June 30, 2023

Electronic submission to https://www.regulations.gov
Docket No. HHS-OASH-2022-0021-0001

Dear Dietary Guidelines Advisory Committee,

These comments are submitted for the information of the Dietary Guidelines Advisory Committee (DGAC) by the Egg Nutrition Center (ENC). ENC is the science and nutrition education division of the American Egg Board (AEB), the research, education and promotion arm of the U.S. egg industry funded by American egg farmers. ENC is dedicated to providing balanced, accurate information on the science surrounding eggs, nutrition, and health. ENC sponsors scientific research that is focused on the impact of egg intake on health outcomes and provides science-based information to health professionals regarding the role of eggs and eggs’ nutrients in healthy diet patterns across the lifespan. In parallel, AEB recently launched a new sustainability program to support U.S. egg farmers producing a sustainable high-quality protein to help feed the world.

As a research and promotion organization, AEB does not and cannot attempt to influence policy. However, we offer this scientific information that may be relevant to the proposed protocol for the question “What is the relationship between dietary patterns consumed and risk of cardiovascular disease?” [1].

Key Points

  • The current exclusion criteria of <12 weeks study duration in the proposed protocol for the question “What is the relationship between dietary patterns consumed and risk of cardiovascular disease?” may eliminate a significant portion of the relevant scientific literature on this topic.
  • There is growing appreciation that indicators like high-density lipoprotein cholesterol (HDL-c) functionality as measured by cholesterol efflux capacity, cholesterol particle size, and low-density lipoprotein cholesterol (LDL-c)/HLD-c ratio should be taken into consideration when evaluating cardiovascular risk.

Excluding interventions <12 weeks duration will eliminate a significant number of intervention studies for which change in blood lipids is a primary or secondary outcome

The current proposed protocol’s article inclusion criteria include an intervention length ≥12 weeks, and a variety of proposed outcomes (e.g., blood lipids, blood pressure, hypertension, CVD morbidity and mortality) [1]. The length of time to measure these proposed outcomes can vary. For example, blood lipid changes can be observed in a much shorter time period (weeks) as compared to CVD morbidity and mortality outcomes (years or decades), which will be reflected in study design (i.e., randomized controlled trials might measure blood lipid changes; prospective cohort studies could evaluate CVD morbidity and mortality). For the vast majority of dietary pattern randomized interventions, changes in cardiovascular biomarkers can be measured in <12 weeks. As a result, the current exclusion criteria may eliminate a significant portion of the relevant scientific literature on this topic.

The American Heart Association (AHA) released a Science Advisory titled “Dietary Cholesterol and Cardiovascular Risk” in 2019 that was developed “…after a review of human studies on the relationship of dietary cholesterol with blood lipids, lipoproteins, and cardiovascular disease risk to address questions about the relevance of dietary cholesterol guidance for heart health [2].” In this document, AHA provides a table of “Controlled Feeding Studies Examining the Effect of Dietary Cholesterol on Total, LDL, and HLD Cholesterol” which includes 11 studies with intervention periods of 4-8 weeks in length. Similarly, AHA documents a “meta-analysis of 17 intervention trials that ranged from 4-12 weeks long…” which reported changes in total cholesterol, LDL cholesterol, and HDL cholesterol concentrations in the intervention group compared to the control group [2, 3]. Additionally, Clinical Practice Guidelines recommend medical professionals “Assess adherence and percentage response to LDL-C—lowering medications and lifestyle changes with repeat lipid measurement 4 to 12 weeks after statin initiation or dose adjustment…[4].” These are examples that illustrate blood lipid responses can be measured in <12 weeks.

Studies supported by the American Egg Board also align with this larger body of literature around dietary patterns and biomarkers of cardiovascular health, with intervention studies generally around 4-6 weeks duration, for example:

  • “A randomized, controlled, single-blind, crossover trial of 35 adults at risk of T2DM assigned to 1 of 2 sequence permutations of 2 dietary treatments…for a 6-wk interval [5].” The primary outcome in this study was endothelial function measured as flow-mediated dilation, and secondary outcomes included lipid profile, blood pressure, insulin sensitivity, anthropometry, and dietary intake.
  • “In this randomized controlled crossover intervention…were randomly allocated to consume spinach with either two eggs or the equivalent amount of egg substitute for breakfast for 4 weeks…Plasma lipids, glucose, insulin, anthropometrics, plasma lutein, zeaxanthin, choline and trimethylamine oxide (TMAO) were assessed at baseline and the end of each intervention [6].”
  • “…randomized crossover dietary trial with two 4-wk intervention periods in 20 overweight, postmenopausal women…Fasting blood samples were taken at the beginning and end of each treatment period to determine the effects on HDL composition and function [7].”

On the other hand, when the outcomes are longer-term (e.g., hypertension, CVD morbidity and mortality), it would be expected that the study would be much longer in duration because it can take years or decades for these conditions to develop. While randomized controlled trials and observational studies both provide valuable information when developing dietary guidance, it might be important for DGAC to distinguish between different study designs and corresponding cardiovascular outcomes within the proposed systematic review protocol.

