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

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.

Figure 1.. Associations Between Dietary Cholesterol Consumption and Incident CVD and All-Cause Mortality

There were 5400 incident cardiovascular disease (CVD) events and 6132 all-cause deaths (N=29 615 participants). Incident CVD included fatal and nonfatal coronary heart disease, stroke, heart failure, and other CVD deaths. Cohort-stratified cause-specific hazard models for incident CVD and standard proportional hazard models for all-cause mortality were applied and included dietary cholesterol, dietary cholesterol squared, age, sex, race/ethnicity (white, black, Hispanic, Chinese), education (z score, alcohol consumption (gram), and use of hormone therapy (y/n). The dashed line indicates the cutoff for the 95th percentile of consumption (640 mg/d). The distribution of dietary cholesterol was winsorized at the 0.5 and 99.5 percentiles. For quadratic cholesterol consumption term for incident CVD, P value = .19, and for quadratic cholesterol consumption term for all-cause mortality, P value = .83. The hazard ratio (HR [95% CI]) is indicated by the blue line and blue shading.

Figure 2.. Associations Between Each Additional 300 mg of Dietary Cholesterol Consumed per Day and Incident CVDand All-Cause Mortality

See the Figure 1 footnote for conditions included in the incident cardiovascular disease (CVD) definition. There were 5400 incident CVD events and 6132 all-cause deaths (N=29 615 participants). Mean dietary cholesterol consumption in the United States was 293 mg per day. For results interpretation, use model 2 as a reference standard (indicated by dotted line). Each additional 300 mg of dietary cholesterol consumed per day was significantly associated with a higher relative risk (RR) of incident CVD (adjusted hazard ratio [HR], 1.17 [95% CI, 1.09-1.26]) and a higher absolute risk of incident CVD (adjusted absolute risk difference [ARD], 3.24% [95% CI, 1.39%-5.08%]) over the maximum follow-up of 31.3 years. Each additional 300 mg of dietary cholesterol consumed per day was significantly associated with a higher RR of all-cause mortality (adjusted HR, 1.18 [95% CI, 1.10-1.26]) and a higher absolute risk of all-cause mortality (adjusted ARD, 4.43% [95% CI, 2.51%-6.36%]) over the maximum follow-up of 31.3 years. ^aARD estimation (see Figure 4, footnote “a” for description). The maximum follow-up time of 31.3 years, mean of the included covariates, and a difference of 300 mg per day in dietary cholesterol consumption were used. ^bCohort-stratified cause-specific hazard models were used for incident CVD. Cohort-stratified standard proportional hazard models were used for all-cause mortality. ^cModels: see Statistical Analysis section for descriptions of models 1, 2, and 3. ^dIncluded unprocessed red meat and processed meat (adjusted separately). ^eMeat and fish were removed from calculating these dietary scores. ^fFruits, legumes, potatoes, other vegetables, nuts and seeds, whole grains, refined grains, low-fat dairy products, and sugar-sweetened beverages were included. Eggs, meat, and fish were excluded (major sources of dietary cholesterol). See Figure 4 footnote for aHEI-2010, aMED, and DASH term expansions.

Figure 3.. Associations Between Egg Consumption and Incident CVD and All-Cause Mortality

There were 5400 incident cardiovascular disease (CVD) events and 6132 all-cause deaths (N=29 615 participants). See the Figure 1 footnote for conditions included in the incident CVD definition. Cohort-stratified cause-specific hazard models for incident CVD and standard proportional hazard models for all-cause mortality were applied and included egg consumption, egg consumption squared, age, sex, race/ethnicity (white, black, Hispanic, Chinese), education (z score, alcohol consumption (gram), and use of hormone therapy (y/n). The dashed line indicates the cutoff for the 95th percentile of consumption (1 egg/d). For the association between egg consumption and all-cause mortality, cohort- and sex-stratified standard proportional hazard models were used to satisfy proportional hazards assumption. The distribution of egg consumption was winsorized at the 0.5 and 99.5 percentiles. For quadratic egg consumption term for incident CVD, P value = .34 , and for quadratic egg consumption term for all-cause mortality, P value = .48. The hazard ratio (HR [95% CI]) is indicated by the blue line and blue shading.

