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Curiculum Vitae

dr. R. Bowo Pramono, SpPD-KEMD


INFORMASI PERSONAL

Nama : dr. R Bowo Pramono, SpPD-KEMD


Tempat/tanggal lahir : Tegal/27 Januari 1959
Agama : Islam
Alamat Kantor : Sub bagian Endokrinologi &
Metabolik, Bagian Ilmu Penyakit Dalam FK
UGM/RSUP Dr. Sardjito Yogyakarta
No. Telepon/Fax : 0274 (553119) / 0274 (553120)
Alamat rumah : Gg Mijil No 9 Jl. Kaliurang Km 5
Yogyakarta
No. Telepon/Fax : 0271 (7015705)
Handphone : 08122697116
RIWAYAT PENDIDIKAN

Lama Tempat
Pendidika
n
Dokter Umum 1978 UGM
1985
Dokter Spesialis Penyakit 1992 UGM
Dalam 1997
Dokter Spesialis Konsultan 2008 UGM
RIWAYAT PEKERJAAN

Tahun Nama Instansi Jabatan


1985 - Puskesmas Kepala
1992 Kedungwaringin Bekasi Puskesmas
1992 - RSUP Dr. Sardjito Residen (PPDS
1998 Yogyakarta 1)
1999 RSU Selong Lombok Utara Ka SMF Penyakit
2004 Dalam
2004- Sub Bagian Endokrinologi Staf
sekarang Bag Ilmu Penyakit Dalam
FK UGM/RSUP Dr Sardjito
Yogyakarta
ORGANISASI

Keanggotaan Tahun
IDI 1987 sekarang
PAPDI 1992 sekarang
PERKENI 2004 - sekarang
FORXIGA Role of Kidneys in DM Type 2
ID 350355/ Nov 2017

dr. R. Bowo Pramono, SpPD-KEMD FINASIM

FORXIGA is not indicated for the management of obesity.1 Weight change was a secondary endpoint in clinical trials.1,2
1. FORXIGA. Summary of product characteristics, 2015; 2. Bailey CJ, et al. Lancet 2010;375:222333.
1. Epidemiology of Type 2
Diabetes
Diabetesa growing global epidemic
Diabetes* worldwide prevalence, 2011: ~360 million1
2030 prevalence estimates : >550 million1

Of all cases
of diabetes,
90% are type 2
diabetes2

2030
2030 prevalence
prevalence11::
South
South East
East Asia:
Asia: 121
121 million
million
Indonesia:
Indonesia: 7,2
7,2
11,8
11,8 million
million

All cases of diabetes, including type 1 and type 2 diabetes, and impaired glucose tolerance (IGT), in patients aged 20-79 years.
1. International Diabetes Federation. IDF Diabetes Atlas, 5th ed. Brussels, Belgium: International Diabetes Federation, 2011.

Diabetes* worldwide prevalence estimates, 2030: >550 million 1


Diabetesa leading cause of death worldwide

Diabetes
Diabetesaa is
is the
the 9th-leading
9th-leading
cause
cause of
of death
death worldwide
worldwide22

a
All cases of diabetes, including type 1 and type 2 diabetes, and impaired glucose tolerance (IGT), in patients aged 20-79 years.
1. International Diabetes Federation. IDF Diabetes Atlas, 5th ed. Brussels, Belgium: International Diabetes Federation, 2011.
2. WHO. The top 10 causes of death. Fact sheet No. 310. June 2011.
3. Current Treatment & Multiple
Challenge of Type 2 Diabetes
Type 2 diabetesincreasingly challenging to control over
time

1. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854-865. 2. Campbell W. Br J Cardiol. 2000;7(10):625-631. 3. Khatib OMN, ed.
EMRO Technical Publications Series 32. World Health Organization; 2006.
Type 2 diabetesapproximately one-half of patients
are uncontrolled

Wong ND, et al. Persistent undertreatment of cardiovascular risk factors among subjects with type 2 diabetes in the United States 2005-2006.
Presented at: American Diabetes Association 70th Scientific Sessions; June 25-29, 2010; Orlando, FL.
Type 2 diabetesincreased HbA1c elevates
risk of complications

Diabetes-related
complications included:
Fatal or nonfatal
myocardial infarction,
stroke, or microvascular
disease
Amputation or death
from peripheral vascular
disease
Heart failure
Cataract extraction

Stratton IM, et al. BMJ. 2000;321:405-412.


The importance of reducing
HbA1c, weight, blood
pressure, and lipids
Type 2 diabetescontrolling multiple
parameters is essential

Incremental reductions sustained


over time in HbA1c and other
parameters can benefit the
physical health of patients with
type 2 diabetes1-5

1. Stratton IM, et al. BMJ. 2000;321:405-412. 2. Pi-Sunyer FX. Postgrad Med. 2009;121(5):94-107. 3. Williamson DF, et al. Diabetes Care.
2000;23(10):1499-1504. 4. Patel A. Lancet. 2007;370(9590):829-840. 5. Pyrl K, et al. Diabetes Care. 1997;20(4):614-620.
Type 2 diabetesguidelines recommend managing
multiple parameters1-5

Although the EASD and ADA Guidelines each set forth specific HbA1C target goals, an ADA/EASD Joint Position
Statement on management of hyperglycemia (2012) recommends that treatment targets be individualized. 6
ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes; ESC=Task Force on Diabetes and Cardiovascular Diseases of the
European Society
1. Guidelines of Cardiology;
for the prevention, AACE=American
management andAssociation of Clinical
care of diabetes Endