammatory
processes in CVD, as confirmed by the persistent
high levels of CRP in patients treated with these drugs.
Future studies and analysis of the emerging incoming data
will be essential, in clarifying both the overall etiopathogenetic
patterns and more adequate therapeutic strategies
for atherosclerotic diseases

Netea, Mihai G., et al. “Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe gram-negative infections.” The Journal of clinical investigation 97.6 (1996): 1366-1372.


Rabaeus, Mikael, and Michel de Lorgeril. “A Systematic Review of Clinical Trials Testing CETP and PCSK9 Inhibitors: The Cholesterol-Heart Theory—Time for a Requiem?.” Journal of Controversies in Biomedical Research 5.1 (2019): 4-11.
To test the cholesterol-heart theory, the present systematic review aimed at examining whether the most recent clinical trials testing powerful cholesterol-lowering interventions (such as anti-CETP and anti-PCSK9)
report effective reduction of fatal cardiovascular complications and improved survival. Because of high heterogeneity between
studies, a meta-analysis was not feasible. The review did show that neither anti-CETP nor anti-PCSK9 treatment can significantly
reduce the risk of cardiovascular death, thereby giving credit to the questioning of the cholesterol-heart theory. Our review also shows that the quality of the included trials is generally poor with suspicion of inefficient blinding. This undermines the validity of the reported nonfatal events and thereby increases the importance of comparing fatal endpoints in both groups to test the cholesterol-heart theory.


Nicholls, Stephen J., et al. “Effect of evolocumab on coronary plaque composition.” Journal of the American College of Cardiology 72.17 (2018): 2012-2021.

==========================  =

Lipo Protein (a)

Greif, Martin, et al. “Lipoprotein (a) is independently correlated with coronary artery calcification.European journal of internal medicine 24.1 (2013): 75-79.

O’Donoghue, Michelle L., et al. “Lipoprotein (a), PCSK9 inhibition, and cardiovascular risk: insights from the FOURIER trial.Circulation 139.12 (2019): 1483-1492.

Lp(a) was measured in 25 096 patients in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a randomized trial of evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease (median follow-up, 2.2 years). Cox models were used to assess the independent prognostic value of Lp(a) and the efficacy of evolocumab for coronary risk reduction by baseline Lp(a) concentration.


The median (interquartile range) baseline Lp(a) concentration was 37 (13–165) nmol/L. In the placebo arm, patients with baseline Lp(a) in the highest quartile had a higher risk of coronary heart disease death, myocardial infarction, or urgent revascularization (adjusted hazard ratio quartile 4: quartile 1, 1.22; 95% CI, 1.01–1.48) independent of low-density lipoprotein cholesterol.

At 48 weeks, evolocumab significantly reduced Lp(a) by a median (interquartile range) of 26.9% (6.2%–46.7%). The percent change in Lp(a) and low-density lipoprotein cholesterol at 48 weeks in patients taking evolocumab was moderately positively correlated (r=0.37; 95% CI, 0.36–0.39; P<0.001). Evolocumab reduced the risk of coronary heart disease death, myocardial infarction, or urgent revascularization by 23% (hazard ratio, 0.77; 95% CI, 0.67–0.88) in patients with a baseline Lp(a) >median, and by 7% (hazard ratio, 0.93; 95% CI, 0.80–1.08; P interaction=0.07) in those ≤median. Coupled with the higher baseline risk, the absolute risk reductions, and number needed to treat over 3 years were 2.49% and 40 versus 0.95% and 105, respectively.


Higher levels of Lp(a) are associated with an increased risk of cardiovascular events in patients with established cardiovascular disease irrespective of low-density lipoprotein cholesterol. Evolocumab significantly reduced Lp(a) levels, and patients with higher baseline Lp(a) levels experienced greater absolute reductions in Lp(a) and tended to derive greater coronary benefit from PCSK9 inhibition.

In summary, the current findings suggest that plasma Lp(a) concentration is associated with the risk of CV events in patients with stable atherosclerotic disease regardless of LDL-C concentration. Furthermore, Lp(a) may be useful for identifying individuals with a greater absolute benefit from evolocumab and lend support to the study of additional therapies that can lead to marked reductions in Lp(a) concentration.

Lipoprotein (a) Biochemistry Basics by Dr Amit

—————— ———————-

Berglund, Lars, and Rajasekhar Ramakrishnan. “Lipoprotein (a) an elusive cardiovascular risk factor.” Arteriosclerosis, thrombosis, and vascular biology 24.12 (2004): 2219-2226.

Lp(a) is very heterogeneous and the underlying reasons for this heterogeneity were uncovered by the elegant work on the gene structure of apo(a) by Lawn, Scanu, and their collaborators.23 They reported an analogy between the apo(a) and plasminogen genes;

Rehberger Likozar, Andreja, Mark Zavrtanik, and Miran Šebeštjen. “Lipoprotein (a) in atherosclerosis: from pathophysiology to clinical relevance and treatment options.” Annals of Medicine 52.5 (2020): 162-177.

Apo(a) has a very similar structure to plasminogen, although while apo(a) has only two types of kringle domains, as IV and V, plasminogen has five types (I–V). The molecular structure of apo(a) is shown

Dangas, George, et al. “Lipoprotein (a) and inflammation in human coronary atheroma: association with the severity of clinical presentation.” Journal of the American College of Cardiology 32.7 (1998): 2035-2042.

Conclusions. Lipoprotein(a) is ubiquitous in human coronary atheroma. It is detected in larger amounts in tissue from culprit lesions in patients with unstable compared to stable syndromes, and has significant colocalization with plaque macrophages. A correlation of plaque alpha-actin and Lp(a) area suggests a role of Lp(a) in plaque growth.

Objective: To review evidence of existing and new pharmacological therapies for lowering lipoprotein(a) (Lp[a]) concentrations and their impact on clinically relevant outcomes.

Methods: We searched for literature pertaining to Lp(a) and pharmacological treatments in PubMed. We reviewed articles published between 1963 and 2020.

Results: We found that statins significantly increased Lp(a) concentrations. Therapies that demonstrated varying degrees of Lp(a) reduction included ezetimibe, niacin, proprotein convertase subtilisin/kexin type 9 inhibitors, lipoprotein apheresis, fibrates, aspirin, hormone replacement therapy, antisense oligonucleotide therapy, and small interfering RNA therapy. There was limited data from large observational studies and post hoc analyses showing the potential benefits of these therapies in improving cardiovascular outcomes.

Tsushima, Takahiro, et al. “Lipoprotein (a) and Atherosclerotic Cardiovascular Disease, the Impact of Available Lipid-Lowering Medications on Lp (a): An Update on New Therapies.” Endocrine Practice (2022).

Conclusion: There are multiple lipid-lowering agents currently being used to treat hyperlipidemia that also have a Lp(a)-lowering effect. Two RNA therapies specifically targeted to lower Lp(a) are being investigated in phase 3 clinical trials and, thus far, have shown promising results. However, evidence is lacking to determine the clinical relevance of reducing Lp(a). At present, there is a need for large-scale, randomized, controlled trials to evaluate cardiovascular outcomes associated with lowering Lp(a).


Naglic, Dragana Tomic, et al. “Lipoprotein (a): Role in atherosclerosis and new treatment options.” Biomolecules and Biomedicine (2023).  Naglic Dragana Lipoprotein little a Role in atherosclerosis Biomolecules 2023

The mechanism by which Lp(a) causes complications in the form of accelerated atherosclerosis and aortic valvular calcification is most likely fundamentally similar.

The pathogenic potential of Lp(a) can be divided into three categories: promotion of plaque formation, thrombogenicity, and inflammatory effect [37]. As mentioned previously, Lp(a) contains mutated apoB100, associated with apo(a) by a disulphide bridge, which decreases the affinity of these particles for LDL receptors in the liver and prevents their utilization in hepatocytes. Apo(a) has an increased affinity for scavenger
cells in the blood vessel wall. It quickly penetrates macrophages, forms foam cells, and activates a cascade of inflammatory processes that contribute to the acceleration of atherosclerosis [38]. Lp(a) is the carrier of the activator of phospholipase A2, which is responsible for the degradation of oxidized fatty acids. In this way, the content of short-chain fatty acids and lysolecithin in serum increases and enhances the lipotoxic

The oxidized Lp(a) molecule contains an oxidized LDL particle, which is immunogenic itself, and potentiates the production of  autoantibodies against Lp(a) particles. In all studies performed, the mere existence of these antibodies was observed as an integral component of the atheroma plaque.

