Abbreviations

CVD = cardiovascular disease

HDL-C = high-density lipoprotein

LDL-C = low-density lipoprotein

NHANES = National Health and Nutrition Examination Survey

TC = total cholesterol

TC/HDL-C ratio = total cholesterol-to-high density lipoprotein cholesterol ratio

TG = triglyceride

Introduction:

Atherosclerotic cardiovascular disease (e.g., coronary heart disease, stroke, peripheral arterial disease) is the leading cause of morbidity and mortality globally, taking an estimated 17.9 million lives each year. Because of the burden of CVD and the cost to the healthcare system, population-wide prevention of coronary heart disease has included guidelines intended to reduce the risk of getting CVD.^1–4 Since 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines and recommendations for CVD risk reduction.^1,5 In 2014, the Department of Veterans Affairs (VA) and the Department of Defense (DoD) approved a joint clinical practice guideline for managing dyslipidemia to improve cardiovascular health.³

Risk models, such as the ASCVD Risk Estimator Plus, are used to estimate a person’s current 10-year CVD risk, forecast the potential impact of interventions, and help with the clinician-patient discussion. The risk threshold is used to initiate discussion for statin therapy for primary prevention. The importance of adherence to a healthy lifestyle has been recommended in the past few decades to lower the risk of CVDs such as getting more exercise, eating a healthy diet, limiting alcohol intake, stopping smoking, and losing excess body weight. Additionally, routine lipid monitoring (e.g., Coronary Risk Profile) or lipid panel measurements are used to monitor cardiovascular health and assess efficacy of therapy.

Among the CVD risk factors, dyslipidemia is recognized as one of the main metabolic risk factors of major CVDs and is amenable to risk-modifying preventions. Specifically, low levels of high-density lipoprotein cholesterol (HDL-C), and elevated total cholesterol (TC), triglycerides (TG), non-HDL-C, and low-density lipoprotein cholesterol (LDL-C) are considered strong independent risk factors for CVD. While reduction of the LDL-C level is the primary target for statin therapy, the serum total cholesterol-to-high density lipoprotein cholesterol (TC/HDL-C) ratio has been used in many clinical trials as outcome measures to assess the effect of nutrient consumptions and lipid profile improvement training programs. The lipid ratio has been used as outcome measures in heart disease studies,⁶ and as secondary goal of therapy by the Canadian Working Group on Hypercholesterolemia and Other Dyslipidemias.⁷ Also known as the atherogenic or Castelli index, the TC/HDL-C ratio is one of the important biomarkers of cardio-metabolic health and indicators of vascular risk.^8,9 Since the lipid metabolism involves endogenous and exogenous pathways and interplays among lipoproteins, lipid ratios may serve as cost-effective markers to monitor abnormalities in lipoprotein metabolism and various disorders and provide insight into current and future cardiovascular health and inform public health efforts.

Reliable and disaggregated population-based data for cholesterol trends are needed to evaluate overall cardiovascular health, assess the effects of nutritional policies and pharmacological interventions, and guide priority setting.¹⁰ In prior analyses of lipid levels, trends of various lipid panel measurements were described in U.S.^11–16 and various countries.^17–26 It is not known if lipid panel components differentially affect individuals with diverse race/ethnicity background. The purpose of this study was to examine the latest trends in serum TC/HDL-C ratio levels across the life span (6 to 80 years old) in noninstitutionalized U.S. residents in four distinct cross-sectional surveys during 2005-2008, 2009-2012, 2013-2016, and 2017-2020 and compare the ratio trends by race/ethnicity. Data for trends in serum cholesterol provide insight into current and future cardiovascular health and inform public health efforts.

Methods:

Study Design

This was an observational cross-sectional study. We used data from the National Health and Nutrition Examination Survey (NHANES), which is a major program of the National Center for Health Statistics (NCHS), part of the Centers for Disease Control and Prevention (CDC). NHANES includes nationally representative, complex, multistage, probability samples of the U.S. residents, noninstitutionalized population. Participants in NHANES received a detailed in-person home interview followed by physical assessments, including laboratory measures at a mobile examination center. A phlebotomist assessed the participant's fasting status before the blood draw. As part of the laboratory evaluation, serum TC and HDL-C levels were measured in participants aged 6 years and older and fasting TGs were measured in participants aged 12 years and older.

