Tag: LDL

The new study[1] that I mentioned in an article last week indicates that those with a genetic predisposition to having lower LDL cholesterol and systolic blood pressure have a lower lifetime risk of cardiovascular disease (CVD), but what the study doesn’t mention was that research published last year[2] found that people with the low LDL variant also having a genetic predisposition to lower levels of triglycerides. This begs the question as to whether it is really the lower LDL that lowers the lifetime risk of CVD, or the lower triglycerides or both.

*Note: special thanks to George Henderson (@puddleg) from Auckland, New Zealand for bringing this earlier study to my attention.

That is, it could very well be that perceived benefit of having a genetically lower LDL reported in this new study is actually due to the same people also having a genetic predisposition to having lower levels of triglycerides!

In a large-scale study published in 2018 [2], researchers analyzed data from several hundred thousand individuals. First they estimated associations from summary genetic data from more than 670, 000 people from 9 different European databases. Then they analyzed individual-level genetic data from >390 000 people and looked at the associations of naturally occurring genetic variation coding for lipoprotein lipase (LPL) inhibitors with cardiovascular and metabolic health outcomes. Researchers found that a subset of subjects with a genetic variant to lower LDL-cholesterol levels also had a genetic predisposition to lower triglyceride levels and the group that had both had the lowest odds of coronary artery disease [2]. This 2018 study [2] raises the issue as to whether the results of the current study [1] referred to in last week’s article really indicates that genetically lower LDL levels along with lower systolic blood pressure are responsible for lower rates of lower cardiovascular disease, or whether the lower rates of CVD are due to these same people also having genetically lower levels of triglycerides, (or perhaps a combination of both).

The Risk of Higher Triglycerides

A 2016 study published in the Journal of Circulation [3] examined the health risks associated with high levels of triglycerides in those with CVD. Researchers analyzed data from a large-scale study conducted in Israel (Bezafibrate Infarction Prevention (BIP) trial) which followed > 15,300 people with heart disease for a period of 22 years. At the start of the study, participants had their cholesterol and triglyceride levels measured, as well as other health markers. Based on fasting triglyceride levels, subjects were divided into 5 groups, ranging from low triglyceride levels to extremely high triglyceride levels.

Note: Triglycerides below 150 mg/dL (1.70 mmol/L) are considered normal, whereas triglycerides over 200 mg/dL (2.5 mmol/L) are considered high.

After more than two decades of follow-up, researchers found that compared to subjects with low triglycerides, those with the highest triglyceride levels (> 500 mg/dL / 5.6 mmol/L) had almost a 70% greater risk of death over the 22 year period. In fact, even with subjects with triglycerides of 100 to 149 mg/dL (1.13 – 1.68 mmol/L) the elevated risk of death was detected over subjects with lower triglycerides levels (<100 mg/dl / 1.12 mmol/L).

Evidence is emerging that plasma triglycerides represent a causal risk factor for CVD and that genetic variants in a least 6 genes that modulate plasma triglyceride levels have been linked to CVD [4-12].

Using a research method called multivariable Mendelian randomization, researchers are able to group study subjects based on their genetic markers, so they are naturally randomized.  Using this method, researchers are able to separate the effects on CVD associated with triglycerides from those associated with LDL [13]. It has been found that the effect of genetic variations involving triglyceride increases the risk of CVD independently of LDL concentration.

A 2016 review article [14] postulates that the risk factors surrounding increased plasma triglyceride concentration may involve the metabolism of lipoproteins that carry triglycerides in the blood, and that it could lie in a variant gene that encode for the enzyme lipoprotein lipase (which breaks down triglycerides), or for a gene that encodes for regulators of lipoprotein lipase [14].

Final Thoughts

It’s interesting to study whether those with a genetic predisposition to having lower LDL cholesterol have lower lifetime relative risk of cardiovascular events [1], but further study is needed to factor in the subset of subjects that also have a genetic predisposition to lower triglyceride levels, as well as a genetic variant to lower LDL.

More Info?

