Debunking Lipid Arguments
Guest Post
Vertti N., aka @the_nutrition_ninja on Instagram, is a nutrition and lipid enthusiast. He is a close friend of mine, I consider him very knowledgeable when it comes to nutrition and lipidology.
What is lipidology?
Before we discuss lipidology we need to talk about lipids themselves. When we talk about lipids we are talking about fat, fat from food and how fat is used in the body. Lipids actually travel through your blood and are important for your body which is why they need to be studied. Hence, lipidology is the scientific study of lipids. Clinical lipidology deals with the relationship between diseases and lipids, think the relationship between LDL cholesterol and heart disease.
Unfortunately, to get into clinical lipidology you would need to know A LOT. However, there are some pretty good basic resources and more detailed resources on the subject matter.
Diet and Lipids
Diet often comes up in the conversation about lipids. This is due to the fact the fat we ingest influences the cholesterol in our body which can influence our risk of diseases (think heart disease again).
The evidence we do have for the diet/lipid relationship largely points to saturated fat (think lard, mayonnaise, butter, and fatty red meat) causing increases of detrimental forms of cholesterol, such as LDL-C, when ingested above a certain amount. We also have evidence consuming polyunsaturated fat (think fatty fish, canola oil, fish oil, and tree nuts) leads to decreases in LDL cholesterol and a better profile of lipids in the blood.
However, as you all know certain individuals have ideological differences when it comes to diet. Certain diets high in saturated fat from animal sources (the keto and carnivore diet) can lead to more detrimental blood lipid profiles which can increase risk of atherosclerosis (plaque in the arteries). Rather than admitting the long term potential risk of such dietary approaches, zealous supporters opt to downplay or outright reject the relationship between heart disease, lipid profiles, and dietary factors.
This leads us to common but factually wrong talking points you will likely encounter when it comes to the relationship between blood lipids, heart health, and diet.
Common Arguments and Rebuttals
You will often hear in carnivore circles:
"Actually LDL-c tells you nothing. ApoB or particle number - LDL-p would be more informative. Looking at LDL-c without considering the metabolic environment is useless because it tells you nothing of cholesterol quality. Cholesterol is not necessary for plaque to form."
These arguments portray a fundamental lack of understanding of scientific causality and the role of different blood lipids in disease. Although apolipoprotein B is now widely considered the most comprehensive prognostic marker of atherogenicity in any given individual, discordant or not, it's important to emphasize that the retention of cholesterol within the arterial intima is still the initiating process of atherosclerosis [1-3]. Thus, to sustain the case that LDL-c as a biomarker "tells us nothing" is to uphold a ludicrous narrative that grotesquely misrepresents the evidence base.
From a recent review by Sniderman et al. [3]:
"(...) more, smaller, cholesterol-depleted particles will be trapped than will a similar number of larger, cholesterol-enriched particles that have entered an arterial wall. On the other hand, the more cholesterol within an apoB particle that has been trapped within the arterial wall, the more cholesterol that will be released at that site to injure the wall. There is, therefore, an equivalence between greater injury per particle from trapping of cholesterol-richer particles, but greater injury from trapping of more cholesterol-depleted particles. The net result is that all LDL particles pose, more or less, equal risk."
Other common arguments include:
"But with high HDL and TGs under 100 you have an insulin sensitive environment which is an indicator of cholesterol quality - large fluffy vs small sense. You also have less inflammation in an insulin sensitive environment. Chronic high insulin drives inflammation in the endothelial tissue and these people were able to get off of their insulin - much more important than the total weight of the cholesterol. It should be very clear that getting a person off of insulin is far more important than an elevation in LDL-c."
This is categorically untrue. Findings from Mendelian randomization studies and human drug interventions converge in favor of the conclusion that HDL-c, as opposed to an independent causal risk factor like LDL-c, is a systems biomarker that can inform the broader clinical picture about underlying cardiometabolic processes [4-8]. The same applies to inflammation, too: if inflammation measured by hsCRP were causal for atherosclerotic cardiovascular disease, we would see a high prevalence of heart disease among hunter-gathering populations with chronically elevated systemic inflammation but concomitantly low saturated fat intake and total cholesterol. However, this isn't the case [9, 10]. Trials that have achieved clinically meaningful reductions in relative CVD risk irrespective of baseline hsCRP by pharmacologically lowering LDL also contradict this argument [11, 12]. There's no evidence that LDL-c is only atherogenic in the context of insulin resistance and/or high systemic inflammation.
Conclusions
Lipidology is the scientific study of lipids. In addition, from a clinical and public health perspective we are interested in the relationship between blood lipids and heart health. One factor which impacts blood lipids and heart health outcomes is diet.
Certain diets high in saturated fat from animal sources (the keto and carnivore diet) can lead to more detrimental blood lipid profiles which can increase risk of atherosclerosis (plaque in the heart) compared to diets with higher amounts of polyunsaturated fat.
LDL-c is an important biomarker to consider as cholesterol retention in the arteries of any apoB containing particles (this includes LDL-c) can lead to the development of plaque (atherosclerosis).
LDL-c can be atherogenic regardless of insulin levels and inflammation. Make sure to have a diet which the primary source of fat comes from polyunsaturated fat… this can include eating fatty fish, tree nuts, and vegetable or seed oils.
References:
1. Ference et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017 Aug 21;38(32):2459-2472.
2. Borén et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2020 Jun 21;41(24):2313-2330.
3. Sniderman et al. Apolipoprotein B Particles and Cardiovascular Disease: A Narrative Review. JAMA Cardiol. 2019 Dec 1;4(12):1287-1295.
4. Güleç et al. High-density lipoprotein cholesterol and risk of cardiovascular disease. ESC. Vol. 19, N° 3 - 04 Nov 2020.
5. Richardson et al. Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis. PLoS Med. 2020 Mar 23;17(3):e1003062.
6. Voight et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. 2012 Aug 11;380(9841):572-80.
7. Haase et al. LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals. J Clin Endocrinol Metab. 2012 Feb;97(2):E248-56.
8. Ohukainen et al. Vexed causal inferences in nutritional epidemiology - call for genetic help. Int J Epidemiol. 2021 Aug 13:dyab152.
9. Gurven et al. Inflammation and infection do not promote arterial aging and cardiovascular disease risk factors among lean horticulturalists. PLoS One. 2009 Aug 11;4(8):e6590.
10. Kaplan et al. Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study. Lancet. 2017 Apr 29;389(10080):1730-1739.
11. Storey et al. Lowering LDL cholesterol reduces cardiovascular risk independently of presence of inflammation. Kidney International. 2018;93(4):1000-1007.
12. Bohula et al. Inflammatory and Cholesterol Risk in the FOURIER Trial. Circulation. 2018;138(2):131-140.