Dear Osa friends,

As promised earlier this year, we’re talking lipids!  I’ve got a brief primer on lipidology for you and a breakdown of a few tests to consider beyond your standard lipid panel, and then we’ll walk through a study that illustrates the growing nuance that has emerged around saturated fats, carbohydrates, and lipids.  Enjoy! 

A Brief Intro to Lipids

Lipids encompass a broad category of molecules that are insoluble in water and includes fats (aka “triglycerides”), sterols (cholesterol and others), and phospholipids, which famously are the major constituent of all cell membranes in our bodies.  Because lipids are not soluble in water, they require a transporter to travel in the blood. Lipoproteins are just that: the transporters that lipids travel within. You may be most familiar with lipoproteins from low-density lipoprotein (LDL) and high-density lipoprotein (HDL) markers if you have had a traditional lipid panel done.

The Bus Analogy

The bus analogy is commonly used to describe the role of lipoproteins in the body, and it goes like this:  The circulatory system is a collection of freeways and roads, and the lipoproteins are the buses that travel these roads.  Their cargo of cholesterol, triglycerides, and other lipids are the passengers.  The liver, from which these particles originate and also where they return to get recycled, is the central transport hub, so to speak, of lipoprotein metabolism. 

Using this analogy, a traditional lipid panel which measures the cholesterol content of lipoprotein particles in the blood is essentially quantifying the number of cholesterol passengers in the buses.  The amount of cholesterol within low-density lipoprotein particles (LDL-C) was first identified as a key modifiable risk factor for heart disease in the mid-20th century by the eponymous Framingham Heart Study, which since its beginning in 1948 has produced roughly 3,000 articles.¹  Over time the recommendations have evolved to target ever-lower LDL-C levels for those with other risk factors and comorbidities, such that LDL-C<100 mg/dL is a general recommendation, but <70 or even as low as <55 may be goals, depending on the individual’s risk profile.

While this measure of cholesterol content of LDL particles remains the standard, it is increasingly recognized that the number of atherogenic particles carries more weight in terms of risk prediction because it is the exposure of the artery wall to these particles, and particularly the small and dense ones, that conveys the greatest risk for the development of atherosclerosis.²  To be clear, we are talking about the number of buses on the road, as opposed to the number of passengers on the buses.  

It is important to know both of these values because they do not always correlate well with each other.  That is, it is possible to have a low or normal LDL-C but a high number of atherogenic LDL particles (LDL-P).  This is called discordance and warrants attention because these people easily fall through the cracks of conventional screening.³  

Indeed, in longitudinal studies of adults, LDL-P is a better predictor of CVD events than cholesterol measures.  For example, The Multi-Ethnic Study of Atherosclerosis, which involved a cohort of over 6,800 individuals free from cardiovascular disease at the beginning of an observational period of 5.5 years, found that for those with discordant LDL-C and LDL-P, only LDL-P had an association with cardiovascular event incidence.⁴   

How many buses do you have?

In recent decades, the ability to measure LDL-P and LDL particle size has become available, yet it is still underused in primary care practice.  

What tests measure LDL-particle number?  There are two basic options:

1. An NMR lipoprotein test, such as the NMR LipoProfile from Lapcorp, will give you LDL particle count and size.  Sometimes this kind of analysis is called an “advanced lipid profile”. 

One very cool thing about this test is that it provides a lipoprotein insulin resistance score (LPIR), which is a weighted score of the various lipoprotein particles that become out of balance with insulin resistance and is strongly associated with future development of type 2 diabetes. Knowing this opens the door for earlier intervention than would be suggested by single lipoprotein markers such as HDL-C and LDL-C, or by fasting blood glucose, which does not show elevation until a much more advanced stage of dysfunction.⁵

2. Even easier than would be to request an apo(B).  Apo(B) is a protein that exists on all potentially atherogenic particles, which include LDL, VLDL, and Lp(a) (see below for more on this one).  This is a simple add-on to a standard lipid panel that can make a huge difference in gauging individual risk because it essentially enumerates the “number of buses”, which is arguably the most important factor.

Beyond particle number, there is one other important marker to check:  Lp(a) (read: “L-P-little a”). 