The science on risk factors for cardiovascular disease has advanced significantly in recent years, which is not captured with the proposed outcome measurement inclusion criteria

The proposed systematic review protocol: Dietary patterns and cardiovascular disease [1] suggests outcome measurements for infants, toddlers, children and adolescents, adults and older adults: LDL-c, HDL-c, triglycerides, hyperlipidemia, blood pressure (systolic, diastolic), hypertension; and for adults and older adults: CVD morbidity and CVD-related mortality. While the blood lipid biomarkers have historically been used as an indicator of cardiovascular risk, the field has significantly advanced beyond these measurements alone. There is growing appreciation that indicators like HDL-c functionality, cholesterol particle diameter and concentration, the LDL-c/HDL-c ratio, and endothelial function should be taken into consideration when evaluating cardiovascular risk [8, 9]. Including advanced biomarkers may provide a more complete picture of overall CVD risk than that provided by cholesterol concentrations alone.

HDL-c is typically labeled as “good cholesterol,” with epidemiological studies showing lower risk for heart disease with higher concentrations of high-density lipoprotein cholesterol [9]. Recent data, however, indicate that improved functional capacity of HDL-c as measured by cholesterol efflux capacity, rather than elevated levels alone, may be responsible for the beneficial relationship with cardiovascular health [10]. In fact, there is evidence that “Markedly elevated HDL-c levels appear instead to be associated to a raised coronary risk, indicative of a U-shaped relationship [10].”

Recent studies supported by the American Egg Board illustrate advanced analysis of cardiovascular risk, which includes the biomarkers proposed by DGAC, but also new outcomes that can be important for conclusions related to cardiovascular impact:

  • “The consumption of 2 whole eggs/d by overweight, postmenopausal women showed a significant increase in cholesterol efflux capacity. This increase in cholesterol efflux capacity was seen without significant changes in apoA-I, TC, LDL-c or HDL-c, supporting the idea that HDL function rather than HDL-c should be addressed in this population [7].”
  • “When we compared individuals consuming the EGG versus the SUB breakfast, we observed…higher HDL cholesterol after the EGG diet. There were no differences in plasma LDL cholesterol, triglycerides, glucose, insulin, or blood pressure. The number of large HDL particles measured by NMR was higher after EGG as compared to SUB [6].”
  • “Compared with egg exclusion, egg inclusion in the context of plant-based diets did not adversely affect endothelial function…[5]”

Conclusion: Current science supports adjustments in DGAC’s dietary patterns and CVD protocol inclusion criteria for study length requirement and biomarkers

  • There are some study designs which allow for measurement of cardiovascular biomarkers in a time period of <12 weeks.
  • Science has significantly advanced and is no longer focused on historical CVD biomarkers such as LDL-c and HDL-c alone.
  • While this comment refers to one draft protocol, multiple other proposed protocols indicate a 12-week minimum study length, and our comments could be informative and relevant for these protocols as well.

American Egg Board’s Egg Nutrition Center appreciates the opportunity to provide this information to the DGAC.

Sincerely,

Mickey Rubin, PhD
Executive Director

Jen Houchins, PhD, RD
Director of Nutrition Research

References

  1. Hoelscher DM, et al. Dietary Patterns and Risk of Cardiovascular Disease: A Systematic Review Protocol. May 31, 2023; Available from: https://nesr.usda.gov/protocols.
  2. Carson, J.A.S., et al., Dietary Cholesterol and Cardiovascular Risk: A Science Advisory From the American Heart Association. Circulation, 2019: p. Cir0000000000000743.
  3. Berger, S., et al., Dietary cholesterol and cardiovascular disease: a systematic review and meta-analysis. Am J Clin Nutr, 2015. 102(2): p. 276-94.
  4. Grundy, S.M., et al., 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol, 2019. 73(24): p. 3168-3209.
  5. Njike, V.Y., et al., Egg Consumption in the Context of Plant-Based Diets and Cardiometabolic Risk Factors in Adults at Risk of Type 2 Diabetes. The Journal of Nutrition, 2021. 151(12): p. 3651-3660.
  6. Thomas, M.S., et al., Eggs Improve Plasma Biomarkers in Patients with Metabolic Syndrome Following a Plant-Based Diet-A Randomized Crossover Study. Nutrients, 2022. 14(10).
  7. Sawrey-Kubicek, L., et al., Whole egg consumption compared with yolk-free egg increases the cholesterol efflux capacity of high-density lipoproteins in overweight, postmenopausal women. Am J Clin Nutr, 2019.
  8. Fernandez, M.L., The Role of Eggs in Healthy Diets. Supplement to the Journal of Family Practice, 2022. 71(6): p. S71-S75.
  9. Blesso, C.N. and M.L. Fernandez, Dietary Cholesterol, Serum Lipids, and Heart Disease: Are Eggs Working for or Against You? Nutrients, 2018. 10(4).
  10. Sirtori, C.R., A. Corsini, and M. Ruscica, The Role of High-Density Lipoprotein Cholesterol in 2022. Current Atherosclerosis Reports, 2022. 24(5): p. 365-377.