Curriculum Vitae

Name : Dr. Roy Panusunan Sibarani, SpPD-KEMD,FES

Born : Dabo, 27 May 1958
Position : Head of Diabetes Clinic RS Sahid Sahirman Memorial, Jakarta
EDUCATION
1983 General Practitioner FKUI - Jakarta
1994 Internal Medicine FKUI Jakarta
2006 SP II Endocrinology FKUI Jakarta
2011/13 Endocrinology Course Harvard Medical School , MA
ORGANIZATION
Vice President of Persatuan Diabetes Indonesia 2008-2011
Founder of Jakarta Insulin Pump Education Center (JIPEC)
Member of PERKENI Association
Founder of MEETMED.net
Fellow of The Endocrine Society
MAJOR INTEREST
Developing of T2DM Prevention of Diabetes
Endo Update Banjarmasin VII 2015

The Advance on
Strategy to Optimally
Achieve Blood Glucose Control

roy panusunan sibarani

mercure hotel banjarmasin
august 9th 2015
nothing to disclosure
Masalah-masalah lingkungan utama dengan dampak terbesar
terhadap kesehatan global (WHO 2012)

Suhu permukaan rata-rata belahan utara

Populasi
Konsentrasi CO2
GDP
Hilangnya hutan hujan tropis dan daerah berhutan
Kepunahan spesies
Kendaraan bermotor
Penggunanna air
Konsumsi kertas
Eksploitasi perikanan
Penipisan ozon
Investasi asing

1750 1800 1850 1900 1950 2000

a very busy world..
Modern Insulin Resistant Man "locked" into Seasonal Insulin
Resistance Syndrome Physiology (Neuroendocrinology)
(Winter Condition All Year Long)

Adaptive IR Mal-Adaptive IR
 14 30-39
A
Male
Diabetes in Asia : 12 40-49

Prevalence (%)
10
Starting at younger age 8
6
4
2
0

10 Female
B 9
8

Prevalence (%)
7
6
5
4
3
2
1
0

Figure 2: Comparison of prevalenc of diabetes between 30

and 40 year-old age-group in male and felmale populations
(A) Male. (B) Female.

Yoon KH, Lancet 2006; 368: 1681 - 1688

 Insulin Secretion and Insulin Resistance
across Glucose tolerance in Japanese subjects
Insulin Resistance -cell dysfunction
Predominant

Similar findings from

Korea, Thailand

1.2 1.5 2.4 10 5.3 1.7

Fukushima et al. Metabolism 2004;53(7):831-5

 Disadvantages of sulphonylurea therapy
Relatively rapid -cell failure (ADOPT Study)
8.0

Glyburide
7.5
Metformin
HbA1c (%)

Rosiglitazone
7.0

6.5

6.0
0
0 1 2 3 4 5
Time (year) Kahn SE, et al. N Engl j Med2006; 55:2427-43
IDF 2011
ADVANCE: Action in Diabetes and Vascular disease:
Coversyl plus and Diamicron-MR Controlled Evaluation
HbA1c target BP intervention

Intensive Perindopril+
Placebo
ADVANCE1 2x2 factorial (HbA1c 6.5%) indapamide
Median 5 years follow- design
up2 n=11,140 Standard Perindopril+
Placebo
(HbA1c >6.5%) indapamide

Primary To determine the effect of blood pressure and glycaemic

objective: intervention on micro- and macrovascular complications

Glycaemic Intensive treatment: gliclazide modified release (30120mg)

intervention: plus non-pharmacological intervention, other oral agents and
insulin, as required, to achieve HbA1c 6.5%
Standard treatment: based on standard guidelines

Blood pressure All patients: fixed low-dose combination of perindopril (2

intervention: 4mg) and indapamide (0.6251.25mg), or placebo
Other antihypertensive medications were prescribed, if
required, at the discretion of the clinician

