Clinical Feature: Racial and Ethnic Differences Associated with Disparities in Lipidology

Concept of Race/Ethnicity: A Social Construct

Increasingly, clinicians and public health officials recognize the need to pursue, and potentially achieve, health equity in the United States (US). In order to reduce and eliminate health disparities, our society must do more than offer health equality, which is providing the same resources regardless of needs. It is important that we do more and target areas of concern to achieve health equity. Specifically, health equity can be best recognized as the status of fair and just opportunities for each individual in our society to be as healthy as possible, regardless of sex/gender, race/ethnicity, socioeconomic status (SES) or geography.(1) Clinicians need to recognize differences (unique aspects of one population versus another which do not reflect discrimination or barriers to care) as opposed to disparities, inappropriate and unacceptable levels of disease burden across subpopulations.

Race/ethnicity are social constructs and not true biologic or genetic classifications. Nevertheless, the US Federal guidelines describe racial/ethnic terms based on self-identified status. (2,3) In order to avoid inappropriate characterization of individuals in research and clinical care, racial/ethnic categories should be used as adjectives versus nouns (e.g., avoid describing individuals as Blacks, Whites, Hispanics, or Asians).(2) Moreover, the excess burden of atherosclerotic cardiovascular disease (ASCVD), such as in Non-Hispanic Black/African American individuals and members of certain other communities of color, is determined primarily by lifestyle, traditional risk factors and by multiple social determinants of health (SDOH) (Figure 1).

Unique Aspects of ASCVD Risk Among Racial/Ethnic Populations

Unfortunately, 10-year estimated ASCVD risk, based on the Pooled Cohort Equations (PCE), although validated in non-Hispanic Black (NHB) and Non-Hispanic White (NHW) populations, may not accurately estimate risk in Hispanic/Latinx adults, Asian American individuals, including Pacific Islander, Native Hawaiian, South Asian and American Indian (AI)/Alaska Native (AN) persons.(4,5) Furthermore, South Asian descent is considered an “ASCVD risk enhancer”, reflecting visceral adiposity and insulin resistance, despite comparatively low BMI. (6,7,8,9) A comprehensive recent expert consensus document from the National Lipid Association (NLA) highlights important clinical perspectives on the prevention of ASCVD in South Asians living in the US (SAUS).(11)

Additionally, elevated lipoprotein(a) [Lp(a)], a proven genetic risk factor for premature ASCVD, is more prevalent in NHB/African American or South Asian individuals and clinicians should consider screening for Lp(a), especially in higher risk patients.(12,13,14) In a large United Kingdom biobank (N=460,506), Lp(a) concentrations were variable across racial/ethnic subgroups, but the increased risk appeared similar among subpopulations. However, these data had several limitations, including large overall numbers, but small percentages of South Asian (8,940, 1.9%) and Black individuals (7,144, 1.6%).(15) Investigational agents for reducing Lp(a) may show benefit, especially in NHB and South Asian subjects, considering their higher levels.(16)

Hispanic/Latinx individuals have often under-recognized, significant heterogeneity.(5) The Hispanic Community Health Study/Study of Latinos (HCHS/SOL), the largest ever diverse Hispanic/Latinx cohort, has reported disaggregated data, highlighting unique aspects of various Hispanic/Latinx subpopulations.(17) Overall, total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) are higher among certain Hispanic/Latinx men, and slightly lower for certain Hispanic/Latinx women compared to NHW men and women.(18) In addition, high-density lipoprotein cholesterol (HDL-C) is often lower and the mean triglycerides (TG) are higher for both Hispanic/Latinx men and women compared to NHW adults.(10) The contribution of Lp(a) to ASCVD risk in Hispanic/Latinx populations is unclear.(19,20)

There are unacceptable health inequities in healthcare and risk factor control, leading to higher rates of ASCVD, including coronary heart disease (CHD) and stroke, and cardiovascular disease (CVD) mortality, among African American, or NHB populations. Strikingly, NHB adults experience two to three times higher CVD mortality, with reduced life expectancy, reflecting long standing structural inequities.(18,21)

In general, NHB adults have apparently healthier lipid profiles (lower TG and higher HDL-C).(22) Dyslipidemia, per se, other than perhaps higher Lp(a), is not the primary reason for ASCVD excess in NHB adults. In fact, hypertension is the most prevalent and powerful determinant of disparate ASCVD in NHB adults. The suboptimal blood pressure and conventional risk factor control in this population, including type 2 diabetes (T2D), smoking, low physical activity, and overall cardiovascular health status drive the overall mortality disparity in NHB adults compared to NHW adults. (10)