The thrombogenicity of Lp(a) is reflected in the inhibition of
fibrinolysis [37].

There is homology in the chemical composition of apo(a)
and plasminogen, but apo(a) does not have the plasminogen
enzymatic activity. Because of the structural similarity, the production
of active plasminogen is inhibited and the homeostasis
of thrombogenic and fibrinolytic activity is disrupted, with
inhibition of fibrinolysis and enhancement of thrombogenesis

broader use of genetic and epidemiological studies that documented
a strong association of Lp(a) > 30 mg/dL (>75 nmol/L) with
higher ASCVD risk. Although an absolute risk threshold is not
yet generally accepted, an estimated 20%–25% of the world’s
population has an Lp(a) level of 50 mg/dL or more, a level
recognized by the European Atherosclerosis Society to confer
higher CV risk

Lp(a) levels above the 75th percentile multiply the risk for
myocardial infarction and aortic valve stenosis, whereas higher
levels (above 90th percentile) are associated with a higher
risk for heart failure. The risk of CV mortality and ischemic
stroke especially increased at very high levels (above 95th
percentile) [43–45].

Mehta et al. demonstrated that Lp(a) level and CAC score
are independently associated with an increased risk of developing
ASCVD. Lp(a) level > 50 mg/dL and CAC score were
independently associated with ASCVD risk,

For patients with Lp(a) level>50 mg/dL, the next step is CAC assessment and vice versa. For those with CAC > 100, the Lp(a) level is the standard. This approach would benefit the screening of patients with risk factors and higher CVD risk and sort them into the secondary prevention level group with Lp(a) target therapy

Aortic valve stenosis is the most common valvular heart
disease in developed countries. A sensitive technique to detect
this disease in its early stages, even before clinical manifestations, is non-contrast CT [49–52]. Modern approaches to lower Lp(a) concentrations by up to 90% highlight the importance
of lowering Lp(a) levels in people in the early stages of this
disease. Namely, Kaiser et al. [53] presented the results of a
comprehensive study demonstrating that aortic valve stenosis
occurs in 1% of participants younger than 45 years and that the
prevalence of this condition increases with age, occurring in
59.4% of people older than 80 years.

According to the authors of the aforementioned study,
it is precisely these individuals with Lp(a) levels > 50 mg/dL
who would benefit most from non-contrast CT imaging and,
in the case of AVC, from intensive treatment with drugs that
effectively lower Lp(a) [53].

Using this precise technique, Kaiser et al. [53] demonstrated
that Lp(a) levels correlate positively with volume progression
of both calcified coronary artery plaques and fibrous plaques,
independent of other risk factors. In this study, rapid plaque
progression was documented within 12 months in individuals
with cut-off values of Lp(a)  70mg/dL.

During the lifespan of an average adult, there is no significant
variation in Lp(a) levels. Variations of a purely physiological
nature amount to about 10%. For this reason, it is advisable
to screen high-risk patients only once, without further repeated
Lp(a) level controls, unless medication therapy is added. In
addition, no sex difference in Lp(a) levels was documented,
but ethnic and population differences were noted. Namely, the
lowest Lp(a) levels were found in white race subjects, while
the highest levels were recorded in black subjects. However, the
80th percentile is set as the cutoff value, more specifically, a
value above 50 mg/dL, regardless of race

LDL apheresis has proven to be an effective therapeutic solution,
since literature data and clinical experience suggest that it
can reduce Lp(a) plasma levels by up to 60%[73]. Moreover, LDL
apheresis has been shown to reduce the risk of major adverse CV
events, defined as CV death, coronary bypass surgery, nonfatal
myocardial infarction, percutaneous coronary intervention, or
stenting, by up to 86%, as well as to reduce the annual risk
of myocardial infarction by up to 97%

