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.
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References
- 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]
- 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
- 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. - 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
- 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.
- Sigurdsson AF, The Triglyceride/HDL Cholesterol Ratio, updated January 12, 2019, https://www.docsopinion.com/2014/07/17/triglyceride-hdl-ratio/
- 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
- 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
- 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
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