CURICULLUM VITAE

Dr.dr. Imam Subekti, SpPD-KEMD

 Lulus Dokter FKUI ………….……………………….. 1983

 INPRES I Ogan Komerling Ilir, Sumsel …….... 1984-1987
 Lulus Dokter Ahli Penyakit Dalam FKUI …... 1993
 INPRES II Kabupaten Pandeglang, Banten... 1993-1995
 Staf Pengajar Departemen IPD FKUI ……..... 1993- skrg
 Konsultan Endokrin Metabolik Diabetes .... 2000
 Ketua Program Studi Subspesialis IPD FKUI 2006-2011
 Ketua Divisi Metabolik Endokrinologi ……... 2008-2011
 Ketua Departemen Ilmu Penyakit Dalam
FKUI/RSCM ………. 2011-skrg
The Management of Dyslipidemia
in Diabetes

Imam Subekti
Division of Endocrinology and Metabolism
Department of Internal Medicine,
Faculty of Medicine, University of Indonesia
 Relationship of
Dyslipidemia – Coronary Heart Disease

Dyslipidemia is a major risk factor for coronary heart

disease (CHD)1
Clinical trials conclusively have demonstrated that
treatment of lipid disorders can reduce CHD morbidity
and mortality.
• 10% reduction in TC = 15% reduction in CHD
mortality risk and 11% reduction in total mortality
risk according to meta-analysis of 38 statin trials2
LDL-C is the primary target to prevent CHD3

1. Goode et al.Lancet.1995;345(8946):362-64
2. Gould AL, et al. Circulation. 1998;97:946-952.
3. NCEP, Adult Treatment Panel III. JAMA. 2001;285:2486-2497.
 Effect of Lowering LDL-C on CHD Events
in Statin Trials – Lower is Better
30
4S - Placebo

25
Rx - Statin therapy
PRA – pravastatin Secondary Prevention
ATV - atorvastatin 4S - Rx
20

LIPID - Placebo
15
CARE - Placebo
LIPID - Rx
CARE - Rx
HPS - Rx TNT – ATV10 HPS - Placebo Primary Prevention
10 PROVE-IT - PRA WOSCOPS – Placebo
TNT – ATV80
PROVE-IT – ATV AFCAPS - Placebo
6
5 AFCAPS - Rx WOSCOPS - Rx
ASCOT - Placebo
ASCOT - Rx
0
40 60 80 100 120 140 160 180 200
(1.0) (1.6) (2.1) (2.6) (3.1) (3.6) (4.1) (4.7) (5.2)
LDL-C achieved mg/dL (mmol/L)
Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004;9(2):269-279
LaRosa JC et al. N Engl J Med 2005;352:1425-1435
Residual coronary heart disease in statin-treated
patients: room for improvement
Study n No. events % Risk % Events not
Control Statin reduction avoided

4S1 30,187 2042 1490 26 74

CARE2
WOSCOPS3
AFCAPS4
LIPID5
HPS6 20,536 1212 898 27 74
PROSPER7 5804 356 292 19 82
ALLHAT-LLT8 10,355 421 380 9 91
ASCOT-LLA9 10,305 154 100 36 64
Total 77,817 4185 3160 25 75

1Lancet
199419;344:1383-9; 2NEJM 1995;333:1301-7; 3Circulation 1999;99:216-23;
4JAMA 1998;279:1615-22; 5NEJM 1998;33:1349-57; 6Lancet 2002;360:7-22; 7Lancet 2002;360:1623-30;
8JAMA 2002;288:2998-3007; 9Lancet 2003;361:1149-58.
 Aggressive LDL-C lowering with maximal doses
of statins does not eliminate residual
macrovascular risk
TNT study HDL-C, TG
5-yr risk major cardiovascular

15 Blood Pressure
IA Adiposity
22% relative Modifiable Insulin resistance
10 10.9 risk reduction Smoke
Risk Factors Inflammation, etc.
event rate (%)

8.7
5
RESIDUAL CV RISK

0
Atorvastatin 10 mg 80 mg
Non-Modifiable Age
Gender
LDL-C 101 mg/dl 77 mg/dl Risk Factors Family history
(n=5,006) (n=4,995)

* Composite of death from CHD, nonfatal MI, resuscitation after cardiac arrest,
and fatal or nonfatal stroke.

