Associations of Dietary Cholesterol or Egg Consumption With Incident Cardiovascular Disease and Mortality

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RxCowboy

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#1
From JAMA:

Associations of Dietary Cholesterol or Egg Consumption With Incident Cardiovascular Disease and Mortality
Victor W. Zhong, PhD; Linda Van Horn, PhD; Marilyn C. Cornelis, PhD; et al

JAMA. 2019;321(11):1081-1095. doi:10.1001/jama.2019.1572

Question Is consuming dietary cholesterol or eggs associated with incident cardiovascular disease (CVD) and all-cause mortality?

Findings Among 29?615 adults pooled from 6 prospective cohort studies in the United States with a median follow-up of 17.5 years, each additional 300 mg of dietary cholesterol consumed per day was significantly associated with higher risk of incident CVD (adjusted hazard ratio [HR], 1.17; adjusted absolute risk difference [ARD], 3.24%) and all-cause mortality (adjusted HR, 1.18; adjusted ARD, 4.43%), and each additional half an egg consumed per day was significantly associated with higher risk of incident CVD (adjusted HR, 1.06; adjusted ARD, 1.11%) and all-cause mortality (adjusted HR, 1.08; adjusted ARD, 1.93%).

Meaning Among US adults, higher consumption of dietary cholesterol or eggs was significantly associated with higher risk of incident CVD and all-cause mortality in a dose-response manner.

Abstract
Importance Cholesterol is a common nutrient in the human diet and eggs are a major source of dietary cholesterol. Whether dietary cholesterol or egg consumption is associated with cardiovascular disease (CVD) and mortality remains controversial.

Objective To determine the associations of dietary cholesterol or egg consumption with incident CVD and all-cause mortality.

Design, Setting, and Participants Individual participant data were pooled from 6 prospective US cohorts using data collected between March 25, 1985, and August 31, 2016. Self-reported diet data were harmonized using a standardized protocol.

Exposures Dietary cholesterol (mg/day) or egg consumption (number/day).

Main Outcomes and Measures Hazard ratio (HR) and absolute risk difference (ARD) over the entire follow-up for incident CVD (composite of fatal and nonfatal coronary heart disease, stroke, heart failure, and other CVD deaths) and all-cause mortality, adjusting for demographic, socioeconomic, and behavioral factors.

Results This analysis included 29 615 participants (mean [SD] age, 51.6 [13.5] years at baseline) of whom 13 299 (44.9%) were men and 9204 (31.1%) were black. During a median follow-up of 17.5 years (interquartile range, 13.0-21.7; maximum, 31.3), there were 5400 incident CVD events and 6132 all-cause deaths. The associations of dietary cholesterol or egg consumption with incident CVD and all-cause mortality were monotonic (all P values for nonlinear terms, .19-.83). Each additional 300 mg of dietary cholesterol consumed per day was significantly associated with higher risk of incident CVD (adjusted HR, 1.17 [95% CI, 1.09-1.26]; adjusted ARD, 3.24% [95% CI, 1.39%-5.08%]) and all-cause mortality (adjusted HR, 1.18 [95% CI, 1.10-1.26]; adjusted ARD, 4.43% [95% CI, 2.51%-6.36%]). Each additional half an egg consumed per day was significantly associated with higher risk of incident CVD (adjusted HR, 1.06 [95% CI, 1.03-1.10]; adjusted ARD, 1.11% [95% CI, 0.32%-1.89%]) and all-cause mortality (adjusted HR, 1.08 [95% CI, 1.04-1.11]; adjusted ARD, 1.93% [95% CI, 1.10%-2.76%]). The associations between egg consumption and incident CVD (adjusted HR, 0.99 [95% CI, 0.93-1.05]; adjusted ARD, -0.47% [95% CI, -1.83% to 0.88%]) and all-cause mortality (adjusted HR, 1.03 [95% CI, 0.97-1.09]; adjusted ARD, 0.71% [95% CI, -0.85% to 2.28%]) were no longer significant after adjusting for dietary cholesterol consumption.

Conclusions and Relevance Among US adults, higher consumption of dietary cholesterol or eggs was significantly associated with higher risk of incident CVD and all-cause mortality in a dose-response manner. These results should be considered in the development of dietary guidelines and updates.
 

