CURRICULUM VITAE

SALLY AMAN NASUTION, MD, FINASIM, FACP

- Born in Medan, August 8th 1967

- Internist – Cardiologist

- Faculty Member Division of Cardiology, Department of

Internal Medicine at Faculty of Medicine University of

Indonesia, Jakarta

- Head of Intensive Coronary Care Unit (ICCU), Cipto

Mangunkusumo National General Hospital Jakarta

- Secretary General of Indonesian Society of Internal Medicine

1

Diabetes and Ischemic Heart Disease : Can We Improve the Treatment by

Better Understanding the Heart

Dr Sally Aman Nasution, SpPD-KKV, FINASIM, FACP Cardiology Division Department of Internal Medicine

Faculty of Medicine Universitas Indonesia

Cipto Mangunkusumo National General Hospital

Jakarta

Diabetes and Morbidity: Physician’s Perspective

1Fong DS et al. Diabetes Care. 2003;26:S99-S102; 2Molitch ME et al. Diabetes Care. 2003;261:S94-8; 3Kannel WB et al. Am Heart J 1990;120:672–6; 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997; 5Mayfield JA et al. Diabetes Care 2003;26:S78–9.

Diabetic

retinopathy Leading cause

of blindness in working-age adults1

Diabetic

nephropathy Leading cause of

end-stage renal disease2

Cardiovascular

disease

Stroke 2- to 4-fold increase in cardiovascular mortality and stroke3

Diabetic

neuropathy Leading cause of non-

traumatic lower extremity

amputations5

8/10 diabetic

patients

die from CV events4

Major historic T2D CV outcomes trials had different

durations and baseline CV risk

1. UKPDS 33. Lancet 1998;352:837; 2. Patel A et al. N Engl J Med 2008;358:2560; 3. Gerstein HC et al. N Engl J Med 2008;358:2545; 4. Duckworth W et al. N Engl J Med 2009;360:129

Trial N

Duration

of follow-

up (years)

Glycaemic target

Main inclusion criteria Intensive

treatment

Standard

treatment

UKPDS1 3867 10.0* FPG

<6 mmol/l

FPG

<15 mmol/l T2D newly diagnosed

ADVANCE2 11,140 4.3* HbA1c

≤6.5%

per local

guidelines

T2D and macrovascular or

microvascular disease, or

1 CV risk factor

ACCORD3 10,251 3.5† HbA1c

<6.0%

HbA1c

7.0–7.9%

T2D and CVD or 2 CV

risk factors

VADT4 1791 5.6* HbA1c

≤6%

HbA1c

8–9%

Long-standing, poorly

controlled T2D

*Median; †Mean

UKPDS: intensive glycemic control reduced microvascular

but not macrovascular outcomes

UKPDS 33. Lancet 1998;352:837

*Median follow-up, 10 years

†Assessed as surrogate endpoints; follow-up, 12 years

0 10 20 30 40

Any diabetes-related endpoint* p=0.029 12%

Microvascular complications* p=0.0099 25%

Retinopathy progression† p=0.015 21%

Microalbuminuria† p=0.000054 33%

Risk reduction (%)

Myocardial infarction* p=0.052 16%

Diabetes-related death* p=0.34 10%

All-cause mortality* p=0.44 6%

What happen in the heart of diabetic patient

The main effect of DM on cardiac metabolism is a switch away from glucose oxidation to fatty acid and/or ketone body oxidation, mainly due to:

1. Insulin resistance in the heart, liver, and adypocytes, and subsequent elevation in circulating fatty acids, ketone bodies and glucose levels, and

2. Impaired insulin stimulation of cardiac glucose

Metabolic changes in diabetes patients

Stanley WC et al. Cardiovasc Res. 1997;34:25-33. - Herrero P et al JACC 2006,47(3):598-604.

Myocardium

Extraction

Glucose FFA

Utilization

ND

DM

0.12

0.10

0.08

0.06

0.04

0.02

0.00

0.12

0.10

0.08

0.06

0.04

0.02

0.00

ND

DM

700

500

400

300

200

100

0

600

ND DM

0.40

0.30

0.20

0.10

0.00

0.50

ND

DM

400

300

200

100

0

Extraction Utilization(nmol/g/min) (nmol/g/min)

Myocardium

Extraction

Glucose FFA

Utilization

ND

DM

0.12

0.10

0.08

0.06

0.04

0.02

0.00

0.12

0.10

0.08

0.06

0.04

0.02

0.00

NDND

DM

DM

0.12

0.10

0.08

0.06

0.04

0.02

0.00

0.12

0.10

0.08

0.06

0.04

0.02

0.00

0.12

0.10

0.08

0.06

0.04

0.02

0.00

0.12

0.10

0.08

0.06

0.04

0.02

0.00

ND

DM

700

500

400

300

200

100

0

600

NDND

DM

DM

700

500

400

300

200

100

0

600

700

500

400

300

200

100

0

600

ND DM

0.40

0.30

0.20

0.10

0.00

0.50

ND DM

0.40

0.30

0.20

0.10

0.00

0.50

ND

DM

400

300

200

100

0

NDND

DM

DM

400

300

200

100

0

400

300

200

100

0

Extraction Utilization(nmol/g/min) (nmol/g/min)

Metabolic Alteration in Patients with Diabetes

• Increased FFA concentration

• Increased skeletal muscle

and myocardial FFA uptake

and oxidation

• Decreased glucose

utilization as compared to

non diabetic patient in using

heart as a source of energy

• Increased susceptibility of diabetic

patient to ischemia

• Greater decrease of myocardial

performance to a given amount of

ischemia

Decreased

glucose/lactate

pathway

Increased

free fatty acid

pathway

Resembling ischemic state

Normal State

Lopaschuk G. Heart Metab 2016;70:32-5

Normal heart derives 60–80% of the energy it consumes from FFAs and the remainder from glucose & lactate. FFA metabolism yields more ATP /gram, but requires higher O2 consumption

Metabolism 02 usage ATP

production ATP/02

Glucose oxidation

5.02 38 ATP 6.4

FFA oxidation

26.02 147 ATP 5.6

Anaerobic glycolysis

0 2 ATP

Aerobic Heart Diabetic/Ischemic State

Lopaschuk G. Heart Metab 2016;70:32-5

Ischemic state because of diabetes resulted in major disturbances of energy production

Imbalances between Energy Supply and

Demand Means ENERGY CRISIS

What can we do better to improve the quality of life in our diabetic patient

L Opie. Lancet 1999;353:768-769.

“The heart is more than a pump. It is also an organ that needs energy from metabolism.

A metabolic disease

should ideally be treated by metabolic therapy”

Prof L. Opie

Aerobic Heart Diabetic/Ischemic State

TRIMETAZIDINE

33%

Acting at the Cellular Level The Unique Mode of Action of Trimetazidine

Lopaschuk G. Heart Metab 2016;70:32-5

Circ Res. 2000;86:580-588.

TRIMETAZIDINE Inhibits Fatty Acid Oxidation and Stimulates Glucose Oxidation

0

675

1350

2025

2700

*

(nm

ol.

g d

ry w

t-1.m

in-1

)

Control TMZ (1 µM)

GLUCOSE

OXIDATION

0

110

220

330

440

550

FATTY ACID

OXIDATION

*

Control TMZ (1 µM)

(nm

ol.

g d

ry w

t-1.m

in-

1)

1,00

1,50

2,00

Pcr/

ATP

rat

io

placebo TMZ healthy subjects

Fragasso G, et al. Eur Heart J 2006,27: 942-948

TRIMETAZIDINE improves energetic metabolism of the ischemic heart caused by diabetes

33%

Energy increase

P=0.04

Trimetazidine provides a vast scientific data in Diabetic Patient

Angina patients • Glezer (2017)

