Clinical Feature: Dyslipidemia and ASCVD in Non-White Ethnic, Racial, and Ancestral Groups

Introduction

While atherosclerotic cardiovascular disease (ASCVD) and dyslipidemia affect all populations, their impact is far from uniform. Many interwoven factors, including genetics, sociocultural determinants, and environmental exposures, create a diverse picture of risk across different groups. Understanding this intricate landscape is crucial for tailoring effective prevention and treatment strategies, ultimately reducing the burden of ASCVD, and promoting equitable health outcomes.

Though not exhaustive, the following discussion highlights key factors influencing lipids and cardiovascular health among South Asian, Non-Hispanic Black/African American (NHB/AA), Hispanic, and East Asian individuals. When discussing race, ethnicity, and genetic ancestry in relation to any group, a few key points need to be discussed. While often confused, race, ethnicity and genetic ancestry differ significantly. In the United States (US), racial and ethnic categories are used for data collection and reporting purposes. Race, a social construct based on appearance, has no biological basis and fuels discrimination. The term “African American” is an example and is a multifaceted identity with rich cultural heritage, resilience, and ongoing struggles against systemic racism, deserving nuanced understanding and respect for individual narratives. Ethnicity centers on shared cultural heritage. The term “Hispanic” represents an ethnicity in the US, but the Hispanic community includes a spectrum of experiences and identities, influenced by factors like national origin, generation, language, culture, and personal choices. Genetic ancestry, traced through DNA, reveals connections to historical populations but isn't equivalent to ethnicity or race. The terms “South Asian” and “East Asian” are complex and encompass both ethnicity and ancestry. Recognizing these distinctions fosters respectful and accurate dialogue about identity, history, and human diversity. 

Dyslipidemia and ASCVD in the South Asian Population

People who identify as South Asian originate from India, Pakistan, Bangladesh, Sri Lanka, Nepal, Bhutan, and The Maldives. South Asian populations comprise over 2 billion individuals, more than a quarter of the world’s population. There are more than 5 million persons of South Asian descent in the US, mostly living in urban and suburban areas.¹ South Asian individuals have a 4-fold higher risk of cardiovascular death than the average US population with 50% of cardiovascular death in India occurring before the age of 50 years.² The high risk of ASCVD is attributed to multiple factors - including dietary patterns and a higher prevalence of type 2 diabetes (T2D), prediabetes, and dyslipidemia - all stemming from less favorable body composition (higher visceral fat, lower lean mass) and the resultant insulin resistance.³ 

Lipid profiles commonly show a pattern of atherogenic dyslipidemia: reduced high-density lipoprotein cholesterol (HDL-C), elevated triglycerides, and small dense low-density lipoprotein (LDL) particles. South Asian individuals also have a high prevalence of elevated lipoprotein(a) (Lp(a)) levels.⁴

Multiple professional societies (National Lipid Association, American Diabetes Association, American Heart Association, American College Cardiology) in the US recognize the increased risk of type 2 diabetes and cardiovascular death and have designated South Asian descent to be a risk enhancing factor. The NLA suggests targeting an LDL-C < 70 mg/dL for primary prevention of ASCVD in South Asian adults.⁵

In India, the Lipid Association of India (LAI) has developed a risk stratification system. LAI recommends an LDL-C goal < 50 mg/dL in all patients for secondary prevention and propose an optional goal ≤ 30 mg/dL in extreme-risk patients and a recommended goal ≤ 30 mg/dL in extreme-risk patients with T2D and target organ damage, familial hypercholesterolemia, or recurrent coronary events despite LDL < 50 mg/dL. Recognizing that dyslipidemia in people with T2D needs a goal beyond typical LDL-C targets, the LAI recommends lowering Apolipoprotein B levels to < 65 or < 50 mg/dL in the extreme risk category depending on risk factors.⁶ 

Evidence for the use of moderate-high intensity statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and bempedoic acid comes from clinical trials largely conducted in the western world, with a recommendation to start therapy early for primary prevention in high-risk individuals. Importantly, pharmacokinetic data has shown that plasma levels of statins are approximately 1.5 to 2.3 times higher in South Asian individuals compared to White counterparts.⁷ The Treatment of Hypercholesterolaemia in South Asian Subjects trial demonstrated greater improvement in LDL-C with moderate intensity atorvastatin than the common population.⁸ Furthermore, the prescribing information for rosuvastatin suggests a starting dose of 5 mg and maximum dose of 20 mg daily, considering the two-fold increased exposure observed in South Asian subjects.⁹

Dyslipidemia and ASCVD in the Non-Hispanic Black/African American Population

Approximately 14% of the US population, thus nearly 50 million individuals, identifies as NHB/AA. Clinical prediction models that emphasize self-identified race/ethnicity may inaccurately measure individual health outcomes. Perhaps, the strongest predictor of disparate cardiovascular morbidity and mortality in US NHB/AA cohorts compared to White individuals are the social determinants of health (SDoH) including inadequate housing, limited transport, lower finances, limited access to healthy foods/lifestyle, inaccessible healthcare, and structural racism.¹⁰