References

1. Ference BA, Bhatt DL, Catapano AL et al, Association of Genetic Variants Related to Combined Exposure to Lower Low-Density Lipoproteins and Lower Systolic Blood Pressure With Lifetime Risk of Cardiovascular Disease, JAMA. 2019 Sep 2. doi: 10.1001/jama.2019.14120. [Epub ahead of print]
2. Lotta LA, Stewart ID, Sharp SJ, et al, Association of Genetically Enhanced Lipoprotein Lipase—Mediated Lipolysis and Low-Density Lipoprotein
   Cholesterol—Lowering Alleles With Risk of Coronary Disease
   and Type 2 Diabetes, JAMA Cardiology, 2018;3(10):957-966. doi:10.1001/jamacardio.2018.2866
3. Klempfner R, Erez A, Ben-Zekry S et al, Elevated Triglyceride Level Is Independently Associated With Increased All-Cause Mortality in Patients With Established Coronary Heart Disease, Circulation: Cardiovascular Quality and Outcomes Vol 9(2), 2016, p 100-108, https://doi.org/10.1161/CIRCOUTCOMES.115.002104
4. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study.
   Lancet. 2012;380:572—580. doi: 10.1016/S0140-6736(12)60312-2.
5. Triglyceride Coronary Disease Genetics Consortium and Emerging
   Risk Factors Collaboration, Sarwar N, Sandhu MS, Ricketts SL, et al.
   Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet. 2010;375:1634—1639.
6.  Jí¸rgensen AB, Frikke-Schmidt R, West AS, Grande P, Nordestgaard
   BG, Tybjí¦rg-Hansen A. Genetically elevated non-fasting triglycerides
   and calculated remnant cholesterol as causal risk factors for myocardial
   infarction. Eur Heart J. 2013;34:1826—1833. doi: 10.1093/eurheartj/
   ehs431.
7. Do R, Stitziel NO, Won HH, et al; NHLBI Exome Sequencing Project.
   Exome sequencing identifies rare LDLR and APOA5 alleles conferring
   risk for myocardial infarction. Nature. 2015;518:102—106. doi: 10.1038/
   nature13917.
8. Pollin TI, Damcott CM, Shen H, Ott SH, Shelton J, Horenstein RB,
   Post W, McLenithan JC, Bielak LF, Peyser PA, Mitchell BD, Miller M,
   O’Connell JR, Shuldiner AR. A null mutation in human APOC3 confers
   a favorable plasma lipid profile and apparent cardioprotection. Science.
   2008;322:1702—1705. doi: 10.1126/science.1161524.
9. TG and HDL Working Group of the Exome Sequencing Project, National
   Heart, Lung, and Blood Institute, Crosby J, Peloso GM, Auer PL, et al Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371:22—31.
10. Jí¸rgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjí¦rg-Hansen A.
    Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014;371:32—41. doi: 10.1056/NEJMoa1308027.
11. Folsom AR, Peacock JM, Demerath E, Boerwinkle E. Variation in
    ANGPTL4 and risk of coronary heart disease: the Atherosclerosis Risk
    in Communities Study. Metabolism. 2008;57:1591—1596. doi: 10.1016/j.
    metabol.2008.06.016.
12. Varbo A, Benn M, Tybjí¦rg-Hansen A, Jí¸rgensen AB, Frikke-Schmidt R,
    Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol. 2013;61:427—436. doi: 10.1016/j.
    jacc.2012.08.1026
13. Do R, Willer CJ, Schmidt EM, et al. Common variants associated with
    plasma triglycerides and risk for coronary artery disease. Nat Genet.
    2013;45:1345—1352. doi: 10.1038/ng.2795.
14. Musunuru K, Kathiresan S, Surprises From Genetic Analyses of Lipid Risk
    Factors for Atherosclerosis, Circulation Research; Compendium on Atherosclerosis, 2016;118:579-585. DOI: 10.1161/CIRCRESAHA.115.306398

Share to Flipboard:

A study published September 2, 2019 [1] reported that lower LDL cholesterol levels combined with lower systolic blood pressure are associated with lower lifetime risk of cardiovascular disease (CVD), however there are several factors that need to be kept in mind in considering the results of this study.

First of all, the study looked at data from people that had inherited a genetic marker for having LDL cholesterol that was on average 15 mg/dl (0.39 mmol.L) lower and NOT people that had lower LDL cholesterol due to diet, medication and/or lifestyle interventions. So, even though people with this genetic predisposition of having lower LDL cholesterol had a 26% lower relative risk in of having a serious cardiac event such as a heart attack, need for a stent or death from a heart attack, it says nothing about the amount of benefit that might be achieved by dietary and lifestyle changes or medication.

Secondly, the average triglyceride to HDL ratio of the population studied in the study was 2.5 mg/dl (0.065 mmol/L), which is far from ideal. As outlined in an earlier article about LDL cholesterol and cardiovascular disease, several studies [2,3,4] have found that triglyceride to HDL ratio is a good reflection of LDL particle size; with the small, dense sub-fraction of LDL being atherosclerotic, and the large, fluffy sub-fraction of LDL not being atherosclerotic [5]. In the US, triglyceride to HDL ratio values are expressed in mg/dl and the ratios are interpreted as follows [6];

TG:HDL-C < 2 is ideal

TG:HDL-C > 4 is too high

TG:HDL-C > 6 is much too high

In the present study, the triglyceride to HDL ratio was 2.5 mg/dl, which means that they already had a higher than optimal level of small, dense LDL, predisposing them to cardiovascular risk. By comparing people with a genetic predisposition to lower LDL cholesterol to the risk of a population that already has a less than ideal triglyceride to HDL ratio, it makes the benefit of low LDL seem larger.

Significance of this Study

Sure, it is interesting to study whether those with a genetic predisposition to having lower LDL cholesterol have lower lifetime relative risk of cardiovascular events, but it doesn’t tell us anything about any possible benefit to ordinary people (without this genetic marker) lowering their LDL cholesterol.

As well, by comparing the risk of those with a genetic predisposition to lower LDL cholesterol to a population that already had a higher than ideal level of small, dense LDL, it exaggerates the appearance of perceived benefit of lower LDL cholesterol.

Comparing Apples with Apples

The question is, of what predictive benefit is a study that uses a group of people with a genetic variant to lower LDL cholesterol compared with a reference group that already has higher than ideal triglyceride to HDL ratio?

What can we deduce about those that don’t eat a standard American diet, such as those that eat a low carb or ketogenic diet and have lower overall levels of triglycerides and higher levels of HDL?

Nothing.

We can’t deduce anything.

Which raises the common question; does a low-carbohydrate diet increase the risk of cardiovascular disease?

Looking at what we know; a 2017 study by Chui et al [7] demonstrated that in those eating a low carbohydrate diet, HDL cholesterol increased and while LDL cholesterol also increases, it tends to be the large buoyant LDL that increased, with no change in the atherosclerotic small, dense LDL [7].

As well, a 2012 meta-study analysis of 19 randomized control trials (RCTs) by Santos et al [8] reported that in those eating a low carbohydrate diet, triglyceride levels dropped by 29.71 mg/dL (0.34 mmol/L) and a 2014 study by Bazzano [9] reported that a low carbohydrate diet had a greater decrease in 10-year cardiovascular heart disease (CHD) risk score based on the Framingham Risk Score, than those on the low fat diet.

Final Thoughts

When we read headlines that indicate that “low LDL lowers lifetime risk of cardiovascular disease” we need to look closer at who is being studied.

A study about those with a specific genetic variation tell us nothing about the general public without it. It also tells us nothing about whether lowering LDL cholesterol through drugs or diet has any of the same benefits as having this genetic variation.

We also need to ask ourselves about whether the group being used for comparison purposes has optimal markers, or are already sub-optimal and inflates the perceived benefit and what about what they are eating? Is it relevant to those of us that follow a low-carbohydrate lifestyle?

UPDATE (Sept 22, 2019): in a new follow-up article, another study from last year raises a question as to how much of the lower CVD in due to lower LDL and blood pressure or due to this same variant also having lower triglycerides. You can read the new article here.

More Info?

References

1. Ference BA, Bhatt DL, Catapano AL et al, Association of Genetic Variants Related to Combined Exposure to Lower Low-Density Lipoproteins and Lower Systolic Blood Pressure With Lifetime Risk of Cardiovascular Disease, JAMA. 2019 Sep 2. doi: 10.1001/jama.2019.14120. [Epub ahead of print]
2. Hanak V, Munoz J, Teague J, et al, Accuracy of the triglyceride to high-density lipoprotein cholesterol ratio for prediction of the low-density lipoprotein phenotype B, The American Journal of Cardiology, Volume 94, Issue 2, 2004, Pages 219-222, https://doi.org/10.1016/j.amjcard.2004.03.069
3. McLaughlin T, Reaven G, Abbasi F, et al. Is there a simple way to
   identify insulin-resistant individuals at increased risk of cardiovascular
   disease? Am J Cardiol. 2005;96(3):399Y404.
4. Vega GL, Barlow CE, Grundy SM et al, Triglyceride to High Density Lipoprotein Cholesterol Ratio is an Index of Heart Disease Mortality and of Incidence of Type 2 Diabetes Melletus in Men, Journal of Investigative Medicine & Volume 62, Number 2, February 2014
5. Lamarche, B., I. Lemieux, and J.P. Després, The small, dense LDL phenotype and the risk of coronary heart disease: epidemiology, patho-physiology and therapeutic aspects. Diabetes Metab, 1999. 25(3): p. 199-211.
6. Sigurdsson AF, The Triglyceride/HDL Cholesterol Ratio, updated January 12, 2019, https://www.docsopinion.com/2014/07/17/triglyceride-hdl-ratio/
7. Chiu S, Williams PT, Krauss RM. Effects of a very high saturated fat diet on LDL particles in adults with atherogenic dyslipidemia: A randomized controlled trial, PLoS One. 2017 Feb 6;12(2):e0170664. doi: 10.1371/journal.pone.0170664
8. Santos FL, Esteves SS, da Costa Pereira A, Systematic review and meta-analysis of clinical trials of the effects of low carbohydrate diets on cardiovascular risk factors. Obes Rev. 2012 Nov;13(11):1048-66. doi: 10.1111/j.1467-789X.2012.01021
9. Bazzano LA, Hu T, Reynolds K, et al. Effects of Low-Carbohydrate and Low-Fat Diets: A Randomized Trial, Ann Intern Med. 2014;161:309—318. doi: 10.7326/M14-0180

Share to Flipboard: