Dr. Dibbendhu Khanra

INDIAN LIPID GUIDELINE

Single problem

Single strategy

Statins

Single calculation

DON’T CHASE TARGETS

2013ACC/ AHA

Paradigm Shift

New cholesterol treatment guidelines could double number of Americans taking statins

About 70 million Americans could take statins under new guidelines

32 year male IT professionalOccasionally drinks/ smokesNon DM/ non HTN85 kgs/ Cant go to gymFather died of heart attack at 50 years of ageRecently marriedVery anxious of heart diseaseCAG normalLDL 100TG 350HDL 30ACC risk calculator: 2%

2016: an Indian story

Would you give statin or not? If given how long? What about the side effects?

8 meetings153 experts18 states 30 cities

INDIAN CVD

BURDEN?

more than 60 million people with coronary heart diseases by 2015

The health & family welfare

ministry Projection

CV Mortality: Trend in India

012345

1990 2000 2010 2020

2.263.01

3.84.77

CV M

orta

lity

(Mill

ions

)

Heart. 2008 Jan;94(1):16-26.

MI at younger Age in Indians

http://www.cadiresearch.org/topic/asian-indian-heart-disease/cadi-india/premature-heart-disease

Changing Epidemiology in India

10

Urbanization

DM,HT,DYSLIP

>Improved Life Expecta

ncy

Changing

dietary pattern

Reduced

physical

activity

Stress

• Increase inthe number ofCVD cases

World Development Indicators, World Bank.India’s Pace of Urbanization Speeds Up, Wall Street Journal, July 2011 Food and Nutrition in India: Facts and interpretation.Dreze J, et al. Economic & Political Weekly, February 2009. Smoking & Heart Disease. Cleveland Clinic. Joshi SR, et. al. India -Diabetes Capital of the World : Now Heading Towards Hypertension. Journal of Association of Physicians in India. 2007; 55:323-324 Xavier D, et.al. Treatment and outcomes of acute coronary syndromes in India (CREATE): a prospective analysis of registry data. The Lancet.2008;371(9622): 1435-1442. World Health Survey, World Health Organization.

• Earlier onsetof disease

CAD in

Indians

However westernized we

get,INDIANS are

still INDIANS, you know?

Oh, I see

High smokingHigh BP

But

Heart diseases amongChinese , very low

& Japanese , the lowest

TRADITIONAL

CV RISKSIN

INDIA?

DIABETES IN INDIA

66 Million Cases35 Million

Undiagnosed8.6% Prevalence Over 1 Million

Deaths

IDF, Diabetes Atlas, 6th edition revision, 2014

 INTERHEART Study

Dyslipidemia is the most common risk factor   

Reducing Cholesterol benefits most

Relative risk reduction

2 yr event rate

Huang et al. Am J Med 2001;111:633-642Turner R.C. BMJ 1998;316:823-828He et al. JAMA 1999;282:2027-2034Antitrombotic Trialits BMJ 2002;324:71-86

Men Women

Total cholesterol

 INDIAN DYSLIPIDEMIA

Jaipur heart watch study

 ATHEROGENIC DYSLIPIDEMIA

Low HDL (Most common)High TG

High Lp(a)

High LDL is very uncommonApo B: Apo A1 is the best

biomrker

Lipid screening at 20 years of age

Asian-Indian

paradox

More severe

form with poor

outcome

ACC/AHA risk

calculatorNot validated in

Indians10 year risk onlyOnly

conventional risk factors

Needs computer

Indian doctors are better in auscultation than statistics

NONTRADITIONA

LCV RISKS

ININDIA?

Coronary calcium

Both LDL-C and HDL-C were found to be independent predictors of CAC

CAC score >400 had 100% specificity

CIMT

For 0.1 mm increase in CIMT the future risk of MI increased by 10-15% A 10% reduction in LDL-C per year accounted for a reduction of CIMT by 0.73 presence of carotid plaques is a marker of already existing ASCVD

Aortic stiffness

Lp(a)

more common among CAD patients with existing family history

Lp(a) levels in Asian Indian newborns were significantly higher than in Chinese in Singapore

Level > 20 mg/dL indicates increased ASCVD risk in Indians

presence of obesity and/or metabolic syndrome in an individual who is otherwise at low 10-year risk of ASCVD should indicate high lifetime ASCVD risk.

