This is a thoughtful discussion with some interesting thoughts. I note that in the comments there are indications that diet can increase or lower lp(a).
"Nonetheless, the apo(a) size distribution in centenarians did not entirely explain the high Lp(a) levels observed in this population. Factors other than apo(a) size, and which may be either genetic or environmental in nature, appear to contribute to the elevated plasma Lp(a) levels of our centenarian population. We conclude therefore that high plasma Lp(a) levels are compatible with longevity." 1998 article by J Thillet
That is based on one 1998 study. More recent studies show that high Lp(a) is a strongly associated with reduced longevity.
"In 18 720 participants from EPIC-Norfolk (5686 cases), the mortality risk for those with Lp(a) levels equal to or above the 95th percentile was equivalent to being 1.5 years older in chronologic age (β coefficient [SE], 0.194 [0.064])."
Older studies are more honest. The study you provided is from many drug companies so of course they will try to find a fault that your Lp(a) levels will always be wrong. The last thing you want is low levels of Lp(a) to completely destroy your health. 2012 article title: Low Lipoprotein(a) Concentration Is Associated with Cancer and All-Cause Deaths: A Population-Based Cohort Study (The JMS Cohort Study)
1996 study: In centenarians the mean Lp(a) level increased (39.6 ± 23.53 mg/dl) compared to that of the control group (16.78 ± 16.24 mg/dl) (p < 0.005). The elevated Lp(a) values observed in centenarians may be attributed to the presence of low molecular weight lipoprotein isoforms which are known to be associated with cardio-cerebrovascular risk. Therefore, it seems that elevated Lp(a) levels alone are not risk factors for the onset of acute vascular accidents and do not influence longevity.
I’m still “wait and see” on the “Lp(a) hypothesis”. But if this phase 3 study shows CV outcome benefits (and helps to demonstrate high Lp(a) to be a causal agent and not merely a marker/bystander), then that will change my approach.
How rare is the testing for this lipid? Given that I had to cajole my doctor just to get ApoB testing (despite a diagnosis of FH) I would think the pool is very small? And the site to check if you’d qualify for the trial seems to only want you if you’ve had a cardiac event. Possibly it works better on a computer
Recognition of Lp(a) importance is growing but I am amazed that I have seen dozens of patients with stents or MI in their 40s or 50s who had never had lipoprotein (a) tested.
I'm not sure which pool is very small.
The trial is enrolling those who have had an event and >18 years old but also those without a cardiac event if >55 years with high enough risk.
Fascinating and I’m glad they are doing the trials. Are the primary outcomes patient-centered (like reduction in ASCVD events)?
The whopping >90% reduction strikes me as too much, but that’s just a knee jerk reaction. I AI’d this (made up that verb just now) and here is what I get as an answer to the question of whether Lp(a) has any beneficial properties in the body. If it does, then such near total reduction might not be good for overall outcomes besides ASCVD?
Quote:
Lipoprotein(a), often abbreviated as Lp(a), is a complex particle in the blood that has been the subject of much research in recent years:
1. What the body uses Lp(a) for:
The exact physiological role of Lp(a) in the body is not fully understood. However, it's believed to have some functions related to:
- Blood clotting: Lp(a) may play a role in the coagulation process and wound healing.
- Tissue repair: It might be involved in delivering cholesterol to sites of tissue injury for cell membrane repair.
- Immune function: Some research suggests it may have a role in innate immunity.
2. Beneficial properties:
While Lp(a) is often discussed in terms of its potential negative effects on cardiovascular health, there are some potentially beneficial aspects:
- Antioxidant properties: Lp(a) contains enzymes that may help reduce oxidative stress in the body.
- Wound healing: Its potential role in tissue repair could be beneficial for wound healing processes.
- Evolutionary advantage: The fact that Lp(a) has been conserved through evolution suggests it may have had some survival benefit, though this is still debated.
It's important to note that while these potential benefits exist, high levels of Lp(a) are generally considered a risk factor for cardiovascular disease. The balance between its potential beneficial and harmful effects is still an active area of research.
2012 article title: Low Lipoprotein(a) Concentration Is Associated with Cancer and All-Cause Deaths: A Population-Based Cohort Study (The JMS Cohort Study)
Fascinating article. Leaves a lot of questions but perhaps there is a sweet spot for Lp (a) - not too high, not too low from this study. Balance between CV risk and malignancy risk?
This 2024 paper based on NHANES data and multiple recent reviews find that both CV death and non CV death and cancer death are positively associated with cancer risk. Higher Lp(a) higher cancer mortality. These are observational studies and both the positive and negative associations with cancer may turn out to be non-causal.
It's a phase 2 study. They are looking at biomarkers and safety signals.
The AI comments also apply to LDL and cholesterol and those who choose to ignore the benefits of LDL lowering often point to the incredibly important role cholesterol plays in brain development, etc. Needless to say, studies have shown LDL-lowering to even super low levels is beneficial without demonstrable harm.