RxCowboy

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#3
The accompanying editorial, also from JAMA:

Reconsidering the Importance of the Association of Egg Consumption and Dietary Cholesterol With Cardiovascular Disease Risk
Robert H. Eckel, MD

JAMA. 2019;321(11):1055-1056. doi:10.1001/jama.2019.1850

Nutrition research, in contrast with randomized clinical trials that compare a drug with placebo, is more difficult for many reasons, including complexities in data gathering and changes in human behavior over time. In this issue of JAMA, Zhong and colleagues1 report new insights about a controversial topic, the association of egg consumption and dietary cholesterol with cardiovascular disease (CVD) incidence and all-cause mortality. Clearly, the topic of this study is important to clinicians, patients, and the public at large because the association of egg consumption and dietary cholesterol with CVD, although debated for decades, has more recently been thought to be less important. Compared with the meta-analyses and reviews previously published, this report is far more comprehensive, with enough data to make a strong statement that eggs and overall dietary cholesterol intake remain important in affecting the risk of CVD and more so the risk of all-cause mortality.

In the 2014 Lifestyle Guidelines from the American College of Cardiology/American Heart Association2 and the 2015-2020 Dietary Guidelines for Americans,3 the association of dietary cholesterol with CVD was minimized. This was because the independent relationship of dietary cholesterol from eggs and other foods with plasma levels of low-density lipoprotein cholesterol (LDL-C) and CVD remained unproven and was deemed to be much less important than the well-substantiated effect of dietary saturated fat on levels of LDL-C, a major risk factor for atherosclerotic CVD. This position was further supported by a meta-analysis4 in which the heterogeneous nature of the clinical trials made it difficult to support a relationship among dietary cholesterol, plasma levels of LDL-C, and CVD risk. In an accompanying editorial,5 some caution was raised using several lines of evidence. First, there are high-quality clinical research studies in humans,6,7 wherein all components of the diet other than the cholesterol content were well controlled. In these trials, increasing amounts of eggs and dietary cholesterol produced incremental increases in LDL-C. Second, a decrease in coronary heart disease (CHD) events following recommendations for dietary cholesterol reductions (from <300 mg to <200 mg daily) has been reported.8 Third, there is epidemiological evidence that dietary cholesterol intake in patients with diabetes may incur more CVD harm.8,9 Conversely, the limitations in applying the evidence of egg consumption on CVD risk and the need for future studies, including studies of the genetic basis of cholesterol intake on CVD risk, were also recently reviewed.10

In the report by Zhong et al,1 a harmonized approach was used to analyze self-reported baseline nutritional data on macronutrient intake in 29 615 adults from 6 prospective US cohorts, a group with high racial and ethnic diversity, to examine cardiovascular disease outcomes over a median of 17.5 years. The main finding was that higher consumption of eggs and dietary cholesterol (which included eggs and meats) was significantly associated with incident CVD and all-cause mortality, with a dose-response relationship. Another important finding in the study was that associations between dietary cholesterol and incident CVD and all-cause mortality were no longer significant after adjusting for consumption of eggs and processed and unprocessed red meat. Moreover, the dietary cholesterol content of eggs fully explained the association between egg consumption and incident CVD and largely explained the association between egg consumption and all-cause mortality.

Despite the limitation of using only 1 set of baseline dietary intake data to predict observations up to 30 years later, a major strength of the analysis was the stringent categorization of dietary constituents to isolate the independent relationships of dietary cholesterol and eggs with CVD outcomes. Although all cohorts used different dietary assessment tools (except the 2 Framingham cohorts), this issue was addressed by implementing a rigorous methodology to harmonize dietary data, performing cohort-stratified analyses, and conducting several sensitivity analyses. The result is that other unhealthy behaviors associated with more egg consumption, such as variations in saturated vs monounsaturated and polyunsaturated fat consumption, tobacco use, physical activity z score, presence or absence of diabetes, body mass index, and dietary patterns were accounted for in the various models. Importantly, the recent emphasis on advocating dietary patterns (ie, the Mediterranean-style dietary pattern or Dietary Approaches to Stop Hypertension [DASH]) rather than specific foods to reduce CVD risk is not only sufficiently evidence based to be recommended by guidelines,2,3 but also these dietary patterns were recently ranked as best diets for 2019.11 Yet, Zhong et al1 found that the effect of egg and dietary cholesterol remained after considering the beneficial effect of a heart-healthy dietary pattern, an issue that hopefully will not discourage implementation or continuation of such healthful dietary patterns. In addition, although 4882 members of the study cohorts were excluded for missing data, their absence in the analysis failed to materially affect the findings.

