Evidence Library: Cholesterol

Have you ever wanted to see some actual studies backing up the Paleo position on cholesterol?

This evidence library is a collection of a few interesting studies and reviews that are interesting from a Paleo perspective. It’s not a comprehensive list of every scientific publication about cholesterol (that would take all year), and it’s not a systematic review with a comprehensive discussion of every study’s merits and flaws.  It's just a look at some interesting, thought-provoking perspectives and experiments relevant to Paleo eating.

Click on one of the tabs below to get started!

About the Studies

• Epidemiological studies: these studies measure associations between things. They can’t prove causation. Many sensationalized media headlines are written by people who don’t understand this – “associated with” does not mean “causes.”
• Randomized controlled studies: these studies divide the subjects into two groups: an intervention group and a control/placebo group. Everything except the intervention is the same for both groups. These studies can measure the effect of changing just one thing (the intervention), and show that the changes were caused by the intervention, not by other confounding factors.
• Meta-analyses and reviews: these studies summarize results from other studies in a convenient package or provide expert opinions – they're great for avoiding potential weird results in one individual study.

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[tab title="Dietary Cholesterol and Blood Cholesterol" id="t1"]

The Paleo take: in most people, dietary cholesterol from whole foods does not raise blood cholesterol. In a minority of people, it does raise blood cholesterol, but not in an atherogenic (causing heart disease) pattern.

Fernandez, ML, and Calle, M. Revisiting dietary cholesterol recommendations: does the evidence support a limit of 300 mg/d?

At a Glance:

• Type of study: review article
• About the study subjects: n/a
• Free full-text: no

“These dietary recommendations proposed in the 1960s had little scientific evidence other than the known association between saturated fat and cholesterol and animal studies where cholesterol was fed in amounts far exceeding normal intakes. In contrast, European countries, Asian countries, and Canada do not have an upper limit for DC [Dietary Cholesterol]. Further, current epidemiologic data have clearly demonstrated that increasing concentrations of DC are not correlated with increased risk for CHD. Clinical studies have shown that even if DC may increase plasma low-density lipoprotein (LDL) cholesterol in certain individuals (hyper-responders), this is always accompanied by increases in high-density lipoprotein (HDL) cholesterol, so the LDL/HDL cholesterol ratio is maintained. More importantly, DC reduces circulating levels of small, dense LDL particles, a well-defined risk factor for CHD. This article presents recent evidence from human studies documenting the lack of effect of DC on CHD risk, suggesting that guidelines for DC should be revisited.”

Herron, KL, et al. Men classified as hypo- or hyperresponders to dietary cholesterol feeding exhibit differences in lipoprotein metabolism. The Journal of Nutrition, 2003.

At a Glance:

• Type of study: randomized controlled trial.
• About the study subjects: 40 men, age 18-57.
• Free full-text: yes.

“These data suggest that additional dietary cholesterol does not increase the risk of developing an atherogenic lipoprotein profile ["atherogenic lipoprotein profile" = a blood cholesterol profile associated with an increased risk of heart disease] in healthy men, regardless of their response classification.”

Herron, KL, et al. Pre-menopausal women, classified as hypo- or hyperresponders, do not alter their LDL/HDL ratio following a high dietary cholesterol challenge. Journal of the American College of Nutrition, 2002.

At a Glance:

• Type of study: randomized controlled trial.
• About the study subjects: 51 women, age 18-49.
• Free full-text: no.

“These data revealed that excess dietary cholesterol does not increase the risk of developing an atherogenic lipoprotein profile in pre-menopausal women, regardless of their response classification”

A B Nichols, C Ravenscroft, D E Lamphiear, and L D Ostrander Jr. Daily nutritional intake and serum lipid levels. The Tecumseh study. American Journal of Clinical Nutrition, 1976

At a Glance:

• Type of study: epidemiological
• About the study subjects: 2039 men and women from Michigan
• Free full-text: yes.

“To determine the influence of diet on serum cholesterol and triglyceride levels among adults, 24-hr dietary recall interviews were conducted among 957 men and 1,082 women resident in the community of Tecumseh, Michigan…Cholesterol and triglyceride levels were unrelated to quality, quantity, or proportions of fat, carbohydrate, or protein consumed in the 24-hr recall period.”

Hu, T., et al. Effects of low-carbohydrate diets versus low-fat diets on metabolic risk factors: a meta-analysis of randomized controlled clinical trials. American Journal of Epidemiology, 2012.

At a Glance:

• Type of study: meta-analysis of randomized controlled trials
• About the study subjects: 2,788 adults (about 40% men and 60% women) in total from 23 separate studies
• Free full-text: yes.

"Compared with participants on low-fat diets, persons on low-carbohydrate diets experienced a slightly but statistically significantly lower reduction in total cholesterol, and low density lipoprotein cholesterol [LDL, "bad" cholesterol], but a greater increase in high density lipoprotein [HDL, "good" cholesterol] cholesterol and a greater decrease in triglycerides...These findings suggest that low-carbohydrate diets are at least as effective as low-fat diets at reducing weight and improving metabolic risk factors"

(note that "low-carbohydrate" here meant up to 45% of calories from carbs, not keto. It's only "low-carb" relative to the Standard American Diet.)

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[tab title="Dietary Cholesterol and Health" id="t2"]

The Paleo take: dietary cholesterol in general in the American diet may be associated with various diseases, but that’s because most people get their dietary cholesterol from Big Macs and pizza – “cholesterol” is really a way to measure junk food. Dietary cholesterol from whole, unprocessed foods is not dangerous.

Hu, F, et al. A Prospective Study of Egg Consumption and Risk of Cardiovascular Disease in Men and Women. Journal of the American Medical Association, 1999.

At a Glance:

• Type of study: prospective cohort study
• About the study subjects: 117,933 American men and women (about 30% men), age 34-74.
• Free full-text: yes.

"These findings suggest that consumption of up to 1 egg per day is unlikely to have substantial overall impact on the risk of CHD [coronary heart disease] or stroke among healthy men and women...Egg consumption was positively associated with smoking, lower physical activity, and a generally unhealthy eating pattern (ie, more whole milk, red meat, and bacon and less skim milk, vegetables, and fruits) in men. Confounding due to these factors would artifactually produce an elevated risk for egg consumption."

(the reason why it only measured 1 egg per day is that they didn't have enough study subjects eating more than that. This does not prove that eating more than 1 egg per day will give you heart disease.)

Note: a 2000 review of the epidemiological evidence found that this study was the only epidemiological study up to that date that adequately controlled for the association of eggs with an overall unhealthy diet pattern. Other studies on egg consumption or cholesterol consumption in general did not adequately control for the junk food association.

Qureshi et al. Regular egg consumption does not increase the risk of stroke and cardiovascular diseases. Medical Science Monitor, 2007.

At a Glance:

• Type of study: prospective cohort study
• About the study subjects: 9734 American adults (men and women) age 25-74.
• Free full-text: yes.

“no significant difference was observed between persons who consumed greater than 6 eggs per week compared to those who consume none or less than 1 egg per week in regards to any stroke…ischemic stroke…, or coronary artery disease.”

Mente, A, et al. A systematic review of the evidence supporting a causal link between dietary factors and coronary heart disease. JAMA Internal Medicine, 2009

At a Glance:

• Type of study: meta-analysis of prospective cohort studies and randomized trials.
• About the study subjects: varies for each nutrient studied; in general they were adults, both men and women.
• Free full-text: yes.

"Insufficient evidence…of association [with coronary heart disease] is present for intake of supplementary vitamin E and ascorbic acid (vitamin C); saturated and polyunsaturated fatty acids; total fat; alpha-linolenic acid; meat; eggs; and milk."

Kratz, M. Dietary cholesterol, atherosclerosis and coronary heart disease. Handbook of Experimental Pharmacology, 2005.

At a Glance:

• Type of study: article
• About the study subjects: n/a
• Free full-text: no.

"Based on these studies, the association between dietary cholesterol and CHD [coronary heart disease] risk is, if anything, minor in nature. This is consistent with the finding that an increase in dietary cholesterol intake results in only a minimal increase in the total/high-density lipoprotein cholesterol ratio. Taken together these studies suggest that the association between dietary cholesterol and CHD is small, as most subjects can effectively adapt to higher levels of cholesterol intake."

Fernandez, ML. Dietary cholesterol provided by eggs and plasma lipoproteins in healthy populations. Current opinion in Clinical Nutrition and Metabolic Care, 2006.

At a Glance:

• Type of study: review article
• About the study subjects: n/a
• Free full-text: no.

"Egg intake has been shown to promote the formation of large LDL, in addition to shifting individuals from the LDL pattern B to pattern A, which is less atherogenic [atherogenic = "causes heart disease"]...We need to acknowledge that diverse healthy populations experience no risk in developing coronary heart disease by increasing their intake of cholesterol."

Scientific Report of the 2015 Dietary Guidelines for Americans Advisory Committee

OK, this one’s not a study. But for the first time, the 2015 recommendations took cholesterol off the “nutrients of concern” list because the authors couldn’t find compelling evidence that it caused heart disease or anything else.

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[tab title="Blood Cholesterol and Health" id="t3"]

The Paleo take: cholesterol is much more complicated than one number, and its relationship to health is still not clear. Even dividing it into "good" HDL and "bad" LDL is completely oversimplifying. And in the well-intentioned but probably misguided flurry to lower cholesterol at all costs, we've lost track of the fact that low cholesterol is also dangerous. You need this stuff: it's there for a reason!

Carmena, R, et al. Atherogenic lipoprotein particles in atherosclerosis. Circulation, 2004.

At a Glance:

• Type of study: review.
• About the study subjects: n/a
• Free full-text: yes.

"increasing research attention over the past decade has been devoted to the heterogeneity of LDL particles and the atherogenicity of lipids and lipoproteins other than LDL. Particularly atherogenic forms of LDL include small, dense LDL particles and oxidized LDL. All lipoproteins that contain apolipoprotein B, such as LDL, very-low-density lipoprotein, and intermediate-density lipoprotein, tend to promote atherosclerosis; however, these particles differ in their apolipoprotein and triglyceride content. High levels of plasma triglycerides increase the risk of acute coronary events. Lipoprotein(a) is now considered an independent risk factor in both men and women. "

This review gives you the long version. The short version: it's complicated.

Mitra, S, et al. The role of oxidized low-density lipoproteins in atherosclerosis: the myths and the facts. Mediators of Inflammation, 2013.

• Type of study: review.
• About the study subjects: n/a
• Free full-text: yes.

"data available so far strengthen the pivotal role for oxidative stress in atherosclerosis."

A lot of recent evidence suggests that it's not it's not LDL per se that causes problems, but oxidized LDL (if you don't know what that means, here's an explanation) - this study looks at the evidence for that and concludes that it's convincing.

Fuchs, FD et al. Proof of concept in cardiovascular risk: the paradoxical findings in blood pressure and lipid abnormalities. Vascular Health and Risk Management, 2012.

• Type of study: review
• About the study subjects: n/a
• Free full-text: yes.

"The lack of equivalent evidence with drugs that lower cholesterol (and LDL-C) or increase HDL-C leads to two interpretations: (1) adverse events of these drugs nullify their beneficial effects over lipoproteins, or (2) abnormalities of lipoproteins are only surrogate markers of the underlying real risks. In any case, drugs cannot be indicated to prevent cardiovascular events based exclusively on their effects over lipoproteins."

This study looks at the evidence that lowering cholesterol actually reduces deaths from cardiovascular disease - statins may work through other mechanisms, but there isn't enough evidence that lowering cholesterol is the reason why they work.

Herron, KL, et al. High intake of cholesterol results in less atherogenic low-density lipoprotein particles in men and women independent of response classification. Metabolism, 2004.

At a Glance:

• Type of study: randomized controlled trial
• About the study subjects: 25 men and 27 women, age 20-50.
• Free full-text: no.

"Because LDL peak diameter was not decreased and the larger LDL-1 subclass was greater in hyperresponders following egg intake, these data indicate that the consumption of a high-cholesterol diet does not negatively influence the atherogenicity of the LDL particle."

(translation: IF cholesterol consumption from whole foods changes your blood cholesterol level, which it only does in a small percentage of the population, even so, the changes it causes are not associated with an increased risk of heart disease).

Nago, N, et al. Low cholesterol is associated with mortality from stroke, heart disease, and cancer: the Jichi Medical School Cohort Study. Journal of Epidemiology, 2010.

At a Glance:

• Type of study: Prospective cohort study
• About the study subjects: 12,334 healthy Japanese adults (men and women) age 40-69
• Free full-text: yes.

“Low cholesterol was related to high mortality even after excluding deaths due to liver disease from the analysis. High cholesterol was not a risk factor for mortality.”

Bae, JM et al. Low Cholesterol is Associated with Mortality from Cardiovascular Diseases: A Dynamic Cohort Study in Korean Adults. Journal of Korean Medical Science, 2012.

At a Glance:

• Type of study: Epidemiological
• About the study subjects: 12,740 Korean adults age 40-69
• Free full-text: yes.

“Groups with the lowest group having TC < 160 mg/dL as well as the highest group having >= 240 mg/dL were associated with higher CVD mortality in Cox proportional hazards analysis adjusting for age, sex, smoking and drinking status, body mass index, level of blood pressure, triglyceride and high density lipoprotein cholesterol.”

Also notice that the cutoff for “too high” was 240, not 200.

Schatz, IJ, et al. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study. The Lancet, 2001.

At a Glance:

• Type of study: Prospective cohort
• About the study subjects: 3572 Japanese-American men, age 71-93
• Free full-text: no.

“Our data accord with previous findings of increased mortality in elderly people with low serum cholesterol, and show that long-term persistence of low cholesterol concentration actually increases risk of death. Thus, the earlier that patients start to have lower cholesterol concentrations, the greater the risk of death.”

Prospective Studies Collaboration, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. The Lancet, 2007.

At a Glance:

• Type of study: Meta-analysis of prospective studies
• About the study subjects: 892,337 adults (age 40-89) in total from 61 studies.
• Free full-text: no.

“Of various simple indices involving HDL cholesterol, the ratio total/HDL cholesterol was the strongest predictor of IHD mortality (40% more informative than non-HDL cholesterol and more than twice as informative as total cholesterol). Total cholesterol was weakly positively related to ischaemic and total stroke mortality in early middle age (40-59 years), but this finding could be largely or wholly accounted for by the association of cholesterol with blood pressure. Moreover, a positive relation was seen only in middle age and only in those with below-average blood pressure; at older ages (70-89 years) and, particularly, for those with systolic blood pressure over about 145 mm Hg, total cholesterol was negatively related to haemorrhagic and total stroke mortality.”

Translation: type of cholesterol matters. It's not just about total cholesterol!