Laboratory Measurements

Samples were received frozen and stored at -80ºC in the freezer until testing was performed. Upon completion of the analysis, specimens were stored at -70ºC and discarded after 1 year. All lipid analyses were analyzed according to a standardized protocol and can be found on the NHANES website (https://wwwn.cdc.gov/nchs/nhanes). Through the past decade, there were no major changes to the laboratory methods. The blood specimen was analyzed using the Roche/Hitachi Cobas 6000 chemistry analyzer in recent years. However, the TC, HDL-C, and TGs were measured on the Roche modular P chemistry analyzer in the 2011-2012 cycle, and were measured on the Roche modular P and Roche Cobas 6000 chemistry analyzers in the 2013-2014 cycle.

NHANES 2005-2020 Data

NHANES data has since been released in two-year cycles. Data from nine NHANES data cycles were included in the analysis, including 2005-2006, 2007-2008, 2009-2010, 2011-2012, 2013-2014, 2015-2016, 2017-2020 (pre-pandemic data). Of the initial 76,496 data records, 13,253 participants were removed because they were younger than 6 years old (no blood test). Additional 8,609 participants were removed because they did not have either TC or HDL-C values. Because we observed some extreme lipoprotein values (e.g., TC/HDL-C > 25 while most of the data had a median TC/HDL-C value smaller than 5.0), we flagged participants with extreme values while comparing with sex- and age group-matched samples. As a result, additional 670 participants were classified as outliers and removed, resulting in a total sample of 53,964 for subsequent analysis.

Written informed consent was obtained from participants aged 12 years and older and written child assent was obtained from those aged 7 to11 years. Approval for use of the NHANES data for this study was provided by the NCHS Research Ethics Review Board. Because this study involved secondary analysis of de-identified data, the Institutional Review Boards of the University of Wisconsin - Milwaukee determined that this study did not fall within the regulatory definition of research involving human subjects and did not require further IRB review.

Demographic Variables

Age in years was reported for survey participants at the time of the screening interview. Because the age of 80 and older was determined to be a disclosure risk, all participants aged 80 years and older were coded as '80' by the NHANES. In this study, age was categorized as 6-8, 9-11 (children), 12-15, 16-19 (adolescent), 20-24, 25-29, 30-34, 35-39, 40-44, 45-49, 50-54, 55-59, 60-64, 65-69, 70-74, 75-79, and 80+ (adult) years. Based on the analytical guidelines, each 2-year cycle, and any combination of 2-year cycles is a nationally representative sample. We categorized data into four distinct cross-sectional survey periods during 2005-2008, 2009-2012, 2013-2016, and 2017-2020. Race/ethnicity variable included Mexican American, other Hispanic, non-Hispanic white, non-Hispanic black, and other race - including multi-racial.

Cholesterol Ratio

The TC/HDL-C ratio was calculated by dividing the TC by HDL-C level. In general, higher levels of TC and lower levels of HDL-C increases risk of CVD. Therefore, The higher the ratio, the higher the risk. A TC/HDL-C ratio below 6, below 5, and below 4 is recommended for people at low, moderate, and high risk for CVD management.²

Statistical Analyses

We described the distributions of TC/HDL-C ratio across the life span 6-80+ by sex, examined the ratio trends between four survey periods, and compared the ratio levels by race/ethnicity. Descriptive statistics (including the mean and confidence interval) of the TC/HDL-C, lipoprotein ratio was tabulated for relevant strata. Box plots and line graphs were used to display mean TC/HDL-C values by age.

To compare lipoprotein ratio measures, a 2 (sex: male vs female) x 4 (survey periods) x 17 (age group) general linear model (GLM) analysis was used to test the hypothesis that these independent variables should be used to stratify lipoprotein ratio measurements. Hypotheses of no survey trends in lipoprotein ratio values over the four survey periods were tested. For independent variables found to have a significant main or interactive effect on lipid measurements, Scheffe pairwise post-hoc comparisons were conducted. The significant level was set at alpha = 0.05. All analyses were performed using the SPSS Statistics for Windows, Version 28.0. (Armonk, NY: IBM Corp).