My understanding is that a similar medication, Pelacarsen, may be available as early as next year. But if you enroll in the trial, you have a 50% chance of being locked into the placebo group for 4 to 5 years. Arguably, you may be better off just waiting to see what happens with Pelacarsen.
We don't have RCT outcomes and long term safety data on any drug specifically targeting Lp(a). Until those become available we don't know if pelacarsen or any other proposed treatment will be safe and result in improved cardiovascular outcomes.
Not to worry, the FDA will not be approving lp(a) lowering drugs based on surrogate outcomes. It is requiring outcomes trials. The pelacarsen outcomes trial is scheduled to be completed in mid-2025. However, it is purely a secondary prevention trial, so I don’t know if (assuming the trial is successful) the initial indications will include primary prevention.
A buddy of mine who used to work at drug approval agency always told me three things: 1) try not to take a drug the first year it is available since they can hardly ever catch the rare side effects like liver damage until it’s been given to many more patients; 2) Avandia taught him that lowering a blood marker may not always make any difference and in some cases can do harm; and 3) he would tell me to see who they studied and how did they react? So for example, if you’re an older African-American male and if they haven’t included anybody of your race and age so far in their trials, you’re going to be the first one. Do you want to be the first one?
No detectable side effect signal in the small trial showing efficacy in Lp(a) lowering I referenced. However, this is why we have to do the large , long duration RCTs. This one will have 12,500 patients. Both efficacy and longer term safety are going to be closely analyzed.
Patients who participate in these trials have to hope a) they get the active drug and b) the active drug lowers their risk of disease without significant side effects. Many of my patients have expressed an eagerness to participate in such a trial.
The Big Deal About Lipoprotein (a):
https://cholesterolcode.com/the-big-deal-about-lipoproteina/
This is a thoughtful discussion with some interesting thoughts. I note that in the comments there are indications that diet can increase or lower lp(a).
Lower LDL leads to higher mortality rates
https://pubmed.ncbi.nlm.nih.gov/18000291/
https://onlinelibrary.wiley.com/doi/full/10.1111/j.1348-0421.2009.00203.x
"Nonetheless, the apo(a) size distribution in centenarians did not entirely explain the high Lp(a) levels observed in this population. Factors other than apo(a) size, and which may be either genetic or environmental in nature, appear to contribute to the elevated plasma Lp(a) levels of our centenarian population. We conclude therefore that high plasma Lp(a) levels are compatible with longevity." 1998 article by J Thillet
Centenarians have elevated levels of Lp(a) so the goal should be to create a lifestyle to get the Lp(a) levels high enough to be optimal right?
That is based on one 1998 study. More recent studies show that high Lp(a) is a strongly associated with reduced longevity.
"In 18 720 participants from EPIC-Norfolk (5686 cases), the mortality risk for those with Lp(a) levels equal to or above the 95th percentile was equivalent to being 1.5 years older in chronologic age (β coefficient [SE], 0.194 [0.064])."
(https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2762018)
Older studies are more honest. The study you provided is from many drug companies so of course they will try to find a fault that your Lp(a) levels will always be wrong. The last thing you want is low levels of Lp(a) to completely destroy your health. 2012 article title: Low Lipoprotein(a) Concentration Is Associated with Cancer and All-Cause Deaths: A Population-Based Cohort Study (The JMS Cohort Study)
There is one 25 year old study which has not been replicated that you are citing.
Here are the author's positions in the study I cited. None of them are employed by drug companies.
1Québec Heart and Lung Institute, Québec City, Québec, Canada
2Department of Medicine, Faculty of Medicine, Université Laval, Québec City, Québec, Canada
3Department of Cardiology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands
4MRC Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom
5Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
6Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec City, Québec, Canada
7Department of Surgery, Faculty of Medicine, Université Laval, Québec City, Québec, Canada
8Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Université Laval, Québec City, Québec, Canada
1996 study: In centenarians the mean Lp(a) level increased (39.6 ± 23.53 mg/dl) compared to that of the control group (16.78 ± 16.24 mg/dl) (p < 0.005). The elevated Lp(a) values observed in centenarians may be attributed to the presence of low molecular weight lipoprotein isoforms which are known to be associated with cardio-cerebrovascular risk. Therefore, it seems that elevated Lp(a) levels alone are not risk factors for the onset of acute vascular accidents and do not influence longevity.
I’m still “wait and see” on the “Lp(a) hypothesis”. But if this phase 3 study shows CV outcome benefits (and helps to demonstrate high Lp(a) to be a causal agent and not merely a marker/bystander), then that will change my approach.
How rare is the testing for this lipid? Given that I had to cajole my doctor just to get ApoB testing (despite a diagnosis of FH) I would think the pool is very small? And the site to check if you’d qualify for the trial seems to only want you if you’ve had a cardiac event. Possibly it works better on a computer
Recognition of Lp(a) importance is growing but I am amazed that I have seen dozens of patients with stents or MI in their 40s or 50s who had never had lipoprotein (a) tested.