Obesity/ MetS

A 5-μmol/L tHcy increment elevates CAD risk by as much as cholesterol increases of 0.5 mmol/L (20 mg/dL)

Very high prevalence of hyperhomocystinemia (>15 µmol/L) in 75% of subjects in India, which was strongly correlated with cobalamin deficiency

impaired cobalamin status appears more important than folate deficiency among Asian Indians

Homocysteine

CRP significant ASCVD risk reduction with statin in individuals with elevated CRP despite relatively normal LDL-C

A value of > 2 mg/l of hs-CRP indicates increased ASCVD risk.

When the value is >10 mg/L, it usually indicates a non-atherosclerotic cause of Inflammation

But Quality control and proper standardization of hs-CRP is challenging in India

Risk factors

NO LDL

NO CRPNO

HOMOCYSTEINE

CACAortic stiffness

CIMTLp(a)MertS

JBS3: Lifetime ASCVD risk calculator

Estimate lifetime riskValidated in indians

Non-conventional risk factors

<30% = LOW RISK30-44% = MODERATE

RISK>45% = HIGH RISK

IdentifyHigh Riskpatients

AssessRisk factors

EstimateLifetime risk

The Indian Approach

1. History of MI or documented CAD2. History of ischemic stroke or TIA3. hemodynamically significant carotid plaque4. Atherosclerotic peripheral arterial

disease(ABPI<0.9)5. Atherosclerotic aortic aneurysms6. Atherosclerotic renal artery stenosis

Pre-existing ASCVD

30-44% risk

>45%

risk

Moderate risk

Highrisk

Indian risk

stratification

SETTING THE

INDIAN TARGETS

Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279

LDL: the lower the better

High dose (ROSUVA)statin

regresses atherosclerosis

• LDL should be the primary target

• the lower LDL the better• LDL<50 mg/dl is safe

4HPS Collaborative Group. Lancet. 2002;360:7-22. 5Shepherd J et al. N Engl J Med. 1995;333:1301-1307.6 Downs JR et al. JAMA. 1998;279:1615-1622.

14S Group. Lancet. 1994;344:1383-1389.2LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 3Sacks FM et al. N Engl J Med. 1996;335:1001-1009.

Δ LDLN 4444 4159 20 536 6595 66059014

-35% -28% -29% -26% -25%-25%Secondary High Risk Primary

Patie

nts

Exp

erie

ncin

g M

ajor

CH

D

Eve

nts,

%

PlaceboStatin

19.4

12.310.2 8.7

5.5 6.8

28.0

15.9 13.

2 11.8 7.

9

10.9

Many CHD Events Still Occur in Statin Treated Patients

25-40% CVD Reduction Leaves High Residual RiskP = 0.003

P <0.001P = 0.003 P =

0.0001 P <0.001 P <0.001

Residual CVD Risk with Intensive Statin Therapy Less, but Still Unacceptably High

Patie

nts

Exp

erie

ncin

g M

ajor

CVD

E

vent

s, %

PROVE IT-TIMI 222 IDEAL3

TNT4

nLDL-C* mg/dL

1Superko HR. Br J Cardiol. 2006;13:131-136. 2Cannon CP et al. N Engl J Med. 2004;350:1495-1504.3Pedersen TR et al. JAMA. 2005;294:2437-2445. 4LaRosa JC et al. N Engl J Med. 2005;352:1425-1435.

4162

8888

10,00195

*Mean or median LDL-C after treatment

62 104

81 101

77

Statistically significant, but clinically inadequate CVD reduction1

Standard statin therapyIntensive high-dose statin therapy

Patients With Diabetes Have Particularly High Residual CVD Risk After Statin Treatment

Event Rate (No Diabetes)

Event Rate (Diabetes)

On Statin On Placebo On Statin On PlaceboHPS1* (CHD patients) 19.8% 25.7% 33.4% 37.8%

CARE2† 19.4% 24.6% 28.7% 36.8%

LIPID3‡ 11.7% 15.2% 19.2% 22.8%

PROSPER4§ 13.1% 16.0% 23.1% 18.4%

ASCOT-LLA5‡ 4.9% 8.7% 9.6% 11.4%TNT6║ 7.8% 9.7% 13.8% 17.9%

*CHD death, nonfatal MI, stroke, revascularizations†CHD death, nonfatal MI, CABG, PTCA‡CHD death and nonfatal MI§CHD death, nonfatal MI, stroke║CHD death, nonfatal MI, resuscitated cardiac arrest, stroke (80 mg versus 10mg atorvastatin)