Why?  Lp(a) is an LDL-like particle which is more highly atherogenic than any other lipoprotein that we are aware of.  It has been recognized as an independent risk factor for cardiovascular disease, meaning that even if everything else is looking “normal,” an elevated Lp(a) level still puts one at risk for development of atherosclerosis. ⁶  And, it’s largely genetically determined.  I imagine that one reason it is not routinely screened for is because there is not an approved pharmaceutical targeting it (not yet, anyway, but stay tuned).  Knowing that you do or do not have this extra risk factor can help you determine how aggressive you need to be with measures to optimize more modifiable risk factors such as apo(B), LDL-P, LDL-C, and triglycerides.  This may include diet, nutrition and supplements, exercise, and/or pharmacological agents.

Big Fat Nuance

Interestingly, as the increasing knowledge about the physiological and pathological potential of various lipoprotein particles has refined our collective understanding of the etiology of atherosclerotic disease, it has become more clear that our dietary approaches also are in need of refinement.  Just as there is a diversity in the lipid profiles that can lead to elevated risk of cardiovascular disease, there is a diversity in the individual lipoprotein response to various dietary components, with many factors including genetics, inflammatory status, and dietary patterns all influencing this response.  On top of that, each broad category of fats that we have defined with respect to structure by degree of carbon saturation (namely, saturated, monounsaturated, and polyunsaturated) contains a great deal of diversity within its classification, such that not all saturated or unsaturated fats have the same physiological effects. 

That said, rather than get bogged down in the sea of observational data about saturated fat and heart disease, and outdated trials conducted mostly in the 1950s and 60s which are not representative of how people realistically eat today (and, by the way, nearly all excluding women as participants), we’re going to take a close look at a more recent and interesting interventional study involving a relevant population: middle aged men and women with insulin resistance and overweight or obesity.

The Framingham State Food Study⁷ caught my attention because it was a controlled feeding study (meaning, food was provided to participants), and a sample daily menu was provided by the authors in the supplemental material, so we have a good idea of what participants actually ate.  This is so rare to see!  And it is so helpful, because we don’t have to guess at the dietary components or meal compositions.  I also noticed that compliance was very high at 90%, which means that the results are reliable.  So, let’s unpack this study.

After a run-in period during which participants achieved 10-14% weight loss, a total of 164 participants, 70% of whom were female, were randomly assigned to one of three weight-loss maintenance diets and followed for 20 weeks.  All three diets contained 20% protein and differed in their amounts of carbohydrate and saturated fat .  Here are the carbohydrate and fat details of the three diet arms:

1. Low-Carb: 20% carbohydrate, 60% total fat (including 21% saturated fat and 39% monounsaturated fat (MUFA) and polyunsaturated fat (PUFA) )

2. Moderate-Carb: 40% carbohydrate, 40% total fat (14% saturated fat and 26% MUFA & PUFA)

3. High-Carb: 60% carbohydrate, 20% total fat (7% saturated fat and 13% MUFA & PUFA) 

What were the sources of saturated fat in these diets?

Based on the sample menu, the saturated fats in these dietary plans came largely from dairy foods (cheese, milk, and a small amount of butter), in addition to a small amount of pork and a serving of macadamia nuts.  Keep in mind that all of these foods also contain other fats, including monounsaturated and polyunsaturated fats.  While 20% of calories from saturated fat is indeed more than twice the amount of saturated fat recommended by the American Heart Association, which currently recommends obtaining no more than 7% of dietary fat from saturated fat, it is not an extreme amount in the context of a controlled low-carbohydrate diet which is obtaining a majority of its energy from fat. What I noticed in looking at the sample menu was that the diet had a reasonable mix of fats–there was some dairy fat, a bit of meat, some fish, some nuts, some vegetable oil, and some olive oil.  So if your idea of a low-carbohydrate diet is bacon, steak, and cheese, this isn’t that.  I would have preferred to see greater quantities of vegetables, but I digress.

I also noted that fiber was kept at a decent level in these diets, even in the low-carb arm: 25 g/2000 kcal. The moderate carb arm contained 30 g/2000 kcal, and the high carb contained 35 g/ 2000 kcal (As a reference point, I recommend 30+ grams of fiber daily.) 

