Asian indian phenotype

Asian Indian Phenotype is a term given to the constellation of phenotypic and genotypic features seen among south east asians that predisposes them to cardiovascular morbidity and mortality.
South east asians (includes indians, pakistanis, sri lankans, bangladeshis and others) with this phenotype have a higher risk of diabetes, dyslipidemia, coronary artery disease, and a higher risk of mortality due to the same.

1. Pharmacotherapeutic relevance of “Asian Indian Phenotype” P Guruprasad DM, Clinical Pharmacology 2/14/2014 1

2. Who are they ?? 2/14/2014 2

3. Asian Indian Phenotype !!! 2/14/2014 3

4. Asian Indian Phenotype - introduction The so called “Asian Indian Phenotype” refers to certain unique clinical and biochemical abnormalities in Indians which include increased insulin resistance, greater abdominal adiposity i.e ., higher waist circumference despite lower body mass index, lower adiponectin and higher high sensitivity C-reactive protein levels. Epidemiology of type 2 diabetes: Indian scenario V. Mohan, S. Sandeep , R. Deepa , B. Shah* & C. Varghese Indian J Med Res 125, March 2007, pp 217-230 2/14/2014 4

5. Asian Indian Phenotype – fat distribution Total body fat – An indian with BMI of 26 = European with BMI of 30 * Fat distribution More abdominal (subcutaneous) and visceral IMPLICATION – increased cardiovascular risk due to lipotoxicity Higher truncal skin fold and truncal to peripheral skin fold ratio Higher central to peripheral skin fold ratio Even indian babies were relatively obese in comparison with white american babies Metabolically Obese Normal Weight (MONW) individual 2/14/2014 5 *Rush EC, Freitas I, Plank LD. Body size, body composition and fat distribution: comparative analysis of European, Maori, Pacific Island and Asian Indian adults. Br J Nutr . 2009 Aug;102(4):632–41.

6. Obesity measures – BMI and Waist circumference BMI cutoffs Waist Circumference (WC) IDF consensus cutoffs - ≥ 94 cm (males) / ≥ 80 cm (females) South asians – cutoffs - ≥ 90 cm (males) / ≥ 80 cm (females) SAM-NCEP cutoffs – a “South Asian modification” of NCEP (national cholesterol education program) 2/14/2014 6

7. Asian Indian Phenotype – diabetes and Blood pressure Blood pressure In comparison with white americans , Indians have significantly higher blood pressures Indian children in the age group 8-14 years had significantly higher blood pressure when compared with their american counterparts* (after adjusting for BMI) Diabetes Diabetes is 3-6 time more common among asian indians than whites (when adjusted for age and BMI) Diabetes occurs 10 years (on an average) earlier among Indians Many indians develop diabetes mellitus at BMI less than 25 kg/m 2 South asian diabetics have 2-4 times the mortality seen among white and Chinese diabetics * Jafar TH, Islam M, Poulter N, Hatcher J, Schmid CH, Levey AS, et al. Children in South Asia have higher body mass-adjusted blood pressure levels than white children in the United States: a comparative study. Circulation. 2005 Mar 15;111(10):1291–7. 2/14/2014 7

8. Asian Indian Phenotype- Metabolic Syndrome (MS) Metabolic syndrome – increases risk of cardiovascular disease by 2 fold Most south asians (Indians) – MONW (Metabolically obese, normal weight) individuals Prevalence of MS among Indians – (≥ 30% )* Prevalence among females higher than in males (by 50%) More than europeans , similar to american whites Cardiovascular disease risk due to MS Hazards ratio of 2.1 among south asians which is higher than that seen among europeans (HR of 1.6) 2/14/2014 8 *Chow CK, Naidu S, Raju K, Raju R, Joshi R, Sullivan D, et al. Significant lipid, adiposity and metabolic abnormalities amongst 4535 Indians from a developing region of rural Andhra Pradesh. Atherosclerosis. 2008 Feb;196(2):943–52.

9. Asian Indian Phenotype – Metabolic Syndrome Three criteria IDF (International Diabetes Federation) NCEP ( National Cholesterol Education Programme ) WHO Since the cut-offs for BMI and WC were not appropriate for Asian Indians – underestimation of MS (Metabolic Syndrome) Only IDF has South Asian Specific Cut-offs for WC . However, IDF criteria uses waist circumference as a compulsory component for diagnosis of MS. This also leads to underestimation of MS among South Asians. Only 30% of indians who have MS satisfy all 3 criteria SAM-NCEP (South Asian Modified- NCEP) New Proposed modification of NCEP criteria for diagnosis among South Asians. 2/14/2014 9

10. Asian indian phenotype – dyslipidemia and procoagulant tendency Higher prevalence of dyslipidemia among indians (when compared with white americans ) “South Asian Dyslipidemia ” * High levels of Apo B, triglycerides, and Lp (a) Borderline high levels of LDL cholesterol Low levels of Apo A1, and HDL cholesterol Also HDL is small and dysfunctional Indians are associated with higher levels of PAI-1( Plasminogen Activator Inhibitor-1) and fibrinogen 2/14/2014 10 *Joshi P, Islam S, Pais P, Reddy S, Dorairaj P, Kazmi K, et al. Risk factors for early myocardial infarction in South Asians compared with individuals in other countries. JAMA J Am Med Assoc. 2007 Jan 17;297(3):286–94.

