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LP(a), Genetics and Cardiovascular Disease

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In my investigation of amla as a possible treatment for my wife's high cholesterol (discussed here and here), I came across this video from Dr. Greger discussing some limited evidence that amla may be beneficial for lowering Lp(a):

Meta-analyses like [1] have shown pretty conclusively that elevated Lp(a) is an independent risk factor for cardiovascular disease. People in the highest third of circulating Lp(a) have about a 60% greater risk of CHD than those in the lowest third, independent of other risk factors including age, sex, smoking status, blood pressure, total cholesterol, triglycerides level, diabetes mellitus, and body mass index.

The last time I had my Lp(a) tested was in 2005 as part of the WUSTL CR study. It was 12mg/dl, which puts me well towards the bottom of the distribution, as shown below:



Fortunately or unfortunately, depending on how you look at it, Lp(a) levels is almost entirely genetically determined, so if you are like my wife and have never at your Lp(a) tested, you can determine whether you are very likely or very unlikely to have elevated Lp(a) if you've had your genetic sequence done by 23andMe or another service.

According to this entry in SNPedia, it is the SNP rs3798220 which is almost entirely responsible for your LP(a) level. Not surprisingly given my low LP(a) blood test reading, I have the low-risk T;T variant for this SNP. I was relieved to find that my wife does too.

This is another one of those cases where genetic testing can provide pretty definitive insights into one's risk factor for a specific, important disease (CHD) that many of us are concerned about. 

For those who have elevated Lp(a), here is a table of interventions from [2] that tend to elevate or lower Lp(a). Surprisingly, statins, a low fat diet, and garlic supplements appear to raise it. Niacin and aspirin are among the things that appear to potentially lower it:




[1] Arch Intern Med. 2008 Mar 24;168(6):598-608. doi: 10.1001/archinte.168.6.598.

Lipoprotein(a) levels and risk of future coronary heart disease: large-scale 
prospective data.

Bennet A(1), Di Angelantonio E, Erqou S, Eiriksdottir G, Sigurdsson G, Woodward 
M, Rumley A, Lowe GD, Danesh J, Gudnason V.

Author information:
(1)Department of Public Health and Primary Care, University of Cambridge, 
Cambridge, England.

Erratum in
    Arch Intern Med. 2008 May 26;168(10):1089.
    Arch Intern Med. 2008 May 26;168(10):1096.

BACKGROUND: Large-scale prospective data are needed to determine whether 
associations between lipoprotein(a) (Lp[a]) and coronary heart disease (CHD) 
risk are independent of established risk factors, to characterize the shape of 
this relationship, and to quantify associations in relevant subgroups.
METHODS: Levels of Lp(a) were measured in samples obtained at baseline from 2047 
patients who had first-ever nonfatal myocardial infarction or who died of CHD 
during the study and from 3921 control participants in the Reykjavik Study (n=18 
569), as well as in paired samples obtained 12 years apart from 372 participants 
to quantify within-person fluctuations.
RESULTS: Baseline Lp(a) levels had little or no correlation with known 
cardiovascular risk factors, such as age, sex, total cholesterol level, and 
blood pressure. The Lp(a) values were highly consistent from decade to decade, 
with a regression dilution ratio (calculated on the log scale) of 0.92 (95% 
confidence interval, 0.85-0.99). The odds ratio for CHD, unaltered after 
adjustment for several established risk factors (age, sex, smoking status, blood 
pressure, total cholesterol, triglycerides level, diabetes mellitus, and body 
mass index), was 1.60 (95% confidence interval, 1.38-1.85) in a comparison of 
extreme thirds of baseline Lp(a) levels. Odds ratios were progressively higher 
with increasing Lp(a) levels and did not vary materially by several individual- 
or study-level characteristics.
CONCLUSIONS: There are independent, continuous associations between Lp(a) levels 
and risk of future CHD in a broad range of individuals. Levels of Lp(a) are 
highly stable within individuals across many years and are only weakly 
correlated with known risk factors. Further assessment of their possible role in 
CHD prevention is warranted.

DOI: 10.1001/archinte.168.6.598
PMID: 18362252 [Indexed for MEDLINE]


[2] Curr Opin Endocrinol Diabetes Obes. 2016 Apr;23(2):157-64. doi: 


Lipoprotein(a): novel target and emergence of novel therapies to lower 
cardiovascular disease risk.

Tsimikas S(1).