Figure 4.. Associations Between Each Additional Half an Egg Consumed per Day and Incident CVD and All-Cause Mortality

See the Figure 1 footnote for conditions included in the incident cardiovascular disease (CVD) definition. There were 5400 incident CVD events and 6132 all-cause deaths (N=29 615 participants). Mean egg consumption in the United States was approximately half an egg per day. For results interpretation, use model 2 as a reference standard (indicated by dotted line). ^aAbsolute risk difference was estimated using 3 R packages: riskRegression, survival, and pec, and 95% CIs were derived from 100 bootstrap samples. The maximum follow-up time of 31.3 years, mean of the included covariates, and a difference of 0.5 per day in egg consumption were used. ^bCohort-stratified cause-specific hazard models were used for incident CVD. Cohort-stratified standard proportional hazard models were used for all-cause mortality that were further stratified by sex to satisfy proportional hazards assumption. ^cModels: see Statistical Analysis section for descriptions of models 1, 2, and 3. ^dMeat and fish were removed from calculating these dietary scores. ^eIncluded unprocessed red meat and processed meat (adjusted separately). ^fFruits, legumes, potatoes, other vegetables, nuts and seeds, whole grains, refined grains, low-fat dairy products, sugar sweetened beverages, poultry, and fish and seafood. ^gFootnote “f” (previous) plus unprocessed red meat, and processed meat. aHEI-2010 indicates alternate Healthy Eating Index 2010; aMED, alternate Mediterranean; DASH, Dietary Approaches to Stop Hypertension.

Figure 5.. Association Between Each Additional 300 mg of Dietary Cholesterol Consumed Per Day and Incident CVD Among Different Subgroups

See the Figure 1 footnote for conditions included in the incident cardiovascular disease (CVD) definition. Adjustment covariates included age, sex, race/ethnicity (white, black, Hispanic, Chinese), education (z score, alcohol consumption (gram), and use of hormone therapy (y/n), where relevant. Mean dietary cholesterol consumption in the United States was 293 mg/d, based on the National Health and Nutrition Examination Survey 2013-2014 data. The results can be interpreted using the following sex-specific estimates as an example: in men, each additional 300 mg of dietary cholesterol consumed per day was significantly associated with a higher relative risk (RR) of incident CVD (adjusted hazard ratio [HR], 1.14 [95% CI, 1.05-1.23]) and a higher absolute risk of incident CVD (adjusted absolute risk difference [ARD], 2.70% [95% CI, 0.08%-5.33%]) over a follow-up of 30 years. In women, each additional 300 mg of dietary cholesterol consumed per day was significantly associated with a higher RR of incident CVD (adjusted HR, 1.26 [95% CI, 1.14-1.40]) and a higher absolute risk of incident CVD (adjusted ARD, 5.12% [95% CI, 2.21%-8.02%]) over a follow-up of 30 years. The difference between men and women was borderline significant (P value for interaction = .051). ^aAbsolute risk difference was estimated using 3 R packages: riskRegression, survival, and pec, and 95% CIs were derived from 100 bootstrap samples. A follow-up time of 30 years (not all subgroups had the maximum follow-up of 31.3 years), mean of the included covariates, and a difference of 300 mg per day in dietary cholesterol consumption were used. ^bCohort-stratified cause-specific hazard models were used for incident CVD. ^cThe maximum follow-up time for the older group was 22.8 years. All other subgroups used 30 years as specified in footnote “a.” ^dHispanic and Chinese participants were combined with white participants (all categorized as other) due to small sample size. ^eBody mass index was calculated as weight in kilograms divided by height in meters squared. ^fFasting glucose (≥126 mg/dL) or HbA_1c (≥6.5%) or taking glucose-lowering medications. ^gBlood pressure (≥140/90 mm Hg) or taking antihypertensive medications. ^hTotal cholesterol (≥240 mg/dL) or taking lipid-lowering medications. ⁱLow-density lipoprotein cholesterol (<70 mg/dL) or non–high density lipoprotein cholesterol (<100 mg/dL) among those who did not take lipid-lowering medications. ^jAlternate Healthy Eating Index (aHEI) 2010 score in the highest quartile (≥51.5). The original version of the aHEI-2010 score has a range of 0 to 110 points, but the score in this study had a range of 0 to 100 points due to the removal of the meat item. ^kPercent of energy consumed from saturated fat in the highest quartile (≥13.8%). ^lPercent of energy consumed from saturated fat (<7%).