In addition to its food source, carbon chain length of the constituent fatty acids is one factor when thinking about which saturated fats may be preferential to include in the diet.  There is some evidence that longer chain lengths (>12 carbons) tend to increase LDL cholesterol more so that shorter chain lengths (<12 carbons), with the exception of 18-carbon stearic acid, which may have a neutral or possibly beneficial effect on cholesterol.⁸  However, it is also true that saturated fat-containing foods generally include a variety of chain lengths, so it is difficult to completely extricate the differential effects of different chain lengths (although if this is a topic of interest we can return to this in the future).  Still, the findings of this study are largely in agreement with observational research that factored in the food source of saturated fat in people’s diets.  An example is a PREDIMED study which found that saturated fats from dairy products or meat did not have any significant association with CVD or all-cause death, whereas SFAs from pastries and processed foods conveyed a 46% increased risk of CVD.⁹  (To be clear, this observational study, and many others, did also conclude that generally speaking, unsaturated fats had an association with reduced risk of cardiovascular disease).

So what were the results of this study?

Back to the current study, the Low-Carb diet containing 20% of calories from saturated fats resulted in a significant drop in lipoprotein insulin resistance (LPIR) score, and in this group there was also observed a 14.7% reduction in Lp(a).  In comparison, the Moderate-Carb diet had a null effect on LPIR, while the High-Carb diet increased this parameter.  LDL-C was not significantly affected by any of these weight-maintenance diets; however, please note that none of the participants had very elevated LDL-C at baseline.

In summary, maintaining protein while lowering carbohydrate and increasing both total and saturated fat (from whole foods) had a dose-dependent relationship with improvement in lipoprotein abnormalities associated with insulin resistance.  Additionally, there were no observed adverse effects on total cholesterol, LDL-cholesterol, LDL particle size, measures of chronic inflammation, or blood pressure.  The Low-Carb diet additionally increased adiponectin, which is a hormone intimately involved in glucose regulation and insulin sensitivity, and which is considered to be protective against development of atherosclerosis.

Here is a chart from the study displaying the percent change in the three measured outcomes among the three diet arms:

(Image from Ebbeling et al., 2022)

Results from this study are most applicable to people who match the study population–that is, middle aged men and women with insulin resistance but without pre-existing extreme elevations in LDL-C.  Average LDL-C at the beginning of the study was 92.2 +/- 25.9 mg/dL.  Likewise, Lp(a) was mostly within normal range, with an average of 10.7 mg/dL and a range of 5.9-34.0 mg/dL.  (Normal Lp(a) is considered to be <30 mg/dL).  

This study illustrates the benefits of looking beyond a traditional lipid panel when gauging CVD risk, choosing nutritional approaches, and tracking the metabolic effects of dietary changes.  Keep in mind that development of type 2 diabetes drastically increases cardiovascular disease, and cardiovascular disease is the number one cause of death for people with type 2 diabetes.¹⁰ Looking at an advanced lipid profile can help detect lipoprotein abnormalities when they are less severe and potentially more amenable to diet and lifestyle interventions. 

The Bottom Line

If you’re eating a standard American diet (that by its nature is not aimed at improvement of any metabolic abnormalities or imbalances), it is wise to follow the general guidelines which have emerged from large population studies: reduce saturated fat and replace it with monounsaturated and/or polyunsaturated fats.  Additionally, you would do well to minimize or eliminate refined carbohydrates such as crackers, chips, cookies, breads, pastas, etc, and replace them with vegetables, fruits, legumes, and whole grains like buckwheat, brown rice, amaranth, farro, etc.  You’ve heard it before!

However, when we are using personalized nutrition, we can go well beyond population-level advice. If you are working with your care team to reverse (or prevent, especially if you’ve got a family history) specific metabolic abnormalities associated with increased risk of cardiovascular disease, get comprehensive lipid data including an advanced lipid profile, or at least an apoB. Use that data to design a sustainable-for-you dietary plan that is based on whole foods, has personalized macronutrient targets, and is satiating.  Then, track your numbers over time and adjust your diet (and possibly medications) as indicated. Nutrition is nuanced and usually involves trial and error when we’re seeking optimization.  This is so much easier said than done, but you are absolutely worth it.

References

1. Mhaimeed, O., Burney, Z. A., Schott, S. L., Kohli, P., Marvel, F. A., & Martin, S. S. (2024). The importance of LDL-C lowering in atherosclerotic cardiovascular disease prevention: Lower for longer is better. American journal of preventive cardiology, 18, 100649. https://doi.org/10.1016/j.ajpc.2024.100649 https://pubmed.ncbi.nlm.nih.gov/38576462/ 
2. Johannesen, C. D. L., Langsted, A., Nordestgaard, B. G., & Mortensen, M. B. (2024). Excess Apolipoprotein B and Cardiovascular Risk in Women and Men. Journal of the American College of Cardiology, 83(23), 2262–2273. https://doi.org/10.1016/j.jacc.2024.03.423 https://pubmed.ncbi.nlm.nih.gov/38839200/ 
3. Kavey, R. E., & Mietus-Snyder, M. (2012). Beyond cholesterol: the atherogenic consequences of combined dyslipidemia. The Journal of pediatrics, 161(6), 977–979. https://doi.org/10.1016/j.jpeds.2012.07.034  https://pubmed.ncbi.nlm.nih.gov/22910102/
4. Otvos, J. D., Mora, S., Shalaurova, I., Greenland, P., Mackey, R. H., & Goff, D. C., Jr (2011). Clinical implications of discordance between low-density lipoprotein cholesterol and particle number. Journal of clinical lipidology, 5(2), 105–113. https://doi.org/10.1016/j.jacl.2011.02.001  https://pubmed.ncbi.nlm.nih.gov/21392724/
5. Harada, P. H. N., Demler, O. V., Dugani, S. B., Akinkuolie, A. O., Moorthy, M. V., Ridker, P. M., Cook, N. R., Pradhan, A. D., & Mora, S. (2017). Lipoprotein insulin resistance score and risk of incident diabetes during extended follow-up of 20 years: The Women’s Health Study. Journal of clinical lipidology, 11(5), 1257–1267.e2. https://doi.org/10.1016/j.jacl.2017.06.008 https://pubmed.ncbi.nlm.nih.gov/28733174/ 
6. Vinci, P., Di Girolamo, F. G., Panizon, E., Tosoni, L. M., Cerrato, C., Pellicori, F., Altamura, N., Pirulli, A., Zaccari, M., Biasinutto, C., Roni, C., Fiotti, N., Schincariol, P., Mangogna, A., & Biolo, G. (2023). Lipoprotein(a) as a Risk Factor for Cardiovascular Diseases: Pathophysiology and Treatment Perspectives. International journal of environmental research and public health, 20(18), 6721. https://doi.org/10.3390/ijerph20186721 https://pmc.ncbi.nlm.nih.gov/articles/PMC10531345/ 
7. Ebbeling, C. B., Knapp, A., Johnson, A., Wong, J. M. W., Greco, K. F., Ma, C., Mora, S., & Ludwig, D. S. (2022). Effects of a low-carbohydrate diet on insulin-resistant dyslipoproteinemia-a randomized controlled feeding trial. The American journal of clinical nutrition, 115(1), 154–162. https://doi.org/10.1093/ajcn/nqab287 https://pubmed.ncbi.nlm.nih.gov/34582545/
8. Kelly, F. D., Sinclair, A. J., Mann, N. J., Turner, A. H., Abedin, L., & Li, D. (2001). A stearic acid-rich diet improves thrombogenic and atherogenic risk factor profiles in healthy males. European journal of clinical nutrition, 55(2), 88–96. https://doi.org/10.1038/sj.ejcn.1601122
9. Guasch-Ferré, M., Babio, N., Martínez-González, M. A., Corella, D., Ros, E., Martín-Peláez, S., Estruch, R., Arós, F., Gómez-Gracia, E., Fiol, M., Santos-Lozano, J. M., Serra-Majem, L., Bulló, M., Toledo, E., Barragán, R., Fitó, M., Gea, A., Salas-Salvadó, J., & PREDIMED Study Investigators (2015). Dietary fat intake and risk of cardiovascular disease and all-cause mortality in a population at high risk of cardiovascular disease. The American journal of clinical nutrition, 102(6), 1563–1573. https://doi.org/10.3945/ajcn.115.116046 https://pubmed.ncbi.nlm.nih.gov/26561617/
10. https://diabetes.org/about-diabetes/complications/cardiovascular-disease

Photo by B R A Y D E N on Unsplash