LaRosa et al., N Engl J Med 2005;352:1425–35

 HDL-Cholesterol: A risk modifier
at all levels of LDL-Cholesterol
The Framingham
Study

Low HDL-C predicts CHD risk independently when LDL-C is low

Castelli WP. Can J Cardiol 1988;4 (Suppl. A):5A-10A
The predictive value of Low HDL-C level remains
significant even when LDL-C <70 mg/dL
TNT study
cardiovascular events (%) 10
9
8 -39%
7 p=0.03
6
5-yr risk of major

5
4
3
2
1
0
Q1 Q2 Q3 Q4 Q5
(<37) (37 to <42) (42 to <47) (47 to <55) (≥55)

Quintile of HDL-C Level (mg/dL)

in patients who achieved LDL-C <70 mg/dL on statin therapy

Barter P et al. N Engl J Med. 2007; 357:1301-10.

 Aggressive LDL-C lowering with maximal doses
of statins does not eliminate residual
macrovascular risk
TNT study HDL-C, TG
5-yr risk major cardiovascular

15 Blood Pressure
IA Adiposity
22% relative Modifiable Insulin resistance
10 10.9 risk reduction Smoke
Risk Factors Inflammation, etc.
event rate (%)

8.7
5
RESIDUAL CV RISK

0
Atorvastatin 10 mg 80 mg
Non-Modifiable Age
Gender
LDL-C 101 mg/dl 77 mg/dl Risk Factors Family history
(n=5,006) (n=4,995)

* Composite of death from CHD, nonfatal MI, resuscitation after cardiac arrest,
and fatal or nonfatal stroke.

LaRosa et al., N Engl J Med 2005;352:1425–35

Increased triglyceride levels confer increased risk
at all levels of LDL-C
PROCAM study: CHD risk according to LDL-C and
TG Increased TG confers CHD risk at all levels of LDL-C
300
CHD cases/1,000 in 8 years

TG < 200 mg/dL (2.3 mmol/L)

250 TG ≥ 200 mg/dL (2.3 mmol/L)

200

150

100

50

0
< 130 130-159 160-189 > 190
< 3.4 3.4-4.1 4.2-4.8 > 4.9
LDL-Cholesterol (mg/dL, mmol/L)

Adapted from Assman G et al Eur Heart J, Vol. 19,suppl A 1998

High TG levels are associated with increased residual
macrovascular risk, even when LDL-C is very low
 Despite achieving LDL-C <70 mg/dL with high-dose statins, patients with TG
≥200 mg/dL show significantly increased CV risk

25
PROVE IT-TIMI 22 study
30-day risk of death, MI or recurrent

20
20.3 +56%
15 p=0.001

10 13.5

5
ACS (%)

0
≥200 <200
(n=603) (n=2,796)

On-treatment TG (mg/dl)
in patients who achieved LDL-C <70 mg/dL on statin therapy

Miller M et al. J Am Coll Cardiol. 2008;51:724-30.

 The Association of low HDL-C with Elevated TG
Confers a Substantial Risk of CHD

Crude incidence of CHD after 8 years of follow-up in

the Copenhagen Male Study

15,0%
Incidence in % of
subjects

10,0%
TG 1,60-22,4

5,0% TG 1,10-1,59
TG thirds in
TG 0,44-1,09 mmol/l
0,0%
HDL 0,29-1,18 HDL 1,19-1,45 HDL 1,46-3,46

HDL thirds in mmol/l

The observed relationship holds after multivariate adjustment for potential confounders

Jeppesen J et al, Circulation 1998;97:1029-1036

 Comprehensive Lipid Approach

 LDL-C Reduction Reduces Cardiovascular Events

 YES - Strong Unequivocal Evidence
 Limitation: 60%-90% of CV events still observed in statin-treated pts
 Concept of Residual Cardiovascular Risk (RR)