40% of the ADVANCE population were

from Asian countries 1ADVANCE Management Committee. Diabetologia
2ADVANCE Collaborative Group. N Engl J Med
2001;44:11181120.
2008;358:25602572.
Advance 87
 UKPDS 35: Tight Glycemic
Control Prevents Complications
Every 1% drop in HbA1c resulted in:

12%
14%
21%
37%

Decrease Decrease Decrease

in any in risk of in risk of Decrease
diabetes myocardial stroke in risk of
related infarction microvascular
endpoint disease

N=3642
Stratton IM et al. BMJ.2000;321:405-412
 12

ADVANCE: effect of intensive glucose control on

major microvascular complications

n (%) patients
with events
Standard 605 (10.9%)
Intensive 526 (9.4%)

RRR 14%

RRR: relative risk reduction

Major microvascular events were defined as new or worsening nephropathy or retinopathy
Additional data on microvascular events were collected at the 1-year and 2-year study visits
ADVANCE Collaborative Group. N Engl J Med 2008;358:25602572.
 Effect of gliclazide-MR based
intensive glucose control on ESRD
1.0

0.9 Standard
Intensive
0.8
Cumulative incidence (%)

0.7
HR=0.35 (65% )
0.6 (CI 0.15-0.83)
P=0.01
0.5

0.4

0.3

0.2

0.1

0.0
0 6 12 18 24 30 36 42 48 54 60 66

Follow-up (months)

Perkovic V et al. Kidney Int. 2013 Jan 9. Epub ahead of print. doi:10.1038/ki.2012.401.
ADVANCE study CV safety of gliclazide MR based
intensive control regimen

Number of patients with event

Intensive Standard Favours Favours Relative risk

(n=5,571) (n=5,569) Intensive Standard reduction (95%CI)

All deaths 498 533 7% (-6 to 17)

Cardiovascular death 253 289 12% (-4 to 26)
Non-cardiovascular death 245 244 0% (-20 to 16)

0.5 1.0 2.0

Hazard ratio

ADVANCE Collaborative Group. N Engl J Med 2008;358:25602572.

 All SU except gliclazide show a trend towards
increased CV Mortality in a Danish diabetes registry

Hazard Ratio (95% CI)

Glimepiride 1.33 (0.13 1.55)

Gliclazide 0.87 (0.65 1.17)

Glibenclamide 1.43 (1.16 1.79)

Glipizide 1.37 (1.13 1.65)

Tolbutamide 1.40 (1.11 1.77)

Repaglinide 1.24 (0.81 1.90)

1.00
Metformin

0.5 0.6 0.7 0.8 0.9 1 1.5 2 2.5 3 4

CV Mortality Hazard Ratio (95% CI)

Reference = Metformin
Schramm TK et al. Eur Heart journal 2009; 30 (abstract suppl)
BMJ Open Diabetes Res Care. 2015;3(1)
 Ramadan: 6.7% of SU-Treated Muslim Patients With
Type 2 Diabetes Experienced Severe Hypoglycemia1

Incidence of Severe Hypoglycemia

12
Study in 2009
10,8
10

8 Glimepiride
Patients, %

6,9 6,7 Gliclazide

6 5,1 Glibenclamide
Glipizide
4
2,6 Overall
2
n=428 n=386 n=535 n=29 n=1378
0

No marked differences in the incidence of severe hypoglycemia between treatment groups

Incidence of severe hypoglycemia requiring medical assistance was 3.7% (n=51) for entire cohort
1.2% (n=16) patients experienced a serious hypoglycemia-related complications during Ramadan

Adapted from Aravind SR et al. Curr Med Res Opin. 2011;27(6):12371242.