Two subtypes of mRNA-interfering molecules have been
developed. A representative of one subtype, antisense oligonucleotides,
is Pelacarsen, and the other subtype, corresponding
to small interfering RNA (siRNA), is olpasiran

Currently, pelacarsen (IONIS-APO(a)(Rx) is the focus of
numerous clinical trials with high expectations regarding
its Lp(a)-lowering potential. In phase I/II clinical trial, this
medication showed a significant, dose-dependent reduction
in Lp(a) levels. The highest dose administered, 20 mg/once
weekly, lowered basal levels of Lp(a) by up to 80%

The phase III clinical trial evaluating the efficacy of
pelacarsen and assessing the 5-year cardiovascular outcomes,
called “Assessing the Impact of Lipoprotein(a) Lowering
with Pelacarsen (TQJ230) on Major Cardiovascular Events in
Patients with CVD (Lp(a) HORIZON)” is still ongoing. Eight

thousand three hundred and twenty-four patients (8324) have
been enrolled in the trial, and the first results are expected to be
published in May 2025 [84].


Tomić-Naglić, Dragana, et al. “Direct adsorption of LDL cholesterol-one center experience.” Srpski arhiv za celokupno lekarstvo 00 (2022): 95-95.



Leebmann, Josef, et al. “Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein (a)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study.” Circulation 128.24 (2013): 2567-2576.

In a prospective observational multicenter study, 170 patients were investigated who commenced LA because of Lp(a)-hyperlipoproteinemia and progressive cardiovascular disease.

In patients with Lp(a)-hyperlipoproteinemia, progressive cardiovascular disease, and maximally tolerated lipid-lowering medication, LA effectively lowered the incidence rate of cardiovascular events.

A total of 120 patients were included. Mean Lp(a) concentration before commencing LA was 4.21±1.50 µmol·L−1 (117.9±42.0 mg·dL−1). The mean annual major adverse coronary events (MACE) rate per patient was 1.06 before versus 0.14 during LA treatment (P<0.0001). This difference was impressive, but the study has several weaknesses. Basically, all patients in this study were approved for chronic LA owing to severe hypercholesterolemia only excluding proven familial forms. Concomitant elevation of Lp(a) was not necessarily regarded as the major risk factor in these patients. Further criticisms were selection of patients, lack of prespecified prospective observation, and highly variable individual observation periods before (5.5±5.8 years) as well as during (5.0±3.6 years) chronic LA. The results, however, were sufficient to raise ethical concerns about withholding LA in such particularly high-risk patients if assigned to the control group of a randomized trial. The protocol of a randomized, controlled trial had been suggested, but it failed to achieve ethical approval in Germany. Investigating a concurrent control group of the same patients not treated by LA was regarded not feasible. A candidate patient would unlikely agree to be assigned to an observation group facing his potential risk and knowing about the possibility of LA reimbursement.

In total, 171 consecutive patients were enrolled; CVD was first diagnosed at a mean age of 49.8 years and a mean of 6.7±5.2 years before commencing chronic LA. At the time of first LA, 156 (91.8%) patients had CAD, 77 (45.3%) had concomitant or sole cerebrovascular disease, and 65 (38.2%) had concomitant or sole peripheral atherosclerosis. Eighty-seven (51.2%) patients had a positive family history for CVD in first-degree relatives before the age of 55 for men or 65 years for women. In 96 CAD patients (56.5%), 3-vessel disease was present at the time of first LA.

LA was performed twice per week in 3 (1.8%) patients, weekly in 157 (92.4%) patients, biweekly in 9 (5.3%) patients, and every 3 weeks in 1 (0.6%) patient. For vascular access, peripheral veins were used in 79.9%, arteriovenous fistulas in 20.1%.

Elevated baseline levels of Lp(a) were reduced ≈70% immediately after LA sessions. During steady state of chronic LA, Lp(a) showed a rebound before the next treatment to ≈80% of baseline levels

In total, 142 MACE before LA versus 31 MACE  (78 per cent reduction) during LA could be translated into a number needed to treat of 3 to prevent 1 MACE per patient per year.