Author information:
(1)Vascular Medicine Program, Sulpizio Cardiovascular Center, University of 
California San Diego School of Medicine, La Jolla, California, USA.

PURPOSE OF REVIEW: This article summarizes recent observations on the role of 
lipoprotein(a) [Lp(a)] as a risk factor mediating cardiovascular disease.
RECENT FINDINGS: Lp(a) is a highly prevalent cardiovascular risk factor, with 
levels above 30 mg/dl affecting 20-30% of the global population. Up until now, 
no specific therapies have been developed to lower Lp(a) levels. Three major 
levels of evidence support the notion that elevated Lp(a) levels are a causal, 
independent, genetic risk factor for cardiovascular disease: epidemiologic 
studies and meta-analyses, genome-wide association studies and Mendelian 
randomization studies. Recent studies also have noted that individuals with low 
levels of Lp(a) are associated with a higher risk of incident type 2 diabetes 
mellitus, and conversely individuals with high levels have a lower risk, but 
this association does not appear to be causal. Novel therapies to lower Lp(a) 
include PCSK9 inhibitors and antisense oligonucleotides directly preventing 
translation of apolipoprotein(a) mRNA.
SUMMARY: With this robust and expanding clinical database, a reawakening of 
interest in Lp(a) as clinical risk factor is taking place. Trials are underway 
with novel drugs that substantially lower Lp(a) and may reduce its contribution 
to cardiovascular disease.

DOI: 10.1097/MED.0000000000000237
PMCID: PMC5061509
PMID: 26825471 [Indexed for MEDLINE]

Conflict of interest statement: Dr. Tsimikas is a co-inventor of and receives 
royalties from patents owned by the University of California San Diego on 
oxidation-specific antibodies and has a dual appointment at UCSD and Ionis 
Pharmaceuticals, Inc.

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yes interesting read even if your not interested in the particular drug, but are interested in how science is so often skewed!

it may very well be that statins are effective not so much for lowering cholesterol but for other effects 



4.4. Conclusions

ClinicalTrials.gov is an important open source that reports trial results in a structured way and enables the inclusion of unpublished data in reviews. Our review did not yield evidence that PCSK9 inhibitors decreased the risk of individual targeted and unintended serious diseases. However, in the clinical outcomes studies, alirocumab decreased the risk of all-cause serious morbidity but not of all-cause mortality, whereas evolocumab did not affect the risk of all-cause serious morbidity but probably increased the risk of death. Differences in numbers of events in articles and on ClinicalTrials.gov deserve more attention.

Preventive therapies require elaborate safety analysis before massive use. Regulatory agencies had a special interest in new-onset DM and neurocognitive disorders when reviewing PCSK9 inhibitors. Systematic reviews based on articles about PCSK9 inhibitor trials found no increased risk for these conditions. In addition, no differences in all-cause serious adverse events (SAE) and all-cause mortality between intervention and control groups were found. Hence, alirocumab and evolocumab were considered to be safe and found their way to the market and international treatment guidelines [73,74]. The published results of two large clinical outcomes trials later confirmed the safety profile.

Although our review based on ClinicalTrials.gov data confirmed the initial findings for new-onset DM, neurocognitive events, and all-cause SAE for evolocumab and alirocumab, we found an increased risk of all-cause mortality for evolocumab. ClinicalTrials.gov reported the number of deaths for 3.0 years of follow-up of the FOURIER-trial while the article reported deaths until 2.2 years of follow-up. The number needed to harm was 213. For a preventive therapy, this reflects an unacceptable lack of safety, which questions whether evolocumab should be recalled from the market.

In addition to being safe, preventive medications should also have unambiguous health benefits. Several systematic reviews based on composite outcome data from articles reported a reduction in the risk of cardiovascular events. Therefore, PCSK9 inhibitors are considered to be effective in improving cardiovascular health.

In contrast to trial results reported in articles, trial results registered on ClinicalTrials.gov enable an analysis of individual cardiovascular events. The attending physicians of the trial participants need to record all SAE including (potentially fatal) targeted cardiovascular diseases and (potentially fatal) non-cardiovascular events. The disorders are coded according to the regularly updated, clinically validated dictionary for medical terminology MedDRA, which is imposed by regulatory authorities for use in pharmaceutical trials. We found that PCSK9 inhibitors did not reduce the risk of myocardial infarction, stroke/TIA, and heart failure.

Edited by Mike41
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