1HPS Collaborative Group. Lancet. 2003;361:2005-2016. 2Sacks FM, et al. N Engl J Med. 1996;335:1001-1009. 3LIPID Study Group. N Engl J Med. 1998;339:1349-1357. 4Shepherd J, et al. Lancet. 2002;360:1623-1630. 5Sever PS, et al. Lancet. 2003;361:1149-1158.6Shepherd J, et al. Diabetes Care. 2006;29:1220-1226.

Beyond targeting LDL there are several

atherogenic lipoproteins and LDL accounts for only about 75% of them

residual risk of ASCVD in statin-treated patients remains as high as 55%-70%.

It is thus evident that in order to reduce ASCVD effectively, we need to concentrate on all atherogenic lipoproteins, and not just LDL alone

Non HDL cholesterol

TG

Small

dense

LDL

non-HDL-C has been shown to correlate well

with subclinical atherosclerosis

Non-HDL-C is particularly informative in diabetics who tend to have higher TG levels

predictive accuracy of non-HDL-C in patients with relatively low TG

(<200mg/dL)

LDL-C lost its predictive value when TG levels exceeded

400mg/dL

Non-HDL-C seems to predict ASCVD risk

equally well regardless of TG levels

increased non-HDL-C is associated

with increased risk of future CV events even if LDL-C is under

control with statin

Better correlate of ASCVD than LDLIncludes TG and Lp(a)Does not need fastingCan be easily calculated by total cholesterol and

HDLSurrogate for small dense LDL

Non HDL cholesterol better than LDL?

Memories of ATPIII targets

strong linear association between TG levels and CHD risk

Do not underestimate high TG

Small dense LDLLarge LDL

AtherogenicTG>250

Phenotype BTG <100

Phenotype A

At a fasting TG concentration <100 mg/dL, 85% of the population has pattern A (less

atherogenic)

At a fasting TG concentration >250 mg/dL, 85% will have pattern B (highly atherogenic)

Non-fasting TG Clinically unimportant increase in TG concentrations, by 0·2–0·4 mmol/L (18-36 mg/dL) on average, two to six hours after eating normal meals.

even a non-fasting concentration predicts increased CV risk

Indian patients are unpredictable

U shaped relation: HDL & CV risk

631,762 individuals with no prior cardiac

conditions, with a mean follow up of

4.9 years,

• very high levels of HDL-C were associated with an increased risk of death from both CV and non-CV causes, compared with intermediate HDL-C levels.

Prevalence of low HDL-C levels was much higher in the South Asian populations than in the other populations (82% vs 60% of acute MI cases)

increaseing HDL-C was associated with a mere 13% reduction in MI risk in South Asians as compared to 23% risk reduction in the other Asians

The patients with low HDL-C are three times more likely to die after an acute coronary event

INTERHEART: HDL in Indians

THERAPY FOR

INDIAN DYSLIPIDAE

MIA

SmokingIt is never too late to

quit smoking. After quitting smoking,

the ASCVD risk decreases by 50% within 2 years.

Alcohol consumption was not found to be protective among South Asians

INTERHEARTAlcohol

Vegetarians are not protected

Eat baked or boiled fish at least twice per

week

As per the ICMR in 2014, 392 million people were inactive

in India which represented nearly 1/3rd of our population.

Mr. Modi, is it true that there

are 4 billion lazy people in India?

Yes, that’s why I invented

WORLD YOGA DAY

Yoga may help in improving lipid profile in patients suffering

from ESRDBairey Merz CN, Dwyer J, Nordstrom CK, Walton KG, Salerno JW, Schneider RH. Psychosocial stress and cardiovascular disease: Pathophysiological links.

Behav Med 2002; 27:141-147

Treatment of 1000 patients with a statin for five years would prevent 18 major ASCVD event (Cochrane)

Reduction of 1 mmol per liter (39 mg/dl) in LDL-C levels yielded 21% risk reduction irrespective of LDL baseline (CTT)

In individuals with 5-year risk of major vascular events <10%, each 1 mmol/L reduction in LDL-C produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years (CTT)

Those who achieved LDL-C <50 mg/dL had 65% reduction in the risk of major CV events (JUPITER)

23% of the subjects reached LDL-C level of <40 mg/dL with no adverse effects (JUPITER)

Statin

Statin

PURE - 10 yrs community based observational study

underuse of low-cost medicines for secondary prevention among participants with a history of CVD

70The PURE Study: a prospective epidemiological survey. Lancet 2011;378:1231–43.

