Clinical Feature: The Unique South Asian Phenotype and Opportunities for Early Intervention to Prevent Diabetes and ASCVD

T.S. is a 58-year-old male of South Asian origin who sought attention for complex dyslipidemia. He had migrated to the US in 1988. He has a strong family history positive for multiple members having coronary artery disease (CAD), percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), diabetes (DM) and one sibling with sudden cardiac death from a myocardial infarction (MI). He has been healthy all his life with no history of hypertension (HTN), smoking or DM. He works at a sedentary desk job at an IT company and has not been active due to 14-hour workdays with a 6-day work week contributing to high levels of stress.  He consumes a 1.5 oz of whiskey twice a week. He follows an ovo-lacto pescatarian high vegetable diet. On exam, his BP was 144/92 mm Hg, HR 88 bpm, weight 164 lbs. and his BMI was 25.4, waist circumference was 100 cm. No pertinent cardiovascular abnormalities noted were on exam, specifically, no evidence of xanthelasma, tendon xanthomas or corneal arcus and no murmurs or bruits. Retinal exam was normal. Fasting lipid panel showed total cholesterol (TC) of 256 mg/ dL, low density lipoprotein cholesterol (LDL-C) 194 mg/dL, Triglycerides 180 mg/ dL, and high density lipoprotein cholesterol (HDL-C) of 26 mg/dL. HbA1c was 6.2%. Other laboratories and EKG were normal.  He was started on simvastatin 40 mg daily. He could not tolerate this and hence was tried on atorvastatin and rosuvastatin all of which gave him severe myalgias. He was switched to pitavastatin, which he took for one week and stopped due to cost. He was then prescribed ezetimibe. His LDL-C came down to 179 mg/dL after 3 months, but the TG and HDL-C did not change significantly. Lipoprotein(a) [Lp(a)] was 179 mg/dL. High sensitivity C-reactive protein (hsCRP) was 0.4 mg/L. Coronary calcium score was 128 Agatston units. He was advised to consult a Lipid Specialist.

The above case represents a typical South Asian phenotype. South Asians (SAs) are people with origins from India, Pakistan, Bangladesh, Sri Lanka, Nepal, Bhutan and the Maldives. They comprise 25% of the global population yet contribute to 60% of 
the global cardiovascular disease burden. There are close to 4 million SAs living in North America (2.84 million in the US). Lipid abnormalities in SAs are closely intertwined with insulin resistance, DM and early CAD.

To discuss the SA cardiometabolic health epidemic, let us respond to specific questions in the following discussion:

What is the prevalence of Diabetes in SAs?

The prevalence of type 2 DM is growing worldwide with a projected rise in the total number of individuals with DM from 171 million in 2000 to 366 million in 2030. However, the predicted increase in prevalence in the Indian subcontinent is 151%.(1) SAs have a 4-fold higher prevalence of DM compared to other ethnicities.(2) Population-based studies that have looked at SAs living in different countries have reported an agestandardized adult diabetes prevalence of 21% in the UK, 15.3% in Canada and Mauritius, 13.1% in Fiji, 12.8% in Singapore and 9.9% in South Africa and Tanzania.(3-7) Data from the US also look similar. In a study conducted in Atlanta, 18.3% of attendees at a religious temple had DM by self-report.(8) In another large US based national sample, 17.4% of SA adults had DM based on self-report.(9) This figure rose to 29% when data were collected after an oral glucose tolerance test conducted in a SA population living in the San Francisco Bay Area, CA.(10) In another large population-based study from New York City, DM prevalence among foreign-born SAs was nearly twice that of foreign-born other Asians (example, East Asians such as Chinese) (13.6 vs. 7.4%, p=0.001). In multivariable analyses, normal-BMI (body mass index) of foreignborn SAs had nearly five times the DM prevalence compared to US-born nonHispanic Whites (14.1 vs. 2.9%, p<0.001) and a 2.5 times higher prevalence than foreign-born other Asians (p<0.001).(11)

What is the prevalence of CAD among SAs?

The American Heart Association/American College of Cardiology/Multisociety Cholesterol Guidelines in 2018 have recognized South Asian ancestry as a high-risk category for cardiovascular events.(12) It is vital to recognize that SAs develop CAD at a younger age, with increased CAD-associated mortality. Numerous studies have demonstrated higher CAD rates amongst SAs at all ages. The prevalence of CAD in rural South Asia is 3-4%, but amongst urban SAs and SA immigrants in Western countries it approaches 10%.(13) The Coronary Artery Disease in Indians (CADI) study demonstrated a 3-fold higher prevalence 
of age adjusted MI (7.2%) amongst first generation South Asian immigrants to the United States, compared to 2.5% in the general population in the Framingham Offspring study.(14) Multiple studies have also shown a roughly 3-fold higher CAD prevalence for SAs younger than 40 years, and 1.5-fold higher prevalence in those older than 60 years. A 1990 World Health Organization study showed that the proportion of cardiovascular deaths occurring before 70 years of age was 26% in developing countries but 52% in India. Although the risk for microvascular complications amongst SAs with DM tends to be similar to the Caucasian population, they have a significantly higher prevalence of macrovascular complications (i.e. cardiovascular disease manifesting at a younger age in non-obese individuals).(1516) In a large multi-ethnic population study of 126,088 adults in Northern California that had 13,448 (10.6%) Asian Americans including 5,951 Chinese, 1,676 Japanese, 4,236 Filipinos, 689 South Asians (mostly Asian Indians), and 896 Other Asians, an increased risk in SAs was present in multiple strata, with the largest risk seen in SA men, younger ages and heavy smokers.(17)

What is the characteristic lipid profile in SAs?

While total cholesterol and LDL levels may be similar to other ethnic groups, SAs have other characteristic lipid abnormalities including higher triglyceride levels, higher Lp(a) levels, increased ratio of apolipoprotein B to apolipoprotein A-1 (apoB/apoA-1), smaller HDL and LDL particle sizes, and lower levels of HDL-C.(18-20) Lp(a), which is genetically determined, is an emerging independent risk factor for the development of CAD, complementing other traditional risks. (21) SAs have the second highest levels of Lp(a) after African Americans and this may explain some of the increased CAD risk in this ethnic group.(22) The INTERHEART study was an international case-control study done in 52 countries that examined the risk factors for an initial MI. It included 12,000 cases of initial MI and 14,000 controls and demonstrated that over 90% of the MI risk can be attributed to 9 modifiable risk factors (smoking, DM, lipids, central obesity, hypertension, diet, physical activity, alcohol consumption, and psychosocial factors). This was true for all populations including SAs. However, SAs presented with initial MI at an earlier age (53 vs. 58 years). Protective factors (moderate daily alcohol consumption, regular physical activity, daily intake of fruits and vegetables) were significantly lower among SAs and deleterious factors such as DM and elevated apoB/apoA-1 ratio was significantly higher. When compared to the other risk factors, elevated apoB/ apoA-1 ratio had the highest attributable risk. When compared to other ethnic groups, certain risk factors had higher attributable risk in SAs: apoB/apoA-1 ratio, low daily consumption of fruits and vegetables, lack of regular exercise, and high waist-hip ratio. Overall obesity rates (by BMI standards) were lower in South Asians. However central obesity rates were significantly higher and associated with insulin resistance, metabolic syndrome, and a 3-fold increased CAD risk. Waist circumference or waist-hip ratios as a screening tool are thus more robust to accurately identify risk in this population.(20)

What are the novel CHD biomarkers in SAs?

In the MASALA (Mediators of Atherosclerosis in South Asians Living in America) study, 2615 subjects underwent assessment of coronary calcium score and body fat quantification of 4 regions - abdominal visceral fat (VF), liver fat, abdominal intramuscular fat, and pericardial fat (PF). South Asian subjects had a higher burden of PF and coronary artery calcification (CAC), as well as higher rates of impaired fasting glucose (IFG) and DM compared to all other populations. Abdominal VF was associated with IFG and no difference in body composition was noted to explain the added risk. In 698 South Asians who had repeat CAC measurements after 4.8 years, the age-adjusted CAC incidence 
was 8.8% (95% CI, 6.8–10.8%) in men and 3.6% (2.5–4.8%) in women. The median annual CAC progression was 26 (interquartile range, 11–62) for men and 13 (interquartile range, 4–34) for women. Compared with MESA, age-adjusted CAC incidence was similar in South Asian men compared with white, black, and Latino men, but significantly higher than Chinese men (11.1% versus 5.7%, P=0.008). After adjusting for age, diabetes mellitus, hypertension, and statin medication use, Chinese, black, and Latino men had significantly less CAC change compared with South Asian men, but there were no differences between South Asian and white men. There was no difference in CAC incidence or progression between South Asian women and women in MESA. Consuming a vegetarian diet was associated with lower body mass index (P = 0.023), fasting glucose (P = 0.015), insulin resistance (P = 0.003), total cholesterol (P = 0.027), and LDL-C (P = 0.004), and lower odds of fatty liver (OR: 0.43; 95% CI: 0.23, 0.78, P = 0.006). The odds of having any coronary artery calcium were lower for vegetarian men (OR: 0.53; 95% CI: 0.32, 0.87, P = 0.013); however, no significant associations were observed among women. In 886 participants, prevalence of high Lp(a) was higher in women, CAC was present in 42 % across all quartiles of Lp(a), carotid intima-media thickness (CIMT) was not significantly associated with Lp(a) and Lp(a) was not associated with CAC or CIMT.(23-25)

While traditional risk factors account for the majority of CAD in South Asians, some novel risk factors are also under study: smaller coronary artery diameter, higher homocysteine levels, and higher CRP levels. CAD risk in SAs may be increased by a prothrombotic milieu (higher levels of homocysteine, lipoprotein(a), plasminogen activator inhibitor-1, and smaller HDL and LDL particles) along with a proinflammatory state  (higher levels of  hsCRP,  leptin, interleukin-6, tumor necrosis factor-alpha) and smaller mean coronary artery diameter.(22-26)

What is the problem with SA diet and exercise?

The South Asian diet also predisposes to developing dyslipidemia and thus increases CAD risk. Use of whole milk and clarified butter (ghee), deep frying, long cooking times and reuse of the same oil multiple times may be contributing to fatty acid oxidation and increased saturated and trans-fat consumption leading to Insulin resistance and CAD.  Regular physical exercise is rare in this population including women.(27-28)

Is there a genetic basis to early onset of diabetes and CAD?

South Asian migration from rural to more affluent urban areas leads to significantly higher rates of early CAD pointing towards a genetic and environmental interaction. The susceptibility towards developing insulin resistance may be partially explained by the “fetal origins hypothesis” which postulates that malnourished fetuses adapt to impaired nutrition by becoming relatively insulin resistant. However, this adaptation may persist into adult life even when calories are abundant thus leading to insulin resistance and adult onset DM. In addition, there may be genetic alterations also that contribute to this interplay - variations in the PNPLA3 genotype contribute to ancestry-related and inter-individual differences in hepatic fat content and susceptibility to NAFLD (Nonalcoholic Fatty Liver Disease), which, in turn, may determine insulin sensitivity. Similarly, allelic variations in the TCF7L2 gene and the Lp(a) gene lead to elevated apo B/apo A-1 ratio and Lp(a) and early CAD.(29-31) 

Are the recommendations for screening and cut points in SAs different?

Two recent publications are guiding the medical community in increasing the awareness of the cardiometabolic epidemic in South Asians.(32-33) The traditional risk factors should be screened and modified in all populations, but especially in South Asians who have higher prevalence of these risk factors at younger ages. We recommend the thresholds for early intervention as depicted in Table 1. The Lipid Association of India is advocating for a lower LDL-C goal (<50 mg/dL) in  high-risk South Asian subjects and <30 in very high-risk subjects. At present, data among the SA community is sparse and more consistent and evidence-based messaging needs to be developed based on forthcoming robust study among SA. 

What is the best intervention strategy for this patient?

The above-mentioned patient seems to fit with the profile seen in many of the SA studies. He has severe hypercholesterolemia with an elevated CAC score. He has cardiometabolic syndrome with mixed dyslipidemia pattern manifesting as high TG and low HDL-C, increased BMI, and borderline hypertension and prediabetic state. In addition, there is another genetic component present in elevated Lp(a). In terms of management of this patient, above and beyond lifestyle modification, weight reduction, and exercise prescription, he will benefit from PCSK9 inhibitors and addition of icosapent ethyl (IPE) to reduce cardiovascular events.

What opportunities exist to address the risk of SA?

There is no data on the specific benefit for the SA population from any of the PCSK 9 inhibitor outcome trials or even from the REDUCE-IT(34) trial to suggest CV risk-reduction. Other agents such as glucagon-like peptide-1 receptor agonists (GLP1-RA)(35), the sodium-glucose cotransporter-2 (SGLT2) inhibitors(36) and EPA-only supplementation have shown to be beneficial in reducing cardiovascular events, mostly researched in Caucasian population. However, given the results from these outcome trials, one can extrapolate that the benefit may be incurred for the SA population as well. Antisense oligonucleotides against Lp(a), and glucagon-like peptide-1 (GLP1) agonist studies in SA is warranted. We will await specific population studies in SA in the future. In the meantime, we recommend that all South Asians over the age of 30 should participate in early screening and prevention strategies with diet and physical activity with lifestyle modifications and personal empowerment to reduce their risk profile. Increasing awareness through social media and other avenues using digital technology may be helpful in reducing risk. All SA should be a target for assessment of traditional risk factors, lipid subfractions including Lp(a), waist to hip ratio, non HDL-C, Apo B and Apo A1 levels and utilizing CAC  score and ankle brachial index to further inform the treatment decision when risk is intermediate or uncertain based on global risk assessment. Aggressive management including weight loss and regular physical activity is recommended as well as dietary modifications with decreased intake of saturated and trans fats, shorter vegetable cooking times, and increased intake of raw vegetables. This will reduce the earlier onset of the twin epidemic of DM and cardiovascular disease.