Incidence of Hypoglycemia was lower with Gliclazide MR
vs other Sulfonylurea1
Primary End Point (APaT Population):
Incidence of Symptomatic Hypoglycemia (Proportion of Patients With 1 Events)
RRR (95% CI) = 0.51 (0.34, 0.75); P < 0.001

14 13,2
50% Risk
12 Reduction
10
Sitagliptin 100 mg qd
Patients, %

8 6,7 metformin (n=507)

6 SU metformin
(n=514)
4

2 Sulfonylurea % (n/total)
0 Glibenclamide 19.7 % (36/183)
Adapted from Al Sifri et al. 2011

195 symptomatic hypoglycemic eventsGlimepiride

were reported by 68 patients12.4 % (22/178)
in the SU group compared
with 128 events in 34 patients for sitagliptin group in the APaT population
Gliclazide 6.6 % (10/156)
Most common symptoms were headache, sweating, dizziness, hunger, and tremor
APaT=all patients as treated; CI=confidence interval; qd=once daily; RRR=relative risk ratio; SU=sulfonylurea.
1. Al Sifri S et al. Int J Clin Pract. 2011;65:11321140.
 Sulphonylureas
Main advantages Main disadvantages
Reduce microvascular Relatively rapid secondary failures
(glibenclamide UKPDS) (?not cell toxicity but cell effect)

Reduce nephropathy Weight gain

(gliclazide ADVANCE) (=2-3 kg)

Inexpensive Moderate risk of hypoglycaemia

(around $15/month) (varies between different agents)

Fixed dose combinations available ?Advance cardiovascular effects

(Metformin, TZDs) alone and with metformin (unlikely)
 Sulphonylureas are not all the same

Important differences exist in terms of :

Propensity to cause hypoglycaemia

Durability of glycaemic control

Cardiovascular effects
 Major Signals in Insulin Secretion
Glucose-induced insulin secretion Potentiation of GIIS
(GIIS) Ca2+ Hormone
Glucose Sulfonylurea
K channel VDCC
(e.g., Incretin)

ATP

Kir6.2 Neural
SUR1
input
Metabolism cAMP (e.g., Acetyl-
Ca2+ choline)
ATP
IP3
DAG

Mitochondria

Insulin granule exocytosis

Subunit Composition of Various KATP Channels

Subunit composition Tissue / Cell

Kir6.2/SUR1 Pancreatic b-cell

VMH (glucose-responsive neuron)
Substantia nigra

Kir6.2/SUR2A Heart (Ventricle)

Skeletal muscle

Kir6.2/SUR2B Smooth muscle

Kir6.1/SUR2B Vascular smooth muscle

Note: Kir6.3 is identified in Zebrafish (Zhang et al., Physiol Genomics, 2006).

Closure of the b-cell KATP Channel Is Essential for
GIIS and SU-induced Insulin Secretion

KATP channel Sulfonylurea

Glucose Kir6.2 Ca2+
SUR1
VDCC
ATP
Ca2+

Metabolism

Insulin secretion (Miki et al., PNAS, 1998)

(Seghers et al., JBC, 2000)
 The b-cell KATP Channel:
primary target of ATP and sulfonylurea
K+

SUR1
Kir6.2
SUR1 Kir6.2 Kir6.2 SUR1
Kir6.2
SUR1

(Seino S, Annu Rev Physiol, 1999)

Kir6.2 (inward rectifier): pore-forming subunit (Inagaki N et al., Science, 1995)

SUR1 (sulfonylurea receptor): regulatory subunit (Aguilar-Bryan et al., Science, 1995)
 Sulfonylureas
R1 SU R2
O O
N
S N N
H
Gliclazide
O

O O
S N N
H
Tolbutamide
O
O
Cl O O
N
H S N N Glibenclamide
O H
O
O O
O O
N N
H S N N
Glimepiride
H
O

Glinides
O O
O
N
H
Nateglinide
O
Cl
N O
H
O
Meglitinide
O
O
O
N
H O Repaglinide
N O
 Gliclazide Is Specific for the b-cell KATP Channel
Kir6.2-SUR1 Kir6.2-SUR2A Kir6.2-SUR2B