Specifically, NHB women demonstrate less hypertriglyceridemia, despite insulin-resistance, higher insulin concentrations, and greater inhibition of hormone sensitive lipase in adipose tissue.(23) Furthermore, persons of African ancestry, notably NHB women, may be less prone to deposit fat in the depots associated with increased cardiometabolic risk and visceral adipose tissue appears significantly lower in NHB versus NHW individuals.(7) A physiologic marker, unique in many African American individuals, is greater lipoprotein lipase (LPL) as compared to NHW adults.(22) Interestingly, ApoCIII, located on the surface of very low-density lipoprotein particles, inhibits LPL and hepatic lipase and may be lower in NHB than in NHW adults.

Regardless of race/ethnicity, high intensity statin is the best proven approach to reduce ASCVD outcomes. Nevertheless, NHB adults often are underdiagnosed and undertreated with appropriate statin therapy and intensity, due to a combination of factors: SDOH, health beliefs, and mistrust. 

Although, overall, Asian American adults are reported to be less likely than NHW adults to have CVD and decreased life expectancy, there is significant Asian American heterogeneity, with higher LDL-C in Asian Indian, Filipino, Japanese, and Vietnamese populations, compared to NHW adults.(8,24,25,26) In addition, reports in some Asian American men may have lower levels of HDL-C (<40 mg/dL) and there is increased TG prevalence than women.(10,26)

In South Asian adults, adverse lipid abnormalities, CVD, T2D, and increased cardiometabolic risk are increasingly recognized, compounded by insulin resistance and diabetes.(7) Despite self-identification as vegetarian, in some South Asian individuals, traditional dietary cultural factors may actually increase ASCVD risk and dyslipidemia: clarified butter (ghee), deep frying, long to extensive cooking, reuse of the same oil with fatty acid oxidation, increased saturated and trans-fat consumption.(11)

Indigenous US populations, specifically AI/AN individuals, have high rates of ASCVD risk factors compared to NHW adults. The higher ASCVD burden is affected by obesity and diabetes and leads to a reduced average life expectancy.(27,28) More research is needed to identify and develop therapeutic interventions for the high metabolic risk factors and diabetes in many AI/AN individuals.(29)

Therapeutic Approaches in a Multi-Cultural Society

Regardless of race/ethnicity, lifestyle modifications, optimal risk factor management, and team-based health education benefits all populations. (6)  Although the Mediterranean and the Dietary Approaches to Stop Hypertension (DASH) dietary patterns are recommended, SDOH, including low SES, inadequate environments for physical activity, and food deserts, greatly impact the ability of individuals to ascertain healthier eating patterns.(30) Professional societies, such as the NLA and the Association of Black Cardiologists (ABC), have developed culturally and literacy appropriate materials to educate patients. Clinicians should inform their South Asian, Hispanic/Latinx, AI/AN, and NHB patients in a culturally competent manner about healthy eating patterns in order to decrease their ASCVD risk.(11,31,32,33) Furthermore, team-based efforts must address appropriate calorie requirements, personal and cultural food preferences, along with adequate physical activity.

Community-based interventions may assist with determination of positive outcomes in racial/ethnic populations. Disparities in ASCVD based on geography have been noted in the US, especially in the Southeast. For instance, Louisiana has a high burden of ASCVD, specifically in the African American population. Healthy Heart Community Prevention Project, a 501(C)(3) non-profit in New Orleans, Louisiana promotes heart health to eliminate disparities in vulnerable populations, using evidence-based health information to educate and empower a predominantly cohort.(34) Similarly, an ongoing, long-term academic, faith-based, community intervention in churches has been recently funded by the National Institutes of Health (NIH) to attempt to document best practices to reduce ASCVD risk in the New Orleans area.(35)

In order to achieve health equity, structural inequalities must be overcome including: reduced lipid level awareness and poor long-term adherence.(36) Although multiple landmark statin studies, which are the basis for contemporary cholesterol guidelines, did not include adequate diversity, statins are the first-line treatment for primary prevention and secondary prevention, regardless of race/ethnicity.(6,37) Unfortunately, statin therapy remains underutilized in Hispanic/Latinx populations and NHB populations in particular.(38)

In the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, even after accounting for access to care, there were disparities in statin use and goal attainment in persons with diabetes and LDL-C >100 mg/dL, with NHW adults more likely to be prescribed statins than NHB adults.(39)