Disclosure statement: Dr. Vijayaraghavan has received honoraria from Novartis, Amarin, Pfizer, BI/Lily, AstraZeneca, Novo Nordisk, Amgen, Legacy Heart Care, Aventyn, Lite 365, and Abrazo Health Network. Dr. Kalra has received honoraria from Amgen. 

References 

1. Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047-53.
2. Abate N, Chandalia M. Ethnicity and type 2 diabetes: focus on Asian Indians. J Diabetes Complications. 2001; 15(6):320-7.
3. Simmons D, Williams DR, Powell MJ. The Coventry Diabetes Study: prevalence of diabetes and impaired glucose tolerance in Europids and Asians. Q J Med. 1991; 81(296):1021-30.
4. Unwin N, Alberti KG, Bhopal R, Harland J, Watson W, White M. Comparison of the current WHO and new ADA criteria for the diagnosis of diabetes mellitus in three ethnic groups in the UK. American Diabetes Association. Diabet Med. 1998; 15(7):554-7.
5. Ministry. Guidelines for the management of diabetes mellitus in Singapore. National Diabetes Commission, Singapore. Singapore Med J. 1993; 34(6 Suppl): S1-35.
6. Zimmet P, Taylor R, Ram P, et al. Prevalence of diabetes and impaired glucose tolerance in the biracial (Melanesian and Indian) population of Fiji: a rural-urban comparison. Am J Epidemiol. 1983; 118(5):673-88.
7. Ramaiya KL, Swai AB, McLarty DG, Bhopal RS, Alberti KG. Prevalence of diabetes and cardiovascular disease risk factors in Hindu Indian subcommunities in Tanzania. Bmj. 1991; 303(6797):271-6.
8. Venkataraman R, Nanda NC, Baweja G, Parikh N, Bhatia V. Prevalence of diabetes mellitus and related conditions in Asian Indians living in the United States. Am J Cardiol. 2004; 94(7):97780.
9. Misra R, Patel TG, Balasubramanyam A, et al. Prevalence of Diabetes, Metabolic Syndrome, Obesity, and CVD Risk Factors in U.S. Asian Indians: Results from a National Study. J Diabetes Complications. 2010 May-Jun;24(3):145-53. Doi 10.1016 /j. jdiacomp.2009.01.003. Epub 2009 Mar 19.
10. Palaniappan L, Wang Y, Fortmann SP. Coronary heart disease mortality for six ethnic groups in California, 1990–2000. Ann Epidemiol. 2004; 14: 499–506
11. Gupta L,  Wu C, et al. Prevalence of Diabetes in New York City, 2002–2008: Comparing foreign-born South Asians and other Asians with U.S.-born whites, blacks, and Hispanics. Diabetes Care August 2011 vol. 34 no. 8 :1791-1793
12. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/ AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. November 2018. doi:10.1016/j.jacc.2018.11.002
13. Sheth T, Nair C, Nargundkar M, Anand S, Yusuf S. Cardiovascular and cancer mortality among Canadians of European, South Asian and Chinese origin from 1979 to 1993: an analysis of 1.2 million deaths. Can Med Assoc J. 1999; 161: 132–138
14. Enas EA, Garg A, Davidson MA, Nair VM, Huet BA, Yusuf S. Coronary heart disease and its risk factors in first-generation immigrant Asian Indians to the United States of America. Indian Heart J. 1996; 48: 343–353
15. Nag T, Ghosh A. Cardiovascular disease risk factors in Asian Indian population: a systematic review. J Cardiovasc Dis Res. 2013;4(4):222-8.
16. Jose PO, Frank AT, Kapphahn KI, Goldstein BA, Eggleston K, Hastings KG, et al. Cardiovascular disease mortality in Asian Americans. J Am Coll Cardiol. 2014;64(23):2486-94
17. Hajra, Li, et al: Risk of Coronary artery disease in South Asian Americans. A new prospect analysis. J Am Coll Cardiol, 2013,61,10 (S)
18. Kulkarni HR, Nanda NC, Segrest JP. Increased prevalence of smaller and denser LDL particles in Asian Indians. Arterioscler Thromb Vasc Biol. 1999; 19: 2749–2755.
19. Bhalodkar NC, Blum S, Rana T, Bhalodkar A, Kitchappa R, Kim KS, Enas E. Comparison of levels of large and small high-density lipoprotein cholesterol in Asian Indian men compared with Caucasian men in the Framingham Offspring Study. Am J Cardiol. 