An important reminder is that the data and findings in the study by Zhong et al1 are observational and reflect associations only, not cause and effect. Nonetheless, of interest is how these data relate to current consumption of eggs and free cholesterol in the United States. Considering that the average individual in the United States consumes approximately 295 mg of cholesterol daily, including 3 to 4 eggs per week,12 the adjusted hazard ratio (HR) for incident CVD (1.06; 95% CI, 1.03-1.10) and for all-cause mortality (1.08; 95% CI,1.04-1.11) associated with an additional one-half egg per day were modest, raising the question of whether these levels of statistical significance are clinically important. However, excessive egg and cholesterol intake appear to be more important in individuals who consume many more eggs and much higher amounts of dietary cholesterol. For instance, for those who consumed 2 eggs per day rather than 3 to 4 eggs per week, the HR for incident CVD was 1.27 (95% CI, 1.10-1.45) and for all-cause mortality was 1.34 (95% CI, 1.15-1.52). For individuals who consumed 600 mg of cholesterol per day, the HR for CVD was 1.37 (95% CI, 1.19-1.59) and for all-cause mortality was 1.38 (95% CI, 1.22-1.58). Estimating from Figure 1 in the article by Zhong et al,1 approximately 2% of individuals in the study consumed at least 600 mg of cholesterol daily, and approximately 2% had intakes of at least 2 eggs per day.

However, the relationships between egg consumption or cholesterol intake with plasma lipids and lipoproteins were not assessed, yet the presumed increase in CVD risk would be secondary to higher levels of LDL-C. When healthy young men consumed 0, 1, 2, or 4 eggs per day for 8 weeks in a clinical trial in which daily cholesterol intake ranged from 128 to 858 mg, total plasma cholesterol and LDL-C increased in parallel by 1.5 mg/dL for every 100 mg of dietary cholesterol added to the diet.6 In women, the effect was greater, with increases in LDL-C of 2.1 mg/dL per 100 mg of dietary cholesterol per day when 0, 1, or 3 eggs per day were consumed and dietary cholesterol intakes ranging from 108 to 667 mg per day were provided.7

Zhong et al1 also examined the association of egg consumption and dietary cholesterol with all-cause mortality. Not surprisingly, dietary cholesterol consumption was significantly associated with CVD mortality (adjusted HR, 1.22 [95% CI, 1.07-1.39]). However, an unanswered question remains: to what mechanism was the association between dietary cholesterol intake and non-CVD causes of death (adjusted HR, 1.16 [95% CI, 1.08-1.26]) attributable? In this study, an adjudication process was not used to define this important and statistically meaningful relationship. Because some cohorts included a small percentage of patients with cancer, it is of interest that an association of dietary cholesterol intake with colon cancer mortality has been documented, and this association was independent of dietary fat quantity and quality.13 However, in the study by Zhong et al,1 there were no data on cancer death or types of malignancy.

The authors suggest that the meaning of their work is that “among US adults, higher consumption of dietary cholesterol or eggs was significantly associated with higher risk of incident CVD and all-cause mortality in a dose-response manner.” Overall, the strength of these relationships is modest, but higher consumption of cholesterol or eggs substantially above the median was associated with a monotonic increase in CVD incidence and all-cause mortality. At the population level, this is an important finding. The association between egg consumption and dietary cholesterol with CVD events and mortality may be mediated by higher levels of LDL-C, but such an increase is not always seen,14 and the mechanism of the observed association with non-CVD mortality remains to be defined. Considering the negative consequences of egg consumption and dietary cholesterol in the setting of heart-healthy dietary patterns, the importance of following evidence-based dietary recommendations, such as limiting intake of cholesterol-rich foods, should not be dismissed.
 

