PHARMACOTHERAPEUTI

C RELEVANCE OF “ASIAN

INDIAN PHENOTYPE”P Guruprasad

DM, Clinical Pharmacology4/5/2015

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Who are they ??

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Asian Indian Phenotype !!!

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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

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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

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*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.

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)

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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/m2

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.

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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)

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*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.

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.

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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

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*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.

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)

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*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.

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 *

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*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.

Asian Indian Phenotype – economic

impact

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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.

Asian Indian Phenotype - theories

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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.

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 4/5/2015

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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

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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

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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

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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

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Asian Indian Phenotype – more questions

than answers !!

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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.

Sleeping or not ??

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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

questions

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