2004; 94: 1561–1563.
20. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P, Varigos J, Lisheng L; INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004; 364: 937–954
21. Anand SS, Enas EA, Pogue J, Haffner S, Pearson T, Yusuf S. Elevated lipoprotein(a) levels in South Asians in North America. Metabolism. 1998;47(2):182-184.
22. Anand SS, Yusuf S, Vuksan V, Devanesen S, Teo KK, Montague PA, Kelemen L, Yi C, Lonn E, Gerstein H, Hegele RA, McQueen M. Difference in risk factors, atherosclerosis, and cardiovascular disease between ethnic groups in Canada: the Study of Health Assessment and Risk in Ethnic groups (SHARE). Lancet. 2000; 356: 279–284
23. Kanaya AM, Kandula NR, Ewing SK, Herrington D, Liu K, Blaha MJ, et al. Comparing coronary artery calcium among U.S. South Asians with four racial/ethnic groups: the MASALA and MESA studies. Atherosclerosis. 2014;234(1):102-7.
24. Kanaya AM, Kandula N, Herrington D, et al. Mediators of Atherosclerosis in South Asians Living in America (MASALA) study: objectives, methods, and cohort description. Clin Cardiol. 2013;36(12):713-720. doi:10.1002/clc.22219.
25. Kanaya AM, Wassel CL, Mathur D, et al. Prevalence and correlates of diabetes in South asian indians in the United States: findings from the metabolic syndrome and atherosclerosis in South asians living in america study and the multi-ethnic study of atherosclerosis. Metab Syndr Relat Disord. 2010;8(2):157-164. doi:10.1089/ met.2009.0062.
26. Makaryus AN, Dhama B, Raince J, et al. Coronary artery diameter as a risk factor for acute coronary syndromes in Asian-Indians. Am J Cardiol. 2005; 96:778–780
27. Johns E, Sattar N. Cardiovascular and Mortality Risks in Migrant South Asians with Type 2 Diabetes: Are We Winning the Battle? Curr Diab Rep. 2017;17(10):100. doi:10.1007/s11892-017-0929-5.
28. Chambers JC, Eda S, Bassett P, et al. C-reactive protein, insulin resistance, central obesity, and coronary heart disease risk in Indian Asians from the United Kingdom compared with European whites. Circulation. 2001;104(2):145-150.
29. Khera A V, Kathiresan S. Genetics of coronary artery disease: discovery, biology and clinical translation. Nat Rev Genet. 2017;18(6):331-344. doi:10.1038/nrg.2016.160.
30. Genetic variation in the patatin-like phospholipase domaincontaining protein-3 (PNPLA-3) gene in Asian Indians with nonalcoholic fatty liver disease. Bhatt SP, Nigam P, Misra A, Guleria R, Pandey RM, Pasha MA. Metab Syndr Relat Disord. 2013 Oct;11(5):329-35. doi: 10.1089/met.2012.0064. Epub 2013 Jun 4.
31. Common variants in the TCF7L2 gene and predisposition to type 2 diabetes in UK European Whites, Indian Asians and Afro-Caribbean men and women. Humphries SE, Gable D, Cooper JA, Ireland H, Stephens JW, Hurel SJ, Li KW, Palmen J, Miller MA, Cappuccio FP, Elkeles R, Godsland I, Miller GJ, Talmud PJ. J Mol Med (Berl). 2006 Dec;84(12):1005-14.
32. Volgman AS, Palaniappan LS, Aggarwal NT et al. Atherosclerotic Cardiovascular Disease in South Asians in the United States: Epidemiology, Risk Factors, and Treatments: A Scientific Statement From the American Heart Association. Circulation 2018;138:e1-e34.
33. Vijayaraghavan K, McCullough PA, Singh B et al. CardiometabolicRenal Disease in South Asians: Consensus Recommendations from the Cardio Renal Society of America. Cardiorenal medicine 2019;9:240-251
34. Bhatt DL, Steg PG, Miller M, et al. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. November 2018. doi:10.1056/NEJMoa1812792 35. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016;375(4):311-322. doi:10.1056/NEJMoa1603827.
36. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720.