RxCowboy

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#10
Thoughts on statins in general? Keep getting caught up in the info war about being worse than high cholesterol or isn't.
There is absolutely no doubt about the use of statins in patients who have known atherosclerotic cardiovascular disease (ASCVD), i.e. secondary prevention. They reduce the risk of heart attack, stroke, and death. The question and the controversy is in patients without known ASCVD, or primary prevention. Exactly who they will benefit is much more difficult to nail down. It is clear that for much of the population the risks of adverse effects outweigh the benefits, so we really only want to give them to the people who are at the highest risk levels for developing ASCVD. Exactly how to find them and how to calculate those risks, well, that is the debate.

There is also some fairly recent controversy over exactly how to dose the statins, i.e. "statin intensity" vs. titrating the statin dose to achieve specific LDL targets (e.g. LDL < 100). The most recent set of guidelines from the American Heart Association and American College of Cardiologists published just last fall suggests that both are true, that for secondary prevention we want people both on high intensity statins AND we want to achieve LDL target levels, which in many cases means adding a second drug for lowering cholesterol (e.g. ezetimibe).
 

llcoolw

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#12
There is absolutely no doubt about the use of statins in patients who have known atherosclerotic cardiovascular disease (ASCVD), i.e. secondary prevention. They reduce the risk of heart attack, stroke, and death. The question and the controversy is in patients without known ASCVD, or primary prevention. Exactly who they will benefit is much more difficult to nail down. It is clear that for much of the population the risks of adverse effects outweigh the benefits, so we really only want to give them to the people who are at the highest risk levels for developing ASCVD. Exactly how to find them and how to calculate those risks, well, that is the debate.

There is also some fairly recent controversy over exactly how to dose the statins, i.e. "statin intensity" vs. titrating the statin dose to achieve specific LDL targets (e.g. LDL < 100). The most recent set of guidelines from the American Heart Association and American College of Cardiologists published just last fall suggests that both are true, that for secondary prevention we want people both on high intensity statins AND we want to achieve LDL target levels, which in many cases means adding a second drug for lowering cholesterol (e.g. ezetimibe).
I owe you one for spelling that out for me. Thank you.
 

okstate987

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#13
The problem with studies such as these is that they are correlatory. The type of diet has a huge impact on cholesterol's effects on health. In a standard american diet, (high carbs, high fat) extra dietary cholesterol is very problematic.

Keto lowers cholesterol in obese patients long term:
"The weight and body mass index of the patients decreased significantly (P<0.0001). The level of total cholesterol decreased from week 1 to week 24. HDL cholesterol levels significantly increased, whereas LDL cholesterol levels significantly decreased after treatment. The level of triglycerides decreased significantly following 24 weeks of treatment. The level of blood glucose significantly decreased. The changes in the level of urea and creatinine were not statistically significant."
https://www.ncbi.nlm.nih.gov/m/pubmed/19641727/

TLDR: dietary cholesterol does not necessarily increase blood cholesterol levels in humans. Other factors are in play.
 

Boomer.....

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#15
Years ago: eggs are bad for you
Recently: eggs are great for you and the "perfect food"
Now: eggs are indeed bad for you.....in excess.

We regularly eat a couple hard boiled eggs and half of an avocado for breakfast. On my last blood test I actually had above average cholesterol which shocked me. I am in excellent health and workout regularly. In looking at the results, my LDL (bad cholesterol) was in great shape and it was my HDL (good cholesterol) which was elevated which made the overall cholesterol levels to be "high". The doctors said there was nothing to worry about and I was in excellent health. This may be contributed to the eggs as we eat healthy most of the time.
 

llcoolw

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#16
Years ago: eggs are bad for you
Recently: eggs are great for you and the "perfect food"
Now: eggs are indeed bad for you.....in excess.

We regularly eat a couple hard boiled eggs and half of an avocado for breakfast. On my last blood test I actually had above average cholesterol which shocked me. I am in excellent health and workout regularly. In looking at the results, my LDL (bad cholesterol) was in great shape and it was my HDL (good cholesterol) which was elevated which made the overall cholesterol levels to be "high". The doctors said there was nothing to worry about and I was in excellent health. This may be contributed to the eggs as we eat healthy most of the time.
I hear that winning consecutive big 12 football titles can do that to a team's fans. I prescribe a couple of decades of not winning another. If you want to live that is.