The current American College of Cardiology/American Heart Association ASCVD risk estimator significantly increases the 10-year risk in NHB/AA individuals when compared to White persons with a similar medical profile.¹¹ Acknowledging these limitations, PREVENT¹², a recently developed raceless ASCVD risk predictor by the AHA, mitigates race-associated risk misestimations. In the future, a race-free risk algorithm could be applied more precisely to a diverse population.¹³

Paradoxically, NHB/AA adults may have higher HDL-C and lower triglycerides (TG) vs. White or Hispanic cohorts. However, they are more likely to die from ASCVD suggesting that abnormal lipid panels may not be the main cause of death compared to contributors like hypertension, disparate obesity, and T2D.^14-16 Hence Black patients with coronary disease may present with more risk factors, less risk factor control, and worse long-term outcomes.¹⁷

Regardless, the use of lipid lowering drugs reduces ASCVD risks in NHB/AA individuals. Despite higher rates of ASCVD in African American individuals, they continue to be undertreated with statins and underdiagnosed with hyperlipidemia. Moreover, the use of statins in NHB/AA adults should not be deferred due to elevated baseline serum creatine kinase compared to other racial/ethnic groups.¹⁸ 

There are multiple sources of data confirming the causal role for elevated Lp(a) and ASCVD, including epidemiological, genome-wide association, and Mendelian randomization studies.¹⁹ 

More diverse strategies in clinical trials should also be employed to include alternate targets for lipid management to fully cater to NHB/AA adults and the wider population. The European Atherosclerosis Society, recognizing elevated Lp(a) as a risk factor for ASCVD highlight potential future therapies directly focusing on Lp(a) reduction.²⁰ NHB/AA cohorts have been shown to have twice the Lp(a) levels when compared to White, Asian, and Hispanic/Latinx participants in the MESA study which may further contribute to increased ASCVD risk in this population.²¹ 

In conclusion, the further development of raceless CVD risk prediction algorithms and lipid management therapies that obviate race-associated risk misestimation and racializing treatment practices, and instead incorporate measures of social determinants of health (SDoH) that mediate race-associated risk differences are recommended.

Dyslipidemia and ASCVD in the Hispanic Population

The US Census Bureau categorizes those of Cuban, Mexican, Puerto Rican, South or Central American, or other Spanish culture as Hispanic or Latino. In 2022, the US Hispanic population reached 63.7 million people; it is the largest ethnic minority group in the nation and accounts for 19.1% of the total US population.²² In 2022, 13 states had over 1 million Hispanic residents, with highest populations in California, Texas, and Florida.²³

Despite comparable or higher disease risk burdens among Hispanic groups²⁴, they were found to be 10% less likely to have ASCVD and 30% less likely to die from ASCVD.²³ However, a 2017 study underscored the importance of subcategorization for risk assessment, revealing that foreign-born Cubans, Mexicans, and Puerto Ricans had higher ASCVD mortality than their US-born Hispanic counterparts. Foreign‐born Cubans, Mexicans, and Puerto Ricans were found to have higher ASCVD mortality than their US‐born Hispanic counterparts.²⁵ It therefore may not be surprising that the Pooled Cohort Equations (PCE) used as risk assessment tools in disease management have not been validated in disaggregated Hispanic populations. Research has shown that the PCE overestimates risk in the Hispanic population, and specifically, the degree of overestimation varies significantly by ethnic subgroup.²⁶

The prevalence of dyslipidemia in the Hispanic population is estimated to be 65.0%. This includes 36.0% with elevated LDL-C, 41.4% with reduced HDL-C,14.8% with high triglycerides, and 34.7% with elevated non-high-density lipoprotein cholesterol (non-HDL-C). There is significant variation between Hispanic subgroups, i.e., Cuban, Puerto Rican, Central American, etc.²⁷ Statistics regarding Lp(a) levels within this population are not well documented, and studies so far have had varying results when compared to other populations.²⁸   

Hispanic individuals are less likely to receive lipid-lowering therapy and to reach lipid goals. Statin therapy remains a mainstay of dyslipidemia treatment but research into alternative treatments for more individualized therapy continues. A 2021 study assessed the effect of evolocumab, a PCSK9 inhibitor, and found similar reductions in LDL-C among ethnic groups.²⁹ The 2018 American College of Cardiology/American Heart Association report for clinical practice guidelines acknowledges population-based discrepancies. They recommend Hispanic groups be disaggregated because of, “regional differences in lifestyle preferences” for more individualized management. This again stresses the importance of subcategorization within the population for risk management. There are no specific modifications to lifestyle counseling, statin response, or statin safety.³⁰

Dyslipidemia and ASCVD in the East Asian Population

East Asia, a prominent region encompassing nations such as China, Japan, Mongolia, North Korea, and South Korea, is inhabited by approximately 1.7 billion individuals, constituting approximately 20% of the global population.³¹ Although exact estimates vary, roughly 10 million individuals in the US are of East Asian descent.