 Comprehensive lipid management (LDL-C, HDL-C, TG)

 Low HDL-C and high TG significantly contribute (by 30-40%) to the
excess residual risk of CV events on optimal LDL-C levels
 Therapeutic Approaches for a Comprehensive Lipid Management
- Effects on Lipid Profile and Safety: YES
- Effect on Clinical Endpoints: Positive Preliminary
 Features of Atherogenic Dyslipidemia

Low HDL-C
Metabolic syndrome

Diabetes Mellitus T2

PCOS Elevated Elevated TG

small-dense
LDL particles

• Atherogenic dyslipidemia is commonly associated with pro-thrombotic

and pro-inflammatory states.
Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults,
JAMA 2001;285:2486-2497
 Insulin Resistance:
Associated Conditions
Type 2 diabetes
Impaired
Atherosclerosis glucose tolerance

Dyslipidemia Hypertension
Insulin
Decreased Resistance
fibrinolytic activity Obesity (central)

Acanthosis Polycystic
nigricans ovary disease
Hyperuricemia
Modifikasi RA Defronzo. Netherlands J of Medicine 50 (1997) 191-197;
HE Lebovitz. Exp. Clin Endocrinol Diabetes 109 (2001) Suppl 2: A135-148
 Mechanisms Relating Insulin Resistance and
Dyslipidemia
Fat Cells Liver

FFA

 TG VLDL
 Apo B
 VLDL
IR X

Insulin
 Mechanisms Relating Insulin Resistance and
Dyslipidemia
Fat Cells Liver

FFA
CE

 TG VLDL (CETP) (hepatic

HDL
 Apo B lipase)
 VLDL
IR X TG
Apo A-1

Kidney
Insulin
 Mechanisms Relating Insulin Resistance and
Dyslipidemia
Fat Cells Liver

FFA CE

 TG (hepatic
VLDL (CETP) HDL
 Apo B lipase)
 VLDL
IR X TG
Apo A-1
CE (CETP) TG
Kidney
Insulin SD
LDL
LDL

(lipoprotein or hepatic lipase)

UKPDS: Typical Lipid Profile in Patients with Diabetes
Compared with No Diabetes
6 4 Women
p<0.001
Women
5.8 3.8
Men
5.6 Men 3.6

5.4 3.4

5.2 no no 3.2 no no
DM DM DM DM DM DM DM DM
5 3
Total cholesterol (mmol/L) LDL-cholesterol (mmol/L)

1.6 2
Women Men Women
p<0.001 1.8 p<0.001 p<0.001

1.4
1.6
Men
1.4
1.2 p<0.001
no
no 1.2 no
no DM
DM DM DM DM DM DM DM
1 1
HDL-cholesterol (mmol/L) DM no DM(mmol/L)
Triglycerides DM

Diabetes Care 1997;20:1683–1687

 Cardiovascular Risk Assessment in MetS
view from PROCAM
20
of myocardial infraction
Observed incidence (%)

15.6
15 A: Myocardial infarction
in 10 years

10.9
10

5 4.7

0
5
stroke in 10 years

B: Stroke
incidence (%) of

4
Observed

3
2.8
1.9
2

1 0.9

0
Control IGT Metabolic Diabetes
syndrome mellitus
Effect of metabolic syndrome or diabetes mellitus on the incidence of myocardial infraction (A) and stroke (B) in 4818
male PROCAM participants aged 35 to 65 years

Assmann G. Endocrinology metabolic clinics of North America June 2004; 33: 377 - 392
 Breaking the Link between Diabetes,
Dyslipidemia and Cardiovascular Disease

• Educate patients

• Encourage lifestyle changes

• Remember the Diabetes ABC

ADA. Diabetes Care 2004; 27: Suppl. 1.

