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: Physicians Perspective
Stroke
2- to 4-fold increase in
cardiovascular
mortality and stroke3
Diabetic
retinopathy
Leading cause Cardiovascular
of blindness in working-age adults1 disease
8/10 diabetic
patients
die from CV events4

Diabetic
neuropathy
Leading cause of non-
Diabetic traumatic lower extremity
nephropathy amputations5
Leading cause of
end-stage renal disease2

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;120:6726;
4Gray RP & Yudkin JS. In Textbook of Diabetes 1997; 5Mayfield JA et al. Diabetes Care 2003;26:S789.
 Major historic T2D CV outcomes trials had different
durations and baseline CV risk

Duration Glycaemic target

Trial N of follow- Intensive Standard Main inclusion criteria
up (years) treatment treatment
UKPDS1 3867 10.0* FPG FPG T2D newly diagnosed
<6 mmol/l <15 mmol/l
ADVANCE2 11,140 4.3* HbA1c per local T2D and macrovascular or
6.5% guidelines microvascular disease, or
1 CV risk factor
ACCORD3 10,251 3.5 HbA1c HbA1c T2D and CVD or 2 CV
<6.0% 7.07.9% risk factors
VADT4 1791 5.6* HbA1c HbA1c Long-standing, poorly
6% 89% controlled T2D

*Median; Mean

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
UKPDS: intensive glycemic control reduced microvascular
but not macrovascular outcomes

All-cause mortality* 6% p=0.44

Diabetes-related death* 10% p=0.34

Myocardial infarction* 16% p=0.052

Microalbuminuria 33% p=0.000054

Retinopathy progression 21% p=0.015

Microvascular complications* 25% p=0.0099

Any diabetes-related endpoint* 12% p=0.029

0 10 20 30 40
Risk reduction (%)
*Median follow-up, 10 years
Assessed as surrogate endpoints; follow-up, 12 years

UKPDS 33. Lancet 1998;352:837

What happen in the heart of
diabetic patient
 Metabolic changes in diabetes patients

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

Glucose FFA
Extraction Utilization Extraction Utilization
0.12 700 (nmol/g/min) (nmol/g/min)
0.10 600 0.50
500 400
0.08 0.40
Myocardium 400 300
0.06 0.30
300
0.04 0.20 200
200
0.02 0.10 100
100
0.00 0 0.00 0
ND DM ND DM ND DM ND DM

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

 Metabolic Alteration in Patients with Diabetes

Decreased
Decreased glucose Increased FFA concentration
utilization as compared to Increased
Increased skeletal muscle
glucose/lactate
non diabetic patient in using free fatty
and myocardial FFAacid
uptake
pathway
heart as a source of energy andpathway
oxidation

Resembling ischemic state

Increased susceptibility of diabetic

patient to ischemia
Greater decrease of myocardial
performance to a given amount of
ischemia
Normal heart derives 6080% of the energy it consumes from FFAs and the remainder from glucose &
lactate. FFA metabolism yields more ATP /gram, but requires higher O2 consumption

Normal State

ATP
Metabolism 02 usage ATP/02
production
Glucose
5.02 38 ATP 6.4
oxidation
FFA
26.02 147 ATP 5.6
oxidation
Anaerobic
0 2 ATP
glycolysis

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

 Ischemic state because of diabetes resulted in major disturbances of
energy production
Aerobic Heart
Diabetic/Ischemic State Imbalances between Energy Supply and
Demand Means ENERGY CRISIS

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

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

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

 Acting at the Cellular Level
The Unique Mode of Action of Trimetazidine
Aerobic Heart
Diabetic/Ischemic State

TRIMETAZIDINE

33%

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

 TRIMETAZIDINE Inhibits Fatty Acid Oxidation and
Stimulates Glucose Oxidation

FATTY ACID GLUCOSE

550
OXIDATION OXIDATION
2700
*

(nmol.g dry wt-1.min-1)

(nmol.g dry wt-1.min-
440 * 2025

330
1)

1350
220

675
110

0 0
Control TMZ Control TMZ
(1 M) (1 M)

Circ Res. 2000;86:580-588.

TRIMETAZIDINE improves energetic metabolism
of the ischemic heart caused by diabetes
2,00
Energy increase

33%
Pcr/ATP ratio

1,50

1,00
P=0.04

placebo TMZ healthy subjects

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

 Trimetazidine provides a vast scientific data in Diabetic Patient

Angina patients Diabetic patients Patients undergoing Left ventricular Acute MI patients
angioplasty dysfunction
Glezer (2017) Shehata (2014) Li (2016)
Peng (2014) Xu (2014) Wang (2016) Grajek (2015) Wang (2016)
Nesukay (2014) Zhang (2015) Demirelli (2013)
Belardinelli (2008) Bubnova (2012)
Xu (2014) Shehata (2014) Kim KAMIR study (2013)
Rosano (2007) Zhang (2012)
Xu (2014) Steg LIST study (2001)
Vitale (2012) Padial - DIETRIC study Fragasso (2012)
Chen (2014) Boissel EMIP FR study
Danchin (2011) (2005) Gao (2011)
Xu (2013) (2000)
Glezer (2007) Fragasso (2003) Tuunanen (2008)
Labrou (2007) Di Pasquale (1999)
Rosano (2005) Rosano (2003) Sisakian (2008)
Chazov (2005) Szwed - TRIMPOL I Bonello (2006) Belardinelli (2008)
Gupta (2005) Polonski (2002)
study (2001) Di Napoli (2007)
Sellier-Broustet (2003) Steg LIST study (2001) Patients undergoing
Belardinelli (2007)
Szwed - TRIMPOL II study (2001) Birand (1997) coronary bypass
Fragasso (2006)
Kober (1992)
Manchanda (1997) Di Napoli (2005)
Michaelides (1997) El Kady (2005) Zhang (2015)
Szwed - TRIMPOL I study (2001) Rosano (2003) Martins (2015)
Detry - TEMS study (1995) Belardinelli (2001) Lopatin (2010)
Levy (1995) Lu-Chierchia (1998) Iskesen (2009)
Dalla-Volta (1990) Brottier (1990) Tunerir (1999)
Fabiani (1992)
16
Trimetazidine : antianginal and anti-ischemic efficacy in
diabetic patients
580 coronary diabetic patients Long-term efficacy in
diabetic patient
Angina attacks Exercise capacity
3,0
450
2,5

Exercise test duration (s)

n=580 440 n=580
P<0.001 430 440
2,0 P<0.001
420

1,5 410
400
1,0 390
380 390
0,5
370
0 360
M0 M6 M0 M6

Mean number of angina attacks

Mean weekly nitrate consumption

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

 Trimetazidine effectively reduces ischemic burden and
episodes of silent MI in Diabetic Patient
Total Episodes of silent
ischemic burden myocardial ischemia

Long-term efficacy in
diabetic patient

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

 Trimetazidine reduces the risk of recurrent angina attack
in diabetes patients

22%
Long-term efficacy in
diabetes patient

A single-centre, prospective, randomized,

double-blind study at 2-year follow-up

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

 HenceTrimetazidine is Recognized by
International Guidelines

1. ESC guidelines on the management of stable coronary artery disease Eur Heart J. 2013;34:2949-3003. 20
 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
sanasution@yahoo.com
Lombok, 2017