WOSCPOS: 20 years follow-up45-64 year old men (n= 6595) with high LDL

cholesterol were randomized to receive pravastatin 40mg once daily or placebo for an average of 4.9 years. And followed up for 20 years (without statin)

Men allocated to pravastatin had - reduced all-cause mortality - 21% decrease in cardiovascular death- 18% for any coronary event (p=0.002), - 24% for myocardial infarction (p=0.01) and - 35% for heart failure (p=0.002)

Statin: Legacy Effect

Atorva=Rosuva

HOPE 3Rosuvastatin for primary prevention

SATURN

Statin doses

Statin Statin Vices

Statin & DM

treatment of 255 people with statins for 4 years would result in to 1 additional case of diabetes mellitus

risk of new onset diabetes with intensive statin therapy is approximately 3 per 1000 patient-years and with moderate intensity statin therapy 1 per 1000 patient-years

Its true frequency is unknown; however, reported incidence is around 10%. Routine monitoring is not needed

Statin & muscle symptoms

FibratesA meta-analysis of 18

trials providing data for 45058 participants, including 2870 major CV events, 4552 coronary events, and 3880 deaths

It was found that fibrates could reduce the risk of major CV events predominantly by prevention of coronary events

patients with higher baseline TG and lower HDL-C levels benefited from fenofibrate therapy in addition to pre-existing simvastatin (ACCORD)

Look for reversible causesEg.DM, hypothyroidsm, CKD, immuocomprised

LSM

TG<500

TG>500

Statin

Achieve LDL target

Achieve non HDL cholesterol

Non-statin drugs

Fibrate

Achieve TG target

Statin

Achieve LDL and non HDL cholesterol target

Hyper

TG

Rising HDLDrugs Trials Outcome Comment

Rosuvastatain ASTEROID, ARBITER, METEOR

Positive Also regression of atherosclerosis

NIACIN HATSARBITER 2ARBITER 3

Positive In combination to statin

HPS2THRIVEAIMHIGH

Negative In combination to statin

FIBRATE FIELD Positive 27% redction in cardiac events

ACCORD Positive In combination to statin

CETP Inh TorcetrapibDalcetrapib

Negative Harmful

AnacerapibEvacetrapib

Ongoing

Curing atheroclerosis

THEINDIAN

LIPID POLICY

Need policies

Screen all adults at 20 years of age/college entry

“magnificent seven”1. No tobacco2. Physical activity: ≥150 min moderate intensity or

equivalent exercise per week 3. Body-mass index <23 kg/m24. Healthy diet: achieving at least four of the five important

dietary components, focusing on fruits and vegetables, fish, fibre, and sodium intake and sweetened beverage intake

5. LDL-C level should be below 100mg/dl6. Blood pressure: <120/80 mmHg 7. Fasting plasma glucose level: <100 mg/d

25 X 25

Recommendations made in the consensus statement

are not a mandate to the medical community

8 meetings153 experts18 states 30 cities

Multiple problem

Multiple strategy

StatinsNon-

statinsYoga

Multiple calculation

Set Target According To Risk

2016Indian

guideline

Risk countingNon-traditional risk

factorsJBS3 – lifetime

Non-fastingNon-HDL

cholesterol

32 year male IT professionalOccasionally drinks/ smokesNon DM/ non HTN85 kgs/ Cant go to gym Father died of heart attack at 62 years of ageRecently marriedVery anxious of heart diseaseCAG normalLDL 100TG 350HDL 30

2016: an Indian storyMajor RF

Moderate RF

Moderate Risk

Major RF

Lp (a)40CIMT normalCAC 250A

High Risk

StatinAt least 5 years

Questions answered

TGNon HDL cholLifetime CV riskNon-traditional risksnoninvasive imaging

20 vs 40Atorva vs rosuvaHF, hemodialysis

INDIAN LIPID GUIDELINEQuestions unanswered

complex lots of investigation till not validated not evidence based statinization

MADE IN INDIA

Thank You