• Peng (2014)

• Nesukay (2014)

• Xu (2014)

• Vitale (2012)

• Danchin (2011)

• Glezer (2007) • Rosano (2005)

• Chazov (2005)

• Gupta (2005)

• Sellier-Broustet (2003)

• Szwed - TRIMPOL II study (2001)

• Manchanda (1997)

• Michaelides (1997) • Szwed - TRIMPOL I study (2001)

• Detry - TEMS study (1995)

• Levy (1995) • Dalla-Volta (1990)

Diabetic patients

• Shehata (2014)

• Xu (2014)

• Belardinelli (2008)

• Rosano (2007)

• Padial - DIETRIC study (2005)

• Fragasso (2003)

• Rosano (2003) • Szwed - TRIMPOL I

study (2001)

Patients undergoing

angioplasty •Wang (2016) •Zhang (2015) •Shehata (2014) •Xu (2014) •Chen (2014)

•Xu (2013) •Labrou (2007) •Bonello (2006) •Polonski (2002) •Steg – LIST study (2001) •Birand (1997)

•Kober (1992)

Left ventricular

dysfunction

• Grajek (2015)

• Bubnova (2012)

• Zhang (2012) • Fragasso (2012)

• Gao (2011)

• Tuunanen (2008)

• Sisakian (2008) • Belardinelli (2008)

• Di Napoli (2007)

• Belardinelli (2007) • Fragasso (2006)

• Di Napoli (2005)

• El Kady (2005)

• Rosano (2003) • Belardinelli (2001)

• Lu-Chierchia (1998)

• Brottier (1990)

Acute MI patients •Li (2016)

•Wang (2016) •Demirelli (2013) •Kim – KAMIR study (2013) •Steg – LIST study (2001) •Boissel – EMIP FR study (2000) •Di Pasquale (1999)

Patients undergoing

coronary bypass

• Zhang (2015)

• Martins (2015)

• Lopatin (2010) • Iskesen (2009)

• Tunerir (1999)

• Fabiani (1992)

16

580 coronary diabetic patients

n=580

P<0.001

Exe

rcis

e te

st d

ura

tio

n (

s)

360

370

380

390

400

410

420

430

440

450

M0 M6

n=580

P<0.001

0

0,5

1,0

1,5

2,0

2,5

3,0

M0 M6

Mean number of angina attacks

Mean weekly nitrate consumption

Angina attacks Exercise capacity

390

440

Trimetazidine : antianginal and anti-ischemic efficacy in diabetic patients

Long-term efficacy in

diabetic patient

Padial LR et al. Rex Clin Esp. 2005;205:57-62.

Trimetazidine effectively reduces ischemic burden and episodes of silent MI in Diabetic Patient

Long-term efficacy in

diabetic patient

G. Marazzi et al. Int J Cardiol. 2007;120:79-84.

Total ischemic burden

Episodes of silent myocardial ischemia

Trimetazidine reduces the risk of recurrent angina attack in diabetes patients

Xu X, Zhang W, Clin Drug Invest. 2014;34:251-258.

A single-centre, prospective, randomized,

double-blind study at 2-year follow-up

Long-term efficacy in

diabetes patient

22%

20

Hence…Trimetazidine is Recognized by International Guidelines

1. ESC guidelines on the management of stable coronary artery disease – Eur Heart J. 2013;34:2949-3003.

Conclusion

• Diabetic patients suffer from increased risk of complications

• Energy crisis (imbalances of energy demand and supply) is one contributing factor of diabetic patients developing ischemia

• To prevent this condition, metabolic approach using Trimetazidine proven to be beneficial to diabetic patient

• Trimetazidine, acting at cellular level, increasing energy supply thus improving heart metabolism of diabetic/ischemic patient

• Trimetazidine, with its wealth of data and recognized by guideline in diabetic patient, can be used early to improve patients’ quality of life

Lombok, 2017

sanasution@yahoo.com