Figure 6.. Association Between Each Additional 300 mg of Dietary Cholesterol Consumed per Day and All-Cause Mortality Among Different Subgroups

Adjustment covariates included age, sex, race/ethnicity (white, black, Hispanic, Chinese), education (z score, alcohol consumption (gram), and use of hormone therapy (y/n), where relevant. Mean dietary cholesterol consumption in the United States was 293 mg/d, based on the National Health and Nutrition Examination Survey 2013-2014 data. The results can be interpreted using the following sex-specific estimates as an example: in men, each additional 300 mg of dietary cholesterol consumed per day was significantly associated with a higher relative risk (RR) of all-cause mortality (adjusted hazard ratio [HR], 1.14 [95% CI, 1.06-1.22]) and a higher absolute risk of all-cause mortality (adjusted absolute risk difference [ARD], 3.28% [95% CI, 0.80%-5.77%]) over a follow-up of 30 years. In women, each additional 300 mg of dietary cholesterol consumed per day was significantly associated with a higher RR of all-cause mortality (adjusted HR, 1.28 [95% CI, 1.17-1.41]) and a higher absolute risk of all-cause mortality (adjusted ARD, 7.51% [95% CI, 4.20%-10.83%]) over a follow-up of 30 years. The association was stronger in women than in men (P value for interaction = .02). ^aAbsolute risk difference was estimated using 3 R packages: riskRegression, survival, and pec, and 95% CIs were derived from 100 bootstrap samples. A follow-up time of 30 years (not all subgroups had the maximum follow-up of 31.3 years), mean of the included covariates, and a difference of 300 mg per day in dietary cholesterol consumption were used. ^bCohort-stratified standard proportional hazard models were used for all-cause mortality. ^cThe maximum follow-up time for the older group was 22.8 years. All other subgroups used 30 years as specified in footnote “a.” ^dHispanic and Chinese participants were combined with white participants (all categorized as other) due to small sample size. ^eBody mass index was calculated as weight in kilograms divided by height in meters squared. ^fFasting glucose (≥126 mg/dL) or HbA_1c (≥6.5%) or taking glucose-lowering medications. ^gBlood pressure (≥140/90 mm Hg) or taking antihypertensive medications. ^hTotal cholesterol (≥240 mg/dL) or taking lipid-lowering medications. ⁱLow-density lipoprotein cholesterol (<70 mg/dL) or non–high density lipoprotein cholesterol (<100 mg/dL) among those who did not take lipid-lowering medications. ^jAlternate Healthy Eating Index (aHEI) 2010 score in the highest quartile (≥51.5). The original version of the aHEI-2010 score has a range of 0 to 110 points, but the score in this study had a range of 0 to 100 points due to the removal of the meat item. ^kPercent of energy consumed from saturated fat in the highest quartile (≥13.8%). ^lPercent of energy consumed from saturated fat (<7%).

Figure 7.. Association Between Each Additional Half an Egg Consumed per Day and Incident CVD Among Different Subgroups