In East Asians, stroke is the primary contributor to ASCVD-related mortality³², accounting for 48%, followed by ischemic heart disease at 41%. The escalating ASCVD prevalence in Eastern Asia can be attributed to intricate interactions among changes in socioeconomics, living environments, demographic shifts, lifestyles, the prevalence of ASCVD risk factors, and the efficacy in achieving ASCVD prevention and treatment objectives. 

A noteworthy phenomenon is the nutritional transition from traditional Asian diets to Westernized dietary patterns, observed across several Eastern Asian countries.³³ Consequently, there has been a significant surge in the number of ASCVD deaths attributable to non-HDL-C, more than tripling in East Asia from 1990 to 2017 (from 250,000 to 860,000).³⁴ Additionally, Eastern Asia exhibits one of the highest age-standardized smoking prevalence rates³⁵ in men (37.1%), contrasted by the lowest prevalence in women (2.2%). Moreover, hypertension prevails significantly, contributing substantially to ASCVD mortality, particularly in regions where stroke is the predominant ASCVD type. The crude prevalence of hypertension stands at 28% in China, 29% in South Korea, and 42% in Japan.³⁶ Concurrently, there is an upward trend in diabetes prevalence across all Asian regions, with China and Japan ranking among the top 10 countries with a substantial number of adults affected by diabetes³⁷, which further increases the ASCVD risk in this population. 

For the epidemiology of dyslipidemia in Eastern Asia, take China as an example, the prevalence among adults aged ≥ 18 years is documented³⁸ at 35.6%. A marked increase is observed³⁹ in the age-specific prevalence of hypertriglyceridemia, nearly doubling from 4.9% in 2015 to 8.2% in 2018. Likewise, the prevalence of elevated LDL-C has continued its upward trajectory^38,39, with 8.0% of adults aged ≥ 18 years exhibiting LDL-C levels ≥ 158.5 mg/dL (4.1 mmol/L) in 2018, compared to 5.6% in 2010. 

Despite these concerning trends, the utilization of lipid-lowering drugs remains notably low, with only 5.5% of the population at high ASCVD risk in primary prevention receiving treatment. Among individuals with established ASCVD40, the treatment rate for lipid-lowering drugs is 14.5%, and the achievement of target LDL-C rates is only 6.8%.

In accordance with the 2023 Chinese Guideline for Lipid Management, individuals without ASCVD meeting specific criteria, including LDL-C ≥ 189.5 mg/dL (4.9 mmol/L) ((or total cholesterol ≥ 278.4 mg/dL (7.2 mmol/L)), diabetic patients aged ≥ 40 years, or those with chronic kidney disease (CKD) stages 3–5, are directly classified as high-risk without requiring additional 10-year risk assessments for ASCVD. The guideline advocates for ideal LDL-C levels of 100.5 mg/dL (<2.6 mmol/L) and non-HDL-C levels of 131.5 mg/dL (<3.4 mmol/L). Initiating LDL-C-lowering therapy involves the use of moderate doses of statins, with consideration given to cholesterol absorption inhibitors and/or PCSK9 inhibitors if LDL-C targets are not met post-statin therapy. High-risk ASCVD patients with elevated triglycerides despite statin therapy may additionally incorporate high-purity eicosapentaenoic or high-purity omega-3 fatty acids, or fibrates to mitigate ASCVD risk.⁴¹

Conclusion

Key takeaways include:

• South Asians: Reduced HDL-C, elevated triglycerides, and small dense LDL particles are common. Lower LDL-C goals and potentially earlier statin initiation might be necessary.
• African Americans: Despite higher ASCVD mortality, lipid/lipoprotein-related factors may not fully capture risk. Social determinants of health play a significant role. Race-free risk prediction algorithms and therapies that address broader risk factors are needed.
• Hispanics/Latinos: Disparities in treatment and achieving lipid goals exist. Subcategorization based on nativity and other factors may be crucial for individualized management.
• East Asians: Stroke is the primary contributor to ASCVD mortality. Rapidly increasing non-HDL-C levels and undertreatment of dyslipidemia are concerning trends.

Moving forward, addressing the social determinants of health, refining risk prediction tools, and developing culturally appropriate interventions are essential to combat health disparities and achieve equitable cardiovascular health outcomes for all populations.

 

Dr. Agarwal has no financial relationships to disclose. Mr. Maudeke has no financial relationships to disclose.  Dr. Ferdinand has received honorarium from Amgen, Novartis, Eli Lilly, Medtronic, and Janssen. Dr. Savic has no financial relationships to disclose. Dr. Fan has no financial relationships to disclose. Dr. Ahmad has received honorarium from Amryt, grant support from NIH, USDOD, Ionis, and research funds from Ionis. 

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