Clinicians should be aware that the finding of elevated baseline creatine kinase (CK) levels in African American adults, especially men, does not justify withholding statin therapy from at-risk NHB patients, unless CK levels exceed 5.0 times the upper limit of normal.(6,40) A variation in drug metabolism, as reported in East Asian patients, may increase statin sensitivity, leading to lower recommended starting doses of rosuvastatin.(6, 41) Nevertheless, in a South Asian cohort (N=740), rosuvastatin or atorvastatin were equally effective and well-tolerated.(42) Also, based on recent evidence with pitavastatin, higher versus lower statin therapy statins in Asian populations appear safe and substantially lowered ASCVD event risk.(43)

Unfortunately, despite high ASCVD risk, statin therapy may be also under-utilized in AI/AN populations, including Pacific Islanders and Native Hawaiians, with diminished adherence.(44) Additionally, under-representation of AI/AN in almost all major CV outcomes trials may be impacted by a history of mistrust and unethical practices.(45,46)

Adults with ASCVD or familial hypercholesterolemia (FH) require the highest tolerated, high intensity statin, often with additional lipid-lowering pharmacotherapy. Unfortunately, even in higher risk patients, increased PCSK9 inhibitors (PCSK9i) rejection rates have been observed, most notably in women, racial minorities, and lower-income groups.(47) Although most individuals enrolled in outcomes trials with PCSK9i have been NHW individuals, the efficacy and safety of alirocumab by race and ethnicity (NHB, NHW and Hispanic/Latinx participants) has been demonstrated. Also, alirocumab similarly reduced LDL-C and Lp(a) among various racial/ethnic subpopulations and evolocumab significantly reduced LDL-C among four different racial/ethnic groups.(48,49)

New and emerging agents, which may be beneficial in high risk ASCVD patients, often involve clinical trials with limited racial/ethnic diversity. Bempedoic acid appears useful in heterozygous familial hypercholesterolemia (HeFH) or ASCVD who require additional LDL-C lowering. However, recent approval in the US of bempedoic acid was based on cohorts composed of overwhelmingly NHW adults.(50)

Inclisiran, an investigational small interfering ribonucleic acid (siRNA) preventing translation of PCSK9, has shown over 50% LDL-C reductions but responses have thus far been reported in predominantly NHW subjects.(51) Evinacumab, a monoclonal antibody against angiopoietin-like 3 (ANGPTL3), recently approved for homozygous familial hypercholesterolemia (HoFH), has also reported data mainly in NHW cohorts. (52) Similarly, lomitapide, a microsomal triglyceride transfer protein inhibitor, was approved in the US for treatment of HoFH, based on trials with limited diversity.(53) Icosapent ethyl significantly reduced major adverse ASCVD events in a landmark trial (N=8,179), providing significant risk reduction in individuals with ASCVD (and/or with other risk factors) and hypertriglyceridemia on maximally tolerated statins. However, this major advance in lipid therapy was based on evidence from greater than 90% NHW subjects.(54) It will be crucial for these newer therapies, all of which are branded often with significant cost, to have programs to ensure their accessibility to those within these racial/ethnic populations who could benefit from the most.

Summary: Important Considerations for Lipidology in Racial/Ethnic Populations

Based on overwhelmingly convincing evidence from multiple cardiovascular outcomes trials, statins are the first-line lipid-lowering treatment for ASCVD risk reduction. Despite some evidence of higher sensitivity in East Asians, statins should be applied as needed in high-risk Asian patients with proper guidance regarding their benefits and the availability of non-statin alternatives if needed. The somewhat higher baseline creatine kinase levels, noted in some African American patients, should not preclude statin therapy. It is essential that, in the future, clinical trials for lipid-modifying agents, include adequate racial/ethnic diversity. While clinicians must recognize potential unique aspects of lipid levels among racial/ethnic individuals, the appropriate use of statins and emerging agents will not be successful unless barriers to the attainment of evidence-based medications can be overcome and the SDOH appropriately addressed. Eliminating disparities should be the goal for all clinicians to appropriately treat and control dyslipidemia, based on best evidence, regardless of race/ethnicity, SES, sex/gender, or geography.

Disclosure statement:
Dr. Ferdinand has received honoraria from Amgen, Novartis, Pfizer, and Boehringer Ingelheim.
Ms. Reddy has no financial disclosures to report.
References are listed on the LipidSpin .pdf download on www.lipid.org