See the Figure 1 footnote for conditions included in the incident cardiovascular disease (CVD) definition. Adjustment covariates included age, sex, race/ethnicity (white, black, Hispanic, Chinese), education (z score, alcohol consumption (gram), and use of hormone therapy (y/n), where relevant. Mean egg consumption in the United States was approximately half an egg per day, based on the National Health and Nutrition Examination Survey 2011-2012 data. The results can be interpreted using the following sex-specific estimates as an example: in men, each additional half an egg consumed per day was not significantly associated with a higher relative risk (RR) of incident CVD (adjusted hazard ratio [HR], 1.03 [95% CI, 0.99-1.08]) and a higher absolute risk of incident CVD (adjusted absolute risk difference [ARD], 1.02% [95% CI, −0.34% to 2.38%]) over a follow-up of 30 years. In women, each additional half an egg consumed per day was significantly associated with a higher RR of incident CVD (adjusted HR, 1.13 [95% CI, 1.07-1.20]) and a higher absolute risk of incident CVD (adjusted ARD, 1.86% [95% CI, 0.62%-3.10%]) over a follow-up of 30 years. The association was stronger in women than in men (P value for interaction = .009). ^aAbsolute risk difference was estimated using 3 R packages: riskRegression, survival, and pec, and 95% CIs were derived from 100 bootstrap samples. A follow-up time of 30 years (not all subgroups had the maximum follow-up of 31.3 years), mean of the included covariates, and a difference of half an egg per day consumed were used. ^bCohort-stratified cause-specific hazard models were used for incident CVD. ^cThe maximum follow-up time for the older group was 22.8 years. All other subgroups used 30 years as specified in footnote “a.” ^dHispanic and Chinese participants were combined with white participants (all categorized as other) due to small sample size. ^eBody mass index was calculated as weight in kilograms divided by height in meters squared. ^fFasting glucose (≥126 mg/dL) or HbA_1c (≥6.5%) or taking glucose-lowering medications. ^gBlood pressure (≥140/90 mm Hg) or taking antihypertensive medications. ^hTotal cholesterol (≥240 mg/dL) or taking lipid-lowering medications. ⁱLow-density lipoprotein cholesterol (<70 mg/dL) or non-high density lipoprotein cholesterol (<100 mg/dL) among those who did not take lipid-lowering medications. ^jAlternate Healthy Eating Index (aHEI) 2010 score in the highest quartile (≥51.5). The original version of the aHEI-2010 score has a range of 0 to 110 points, but the score in this study had a range of 0 to 100 points due to the removal of the meat item. ^kPercent of energy consumed from saturated fat in the highest quartile (≥13.8%). ^lPercent of energy consumed from saturated fat (<7%).

Figure 8.. Association Between Each Additional Half an Egg Consumed per Day and All-Cause Mortality Among Different Subgroups

Adjustment covariates included age, sex, race/ethnicity (white, black, Hispanic, Chinese), education (z score, alcohol consumption (gram), and use of hormone therapy (y/n), where relevant. Mean egg consumption in the United States was approximately half an egg per day, based on the National Health and Nutrition Examination Survey 2011-2012 data. The results can be interpreted using the following sex-specific estimates as an example: in men, each additional half an egg consumed per day was significantly associated with a higher relative risk (RR) of all-cause mortality (adjusted hazard ratio [HR], 1.04 [95% CI, 1.01-1.08]) and a higher absolute risk of all-cause mortality (adjusted absolute risk difference [ARD], 1.35% [95% CI, 0.28%-2.42%]) over a follow-up of 30 years. In women, each additional half an egg consumed per day was significantly associated with a higher RR of all-cause mortality (adjusted HR, 1.16 [95% CI, 1.10-1.23]) and a higher absolute risk of all-cause mortality (adjusted ARD, 3.61% [95% CI, 2.12%-5.10%]) over a follow-up of 30 years. The association was stronger in women than in men (P value for interaction = .001). ^aAbsolute risk difference was estimated using 3 R packages: riskRegression, survival, and pec, and 95% CIs were derived from 100 bootstrap samples. A follow-up time of 30 years (not all subgroups had the maximum follow-up of 31.3 years), mean of the included covariates, and a difference of half an egg per day consumed were used. ^bCohort- and sex-stratified standard proportional hazard models were used for all-cause mortality. ^cThe maximum follow-up time for the older group was 22.8 years. All other subgroups used 30 years as specified in footnote “a.” ^dHispanic and Chinese participants were combined with white participants (all categorized as other) due to small sample size. ^eBody mass index was calculated as weight in kilograms divided by height in meters squared. ^fFasting glucose (≥126 mg/dL) or HbA_1c (≥6.5%) or taking glucose-lowering medications. ^gBlood pressure (≥140/90 mm Hg) or taking antihypertensive medications. ^hTotal cholesterol (≥240 mg/dL) or taking lipid-lowering medications. ⁱLow-density lipoprotein cholesterol (<70 mg/dL) or non–high density lipoprotein cholesterol (<100 mg/dL) among those who did not take lipid-lowering medications. ^jAlternate Healthy Eating Index (aHEI) 2010 score in the highest quartile (≥51.5). The original version of the aHEI-2010 score has a range of 0 to 110 points, but the score in this study had a range of 0 to 100 points due to the removal of the meat item. ^kPercent of energy consumed from saturated fat in the highest quartile (≥13.8%). ^lPercent of energy consumed from saturated fat (<7%).