I'm not sure which pool is very small.
The trial is enrolling those who have had an event and >18 years old but also those without a cardiac event if >55 years with high enough risk.
Depending on which state you're in, you can order the lipo(a) test yourself from Labcorp for $49. You don't need a prescription.
Yes. I've had many patients order this for themselves before they came to me.
Fascinating and I’m glad they are doing the trials. Are the primary outcomes patient-centered (like reduction in ASCVD events)?
The whopping >90% reduction strikes me as too much, but that’s just a knee jerk reaction. I AI’d this (made up that verb just now) and here is what I get as an answer to the question of whether Lp(a) has any beneficial properties in the body. If it does, then such near total reduction might not be good for overall outcomes besides ASCVD?
Quote:
Lipoprotein(a), often abbreviated as Lp(a), is a complex particle in the blood that has been the subject of much research in recent years:
1. What the body uses Lp(a) for:
The exact physiological role of Lp(a) in the body is not fully understood. However, it's believed to have some functions related to:
- Blood clotting: Lp(a) may play a role in the coagulation process and wound healing.
- Tissue repair: It might be involved in delivering cholesterol to sites of tissue injury for cell membrane repair.
- Immune function: Some research suggests it may have a role in innate immunity.
2. Beneficial properties:
While Lp(a) is often discussed in terms of its potential negative effects on cardiovascular health, there are some potentially beneficial aspects:
- Antioxidant properties: Lp(a) contains enzymes that may help reduce oxidative stress in the body.
- Wound healing: Its potential role in tissue repair could be beneficial for wound healing processes.
- Evolutionary advantage: The fact that Lp(a) has been conserved through evolution suggests it may have had some survival benefit, though this is still debated.
It's important to note that while these potential benefits exist, high levels of Lp(a) are generally considered a risk factor for cardiovascular disease. The balance between its potential beneficial and harmful effects is still an active area of research.
2012 article title: Low Lipoprotein(a) Concentration Is Associated with Cancer and All-Cause Deaths: A Population-Based Cohort Study (The JMS Cohort Study)
Fascinating article. Leaves a lot of questions but perhaps there is a sweet spot for Lp (a) - not too high, not too low from this study. Balance between CV risk and malignancy risk?
This 2024 paper based on NHANES data and multiple recent reviews find that both CV death and non CV death and cancer death are positively associated with cancer risk. Higher Lp(a) higher cancer mortality. These are observational studies and both the positive and negative associations with cancer may turn out to be non-causal.
https://pubmed.ncbi.nlm.nih.gov/39026192/
It's a phase 2 study. They are looking at biomarkers and safety signals.
The AI comments also apply to LDL and cholesterol and those who choose to ignore the benefits of LDL lowering often point to the incredibly important role cholesterol plays in brain development, etc. Needless to say, studies have shown LDL-lowering to even super low levels is beneficial without demonstrable harm.
Good points, thank you!
A wise man once said "don't bring a mechanism to an epidemiology fight."
I appreciate the outcomes data that bake in all the mechanisms, and know it takes time and lots of effort to get there with RCT's etc.
My understanding is that a similar medication, Pelacarsen, may be available as early as next year. But if you enroll in the trial, you have a 50% chance of being locked into the placebo group for 4 to 5 years. Arguably, you may be better off just waiting to see what happens with Pelacarsen.
We don't have RCT outcomes and long term safety data on any drug specifically targeting Lp(a). Until those become available we don't know if pelacarsen or any other proposed treatment will be safe and result in improved cardiovascular outcomes.
Not to worry, the FDA will not be approving lp(a) lowering drugs based on surrogate outcomes. It is requiring outcomes trials. The pelacarsen outcomes trial is scheduled to be completed in mid-2025. However, it is purely a secondary prevention trial, so I don’t know if (assuming the trial is successful) the initial indications will include primary prevention.
A buddy of mine who used to work at drug approval agency always told me three things: 1) try not to take a drug the first year it is available since they can hardly ever catch the rare side effects like liver damage until it’s been given to many more patients; 2) Avandia taught him that lowering a blood marker may not always make any difference and in some cases can do harm; and 3) he would tell me to see who they studied and how did they react? So for example, if you’re an older African-American male and if they haven’t included anybody of your race and age so far in their trials, you’re going to be the first one. Do you want to be the first one?
No detectable side effect signal in the small trial showing efficacy in Lp(a) lowering I referenced. However, this is why we have to do the large , long duration RCTs. This one will have 12,500 patients. Both efficacy and longer term safety are going to be closely analyzed.
Patients who participate in these trials have to hope a) they get the active drug and b) the active drug lowers their risk of disease without significant side effects. Many of my patients have expressed an eagerness to participate in such a trial.