 Breaking the Link between Diabetes,
Dyslipidemia and Cardiovascular Disease

The Diabetes ABC

A: Haemoglobin A1c
<7%, check every 3 mo

B: Blood pressure
<130/80mmHg, check it every visit

C: Cholesterol (LDL, HDL) and Trygliceride

ADA. Diabetes Care 2004; 27: Suppl. 1.
 FIELD: Patients with atherogenic dyslipidemia
target population of fenofibrate treatment
Low HDL-C
Overall population Low HDL-C High TG + high TG
(n=9,795) (n=5,820) (n=2,517) (n=2,014)
0
Relative risk reduction in total

-5

-10

-15 -11%
-14%
CV events (%)

p=0.035
-20 p<0.05

Low HDL-C (<40 mg/dL for men and <50 mg/dL

-25
for women) and high TG (≥200 mg/dL) defined -23%
according to ATP III criteria
p<0.05
-30 -27%
p=0.005

 Number needed to treat (NNT) to prevent one CV event in patients with

T2D and atherogenic dyslipidaemia treated with fenofibrate: 23

Keech AC et al. Lancet. 2005;366:1849-61. - Scott R et al. Diabetes Care. 2009;31:493-98.

Fibrates are specifically effective in Reducing RR of
CVD in patients with Low HDL-C and Elevated TG
HHS HHS BIP BIP VA-HIT VA-HIT FIELD FIELD
(4,081) (292) (3,090) (1,470) (2,531) (769) (9,795) (2,014)
0
Relative risk reduction in total

-10
-9.4% -11%
p=ns
-20 p=0.035
-21.7%
-30 -25% p=0.006 -27%
CV events (%)

p=0.03
p=0.01
-34% -32%
-40 p=0.004
p<0.02

-50

-60
All Patients
-70 Patients with low HDL-C and High TG
-71%
p<0.005 (Type 2 Diabetes, Metabolic Syndrome)

Low HDL-C (<40 mg/dL for men and <50 mg/dL for women) and high TG (≥150 mg/dL)
defined according to ATP III criteria
Keech et al., Lancet 2005;366:1849–61
Scott et al., Diabetes Care 2009;31:493–98
 Fibrate-Statin combination: The optimal
therapeutic approach in diabetic patients
with combined hyperlipidemia
Atorvastatin 20 mg Fenofibrate 200 mg Atorvastatin 20 mg + Fenofibrate 200 mg

30
22
20 16
9
10
% change from baseline

TC TG LDL
0
HDL
-10

-20 -16

-30
-31 -30 -15
-40 -37
-41 -46
-50 -40
-50
-60
N=120; 24 wks Diabetes Care 2002;25:1198-1202
 Clinical Trials with Statin-Fenofibrate:
Effects on Lipids
+19
% change
20 +10
Simvastatin + Fenofibrate from baseline
10
(SAFARI Trial)
0
Combined hyperlipidemia (n=618)
-10
-20
Simvastatin -30 -26 -20
-40 -31 -43
Simva + Feno
-50
S.M. Grundy et al., Am. J. Cardiol., 95: 462-468, 2005 LDL HDL TG

100%

80% 32.1 Small LDL

60% 72.2 81.0 81.6 Intermediate LDL

Change in
39.3 Large LDL
LDL SIZE 40%
from 20% 18.6 28.6 12.1
Baseline
0% 9.2
Simvastatin
12.1
6.9
Simvastatin Simvastatin
6.3 Fewer LDL
Simvastatin
20 mg/day +
Fenofibrate
160 mg/day
20 mg/day 20 mg/day +
Fenofibrate
160 mg/day
20 mg/day
Better LDL
Baseline Week 12
 Summary
o LDL-C reduction reduces cardiovascular events
o Patients with cardiovascular disease receive significant
cardiovascular benefits from statins therapy, but statins do
not remove the risk associated with a low HDL-C or other
features of the metabolic syndrome (high TG)
o Therapeutic approaches for a comprehensive lipid
management should be focused on effects on lipid profile
and safety and effect on clinical endpoints
o Fibrate appear to be particularly effective in patients with
type 2 DM and/or the features of the metabolic syndrome
o Combination therapy with a statin and a fibrate may be
efficacious for treatment of all three lipid fractions in DM.
THANK YOU