5nA 5nA 5nA

20 s
10mol/l gliclazide 10mol/l gliclazide 10mol/l gliclazide

0.8
Kir6.2-SUR2A
G /GC

0.6

0.4

0.2 Kir6.2-SUR1

0
10-8 10-7 10-6 10-5 10-4 10-3 10-2
Gliclazide (mol/l) (Gribble & Ashcroft, Diabetologia, 1999)
Bindings of SUs and Glinides to the b-cell KATP Channel

Kir6.2 Kir6.2
SUR1 SUR1

B A B A

Meglitinide
Repaglinide Glibenclamide
Gliclazide Glimepiride
Tolbutamide
Nateglinide
Mitiglinide

A: SU-binding site B: Benzamide-binding site

Epac2 and sulfonylureas
 Epac2 (cAMP-GEFII)
Epac2 (cAMP-GEFII) was identified as a cAMP-binding protein interacting with SUR1, a
subunit of the b-cell KATP channel.
(Ozaki et al., Nat Cell Biol, 2000)
cAMP-binding cAMP-binding
domain A DEP domain B

REM RA GEF

GDP GTP

Rap1 Rap1

(Inactive) (Active)
GTP GDP

Cellular responses
Note: Epac2 is now called Epac2A.
Science 325: 607-610, 2009
 Gliclazide-induced Insulin Secretion
from Isolated Pancreatic Islets
NS
8
Insulin secretion
(% of content)

6
Wild-type
NS
Epac2A
4 NS knock-out

0
2.8 8.8 17.6
Glucose (mM)
The effect of gliclazide on insulin secretion is independent of Epac2A.
 Mechanisms of Sulfonylurea Action in Insulin Secretion
Gliclazide Other
sulfonylureas
KATP channel
Incretins
Kir6.2 Ca2+
(GIP, GLP-1) SUR1
Epac2A VDCC

cAMP Ca2+
Rap1
PKA

RRP

RRP:
Readily Releasable Pool Insulin secretion
Modified from Zhang et al., Science, 2009 and Seino et al., JDI, 2010
 Gliclazide is thought to scavenge reactive oxygen species
(ROS) because of the presence of an aminoazabicyclo-octyl
ring in its chemical structure and, therefore, has a protective
effect against oxidative stress.

OBrien RC, Luo M. J Diabetes Complication(14)4, 2000

 HbA1c baseline to final visit: Baseline HbA1c
4

2
Mean base HbA1c 6.3 6.3 7.5 7.5 8.5 8.5 9.5 9.5 11.5 11.4
1

0
Mean
change in -1
HbA1c (%)
-2

-3

-4

N = 2470 2429 1416 1429 753 756 398 379 370 379
-5
<= 7% 7-8% 8-9% 9-10% >10%
Intensive Standard Baseline HbA1c (%)

After multivariate adjustment, the only independent predictors of

in HbA1c were baseline BMI and HbA1c (p<0.001)
Zoungas et al. DRCP 2010;89:126-33
 Eye Disease Reduced 0.79(0.63, 1.00) 53 12 UKPDS
(2 steps)
Eye Disease Reduced 0.67(0.51, 0.87) 62 4 ACCORD
(3 steps)
Kidney (MA) Reduced 0.67(0.53, 0.86) 53 12 UKPDS
Kidney disease Reduced 0.79(0.66, 0.93) 66 5 ADVANCE
Nerve dis (MNSI<2) Reduced 0.92(0.86, 0,99) 62 5 ACCORD
Myocardial infarct Reduced 0.85(0.76, 0.94) 53-66 3.5-5.6 ACCORD

Gerstein and Werstuck. Lancet Diabetes 2013;71

 Take Home Notes
People with type 2 diabetes have increased
throughout the world
Avoiding severe hypoglycemia is important to
prevent cardiovascular disease
Sulfonylureas are wildly used in the treatment of
diabetes type 2 but all sulfonylureas are not the
same
ADVANCE study shows reduced kidney disease on
clinical outcomes and suggest timing is important on
the successful treatment of diabetes