11. Asian Indian Phenotype – Coronary artery disease (CAD) Risk of coronary artery disease related mortality – higher among indians (about 2 times) Not completely explained by known risk factors* Highest incidence of premature CAD in the world CAD occurs 5-10 years earlier among south asians Case fatality rates from CAD – highest among indians (15%) when compared with many countries (low, middle income and developed countries) 2/14/2014 11 * Forouhi NG, Sattar N, Tillin T, McKeigue PM, Chaturvedi N. Do known risk factors explain the higher coronary heart disease mortality in South Asian compared with European men? Prospective follow-up of the Southall and Brent studies, UK. Diabetologia . 2006 Nov;49(11):2580–8.

12. Asian indian phenotype No study has yet linked the Asian indian phenotpye to any gene Known risk factors do not completely explain the increased susceptibility of south asians to cardiovascular disease New biomarkers required Eg .- female, buffalo hump, double chin and age > 35 years * 2/14/2014 12 * Misra A, Jaiswal A, Shakti D, Wasir J, Vikram NK, Pandey RM, et al. Novel phenotypic markers and screening score for the metabolic syndrome in adult Asian Indians. Diabetes Res Clin Pract . 2008 Feb;79(2):e1–5.

13. Asian Indian Phenotype – economic impact 2/14/2014 13 India lost 9.2 million potentially productive years of life in 2000 * India lost USD 9 billion of its national income in 2005 due to premature deaths from cardiovascular disease, stroke and diabetes (WHO) And may lose USD 237 billion in 2015 if proper measures to prevent these premature deaths are not taken (WHO) *Reddy KS. India Wakes Up to the Threat of Cardiovascular Diseases. J Am Coll Cardiol . 2007 Oct 2;50(14):1370–2.

14. Asian Indian Phenotype - theories 2/14/2014 14 Adipose tissue overflow hypothesis* Primary adipose tissue – subcutaneous tissue compartment Small for south asians During excess energy intake, the subcutaneous tissue is saturated early leading to expansion of other adipose tissue compartments Thrifty gene hypothesis * Sniderman AD, Bhopal R, Prabhakaran D, Sarrafzadegan N, Tchernof A. Why might South Asians be so susceptible to central obesity and its atherogenic consequences? The adipose tissue overflow hypothesis. Int J Epidemiol . 2007 Feb;36(1):220–5.

15. Asian indian phenotype – what do current international treatment guidelines say ? ADA (American Diabetic Association) Diabetic Care guidelines, 2013 Overweight + Ethnicity ( asian american ) is an indication for testing for hyperglycemia among asymptomatic adults and children NCEP-ATP III guidelines Remark – type 2 DM associated with a very high risk for coronary heart disease among south asians Advice for treatment of south asians Special attention for identification of risk factors Emphasis on lifestyle changes Cholesterol management guidelines are the same 2013 ACC/AHA Blood Cholesterol Guideline Under safety recommendation for statins – higher dose of statins may be used for patients of asian ancestry 2/14/2014 15

16. Asian Indian Phenotype – what do current international treatment guidelines say ? contd. 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk 10 yr risk for ASCVD (atherosclerotic cardiovascular disease) for asian Americans is lower than for non- hispanic whites Ethnic group specific algorithms for this 10yr risk is not available; but needed to be developed Guidelines with no reference to South Asians 2014 evidence based guideline for the management of high blood pressure in adults (report from the panel members appointed to the Eight joint national committee ) 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction 2013 ESC guidelines on the management of stable coronary artery disease 2/14/2014 16

17. Asian Indian Phenotype – what do current international treatment guidelines say ? contd. 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adult One of the questions the guideline sought to address was – “Are differences across population subgroups in the relationships of BMI and waist circumference cutpoints with CVD, its risk factors, and overall mortality sufficiently large to warrant different cutpoints ? If so, what should they be?” The groups that were considered included “ asian ” The data on the question were mostly poor in quality Not enough quality data to address cutoffs for BMI and WC for CVD risk 2/14/2014 17

18. Recommendations of the Second Indo-US summit on prevention of cardiovascular diseases among South Asians (2009) Framingham risk scores (estimates for 10 year risk for CAD) Risk estimated must be multiplied by a factor of 2 for south asians Threshold lowering of all risk factors Universal screening from the age of 18 years Lifestyle modification Aggressive pharmacotherapy for control of dyslipidemia 2/14/2014 18

19. Indian studies and programs Some important epidemiological studies Jaipur heart watch study (JHWS) Chennai Urban Rural Epidemiology Study (CURES) Cohort studies – Bombay Cohort Study; New Delhi Birth Study National Program on Diabetes, Cardiovascular diseases and stroke Launched in 10 states 3 components Health promotion Targeting high risk subjects to prevent disease Surveillance and research 2/14/2014 19

20. Asian Indian Phenotype – more questions than answers !! 2/14/2014 20 Whether the cutoffs of CAD risk factors need to be reconsidered for the Indian scenario ? Can be answered only by well planned randomized clinical trials Whether any genes have a role to play in increasing the risk for CAD among south asians ? Are current treatment regimens and treatment goals sufficient for decreasing morbidity and mortality due to cardiovascular diseases ? Again the only solution is RCTs Premature CAD and related mortality.

21. Sleeping or not ?? 2/14/2014 21 All the following parameters are used to estimate the 10 year risk for Coronary Heart disease according to the Framingham Point Scores EXCEPT Age LDL cholesterol Smoking status Blood pressure - Correct answer

22. questions 2/14/2014 22