Only 1 cardiovascular death occurred during the first 2 years of LA.

LA can be regarded as a reasonable and available therapeutic option for high-risk patients with Lp(a)-HLP and progressive CVD.

Karwatowska-Prokopczuk, Ewa, et al. “Efficacy and safety of pelacarsen in lowering Lp (a) in healthy Japanese subjects.” Journal of clinical lipidology: S1933-2874.

Background: Pelacarsen is a liver-targeted antisense oligonucleotide that potently lowers lipoprotein(a) [Lp(a)] levels. Its safety and efficacy in diverse populations has not been extensively studied.

Objective: To assess the effect of pelacarsen, including monthly dosing of 80 mg, in subjects of Japanese ancestry.

Methods: A randomized double-blind, placebo-controlled, study was performed in 29 healthy Japanese subjects treated with single ascending doses (SAD) of pelacarsen 20, 40 and 80 mg subcutaneously or multiple doses (MD) of pelacarsen 80 mg monthly for 4 doses. The primary objective was to assess the safety and tolerability in healthy Japanese subjects; secondary objectives to assess the pharmacokinetics of pelacarsen; and exploratory objective to determine the effect of pelacarsen on plasma Lp(a) levels.

Results: No serious adverse events or clinically relevant abnormalities in any laboratory parameters were noted. In the MD cohort, mean plasma concentrations of pelacarsen peaked at ∼4 hours and declined in a bi-exponential manner thereafter. In the SAD cohorts, the placebo-corrected least-square mean (PCLSM) percent changes in Lp(a) at Day 30 were: -55.4% (p=0.0008), -58.9% (p=0.0003) and -73.7% (p<0.0001) for the 20 mg, 40 mg, and 80 mg pelacarsen-treated groups, respectively. In the MD cohort, the PCLSM at Days 29, 85, 113, 176 and 204 were -84.0% (p=0.0003), -106.2% (p<0.0001), -70.0 (p<0.0001), -80.0% (p=0.0104) and -55.8% (p=0.0707), respectively.

Conclusions: Pelacarsen demonstrates an acceptable safety and tolerability profile and potently lowers plasma levels of Lp(a) in healthy Japanese subjects, including with the 80 mg monthly dose being evaluated in the Lp(a) HORIZON trial.

Ionis Pharmaceuticals, Inc. Pelacarsen | Ionis Pharmaceuticals, Inc.

Assessing the Impact of Lipoprotein (a) Lowering With Pelacarsen (TQJ230) on Major Cardiovascular Events in Patients With CVD (Lp(a)HORIZON)
Sponsor: Novartis Pharmaceuticals

Ionis Pharmaceuticals, Inc. Pelacarsen

Data from a Phase 2 study showed pelacarsen reduced Lp(a) levels below the recommended threshold of risk for CVD events (<50 mg/dL, <125 nmol/L) in 98% of participants with the dose being used in the Lp(a) HORIZON study.

Pelacarsen, licensed by Novartis for exclusive worldwide development, manufacturing and commercialization, is an investigational antisense medicine designed to reduce apolipoprotein(a) production in the liver to offer a direct approach for reducing circulating lipoprotein(a), or Lp(a), an atherogenic, pro-inflammatory and thrombogenic lipoprotein that induces additional cardiovascular risk independent of LDL-cholesterol, in patients already treated with LDL-C-lowering therapies (such as statins or PCSK9 inhibitors).
About Ionis Pharmaceuticals, Inc.

For more than 30 years, Ionis has been the leader in RNA-targeted therapy, pioneering new markets and changing standards of care with its novel antisense technology. Ionis currently has three marketed medicines and a premier late-stage pipeline highlighted by industry-leading cardiovascular and neurological franchises. Our scientific innovation began and continues with the knowledge that sick people depend on us, which fuels our vision of becoming a leading, fully integrated biotechnology company.

Atherosclerosis Joel Kahn, MD
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Johri AM et al. Progression of atherosclerosis with carnitine supplementation: a randomized controlled trial in the metabolic syndrome. Nutr Metab 2022 2;19:26

Published May 20, 2023

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