Results

Analytic Sample

The final data for analysis included 53,964 participants aged 6 to 80+ years old. Among them, 50.7% of the sample were females. The majority of the sample was non-Hispanic white (37.6%), followed by non-Hispanic black (22.7%), Mexican American (18.3%), other Hispanic (9.9%), and others including multi-racial (11.5%).

Overall GLM

Cholesterol ratios changed by age and differed by sex. The main effects (sex, age group, survey period, race/ethnicity) were significant (p<0.001). Subsequently, to assist in clinical interpretation of lipoprotein ratios, we summarized ratio measures by sex and age group. The linear trend of the survey years was tested for each age group. The differences in ratio levels were compared between race/ethnicity after stratifying by sex and age group.

TC/HDL-C Ratio

Figure 1 presents the box plot of the TC/HDL-C ratio by sex. The means of TC/HDL-C ratio were lower for younger children, gradually increased to reach a plateau in the adult life, peaked around 40-44 years old for males and 55-59 years old for females, and then gradually declined onwards. Males had a higher TC/HDL-C ratio than females in most age groups (p<0.01), except girls had higher lipid ratio levels than boys in the age group 6-8, 9-11 (p<0.001), and there were no differences between the sexes from age 12 to 15 (p=0.135).

Figure 1: Box plot of the TC/HDL-C ratio by sex

Table 1 summarizes means and 95% confidence intervals of the TC/HDL-C ratio by survey period (2005-2008, 2009-2012, 2013-2016, and 2017-2020). In youth aged <20 years, mean TC/HDL-C ratios were 3.17, 3.15, 3.02, and 3.06 in males; and 3.12, 3.13, 3.03, and 3.02 in females from 2005 to 2020 (linear trend p<0.001). In adults 20 years old and older, mean TC/HDL-C ratios declined from 4.30 in 2005-2008, to 4.27 in 2009-2012, 4.17 in 2013-2016, to 3.96 in 2017-2020 in males; while mean TC/HDL-C ratios declined from 3.67 in 2005-2008, to 3.67 in 2009-2012, to 3.54 in 2013-2016, to 3.47 in 2017-2020 in females (linear trend p<0.001). In the subsequent pairwise comparisons, there were no significant differences between adjacent survey periods 2005-2008 and 2009-2012, as well as most of the comparisons between survey periods 2013-2016 and 2017-2020. Significant changes were observed between survey periods 2005-2008 and 2017-2020, and between 2009-2012 and 2017-2020. Figure 2 illustrates line graphs of the TC/HDL-C ratio by survey period.

Figure 2: Line graphs of the TC/HDL-C ratio by survey period

Table 2 summarizes means and 95% confidence intervals of the TC/HDL-C ratio by race/ethnicity. Overall, non-Hispanic black individuals tended to have lower mean TC/HDL ratio levels compared to other race/ethnic groups on average, while Mexican American individuals tended to have higher TC/HDL ratio levels. The follow-up pairwise comparisons were significant for each age group (all p<0.05). The differences between Mexican American and non-Hispanic black individuals in ratio levels were significant in all age groups (most p <0.001) except in 5 groups (75-79, 80+ years in males, and 70-74, 75-79, 80+ years in females). Most of ratio differences between non-Hispanic white and non-Hispanic black individuals were also significant (most p<0.001), except in 6 age groups (35-39 years in males, and 20-24, 25-29, 55-59, 70-74, 75-79 years in females). Most of the comparisons between Mexican American and non-Hispanic white individuals were not significant, except in 6 age groups (55-59 years in females, 9-11, 25-29, 35-39, 55-59, 60-64 years in males. Figure 3 shows line graphs of the TC/HDL-C ratio by race/ethnicity.

Figure 3: Line graphs of the TC/HDL-C ratio by race/ethnicity

Discussion

Cholesterol levels are important biomarkers associated with cardiovascular disease and there are well-documented race/ethnic disparities in cardiovascular morbidity and mortality risk. The TC/HDL-C ratio is an index of the potential for developing blockages in the arteries of the heart. In this study, we examined the trends in serum lipoprotein ratio (TC/HDL-C) in more recent years between 2005 and 2020 and compared the ratio levels by race/ethnicity. The strengths of this study included analysis of long-term trends; use of substantially more data than previous analyses allowing data stratification; and systematic quantitative analysis of the trends.

Similar to previous studies,^11–13 our results supported the favorable trends in lipid levels in the U.S. population. As described by Perak et al.,¹¹ it is important to understand the reasons for the favorable lipid trends observed to acknowledge public health successes and plan for future efforts. Carroll et al.¹² suggested that the favorable trend may be due in part to a decrease in consumption of trans-fatty acids or other healthy lifestyle changes, an increase in the percentage of adults taking lipid-lowering medications, changes in cigarette smoking and carbohydrate intake, and excluded that likelihood of due to the changes in physical activity, obesity, or intake of saturated fat. Nonetheless, future studies should investigate the impact of pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 2020 on cardiovascular health in general population.

Similar to previous studies,^12–14 our results re-confirmed that cholesterol levels changed by age and differed by sex, and further supported the race/ethnicity differences.^8,29 Most of the studies reported the individual cholesterols (e.g., HDL-C,^{11–15,19,21,25} LDL-C,^{12–14,18,19,21,23} TC,^{11,13,13,14,17,19–22,24,26} non-HDL,^11–13,21 and TG^{12–15,19,21}). Few studies described the distributions of TC/HDL-C lipid ratios by age groups.^6,27,28

Similar to McIntosh’s study (2013),²⁹ they also demonstrated that the non-Hispanic black individuals had lower mean TC/HDL-C (3.9 compared to 5.1 in non-Hispanic white individuals) but the statistics were averaged based on a sample of 97 individuals 20-75 years old. In a study by Willey et al. (2011),⁸ the level of TC/HDL-C was greatest in Hispanic (4.9 compared to 4.6 for non-Hispanic whites and 4.2 for non-Hispanic blacks). However, the results were averaged from a sample of 1,445 community adults without stratifying by age group. Our results further supported that, the lower lipid ratio levels in non-Hispanic black individuals were consistent across most age ranges.

The lower mean TC/HDL-C in non-Hispanic black individuals might have been contributed to the differences in HDL-C levels. In a NHANES-based study, Carroll et al. (2012)¹² showed that Mexican Americans, non-Hispanic whites and non-Hispanic blacks had similar mean TC levels, but non-Hispanic blacks had a higher HDL-C (54.5 compared to 51.2 for non-Hispanic white, and 48.9 for Mexican American). Further studies should investigate the race/ethnicity differences in cholesterol levels a larger population with a broader set of parameters.

Nonetheless, according to Centers for Disease Control and Prevention (CDC), the prevalence of CVD among non-Hispanic black individuals (20.7% of deaths) was similar to non-Hispanic white individuals (21.3% of deaths) while Hispanic individuals had a lower prevalence (15.8% of death). Clinically, the risk of CVD does not solely depend on the cholesterol levels, but also certain health conditions (e.g., hypertension, history of diabetes), lifestyle habits (e.g., alcohol intake, tobacco use, diet, exercise) and access to medical care (e.g., cholesterol-lowering medication). Further work trying to assess the effects of lipid profile components, certain health conditions, lifestyle habits, access to medical care, lipid-lowering medications, and CVD events simultaneously is certainly warranted.

This study involves several limitations. First, this study included secondary data sources. The researchers were not in control of the data collection procedures. Missing values and data entry errors were not correctable. NHANES uses several quality assurance and quality control (QA/QC) protocols, which meet the 1988 Clinical Laboratory Improvement Act mandates, to monitor the quality of the analyses performed by the contract laboratories. Our analysis of trends was based on limited NHANES survey periods. Data from other future surveys are needed to confirm the favorable trends. We only examined the TC/HDL-C ratio, different cholesterol ratios could be explored. Several extraneous factors could influence cholesterol levels, such as lipid-lowering medications and history of diabetes. We prioritized the maintenance of sample size within each stratum to achieve stable estimates of the lipoprotein ratio values. Future studies should endeavor to describe the lipid profile in US residents stratified by extraneous variables. Future studies are needed to fill the gaps in the fundamental knowledge of the factors that influence the cardiovascular health across the life span.

Conclusion

This nationally representative study between 2005 and 2020, showed favorable trends in lipid ratio levels that were observed among noninstitutionalized residents in the US. Further research is needed to determine how racial/ethnic differences in cholesterol ratio affect racial/ethnic differences in cardiovascular disease rates.

Acknowledgements

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Copyrighted material was not used. Copyrighted surveys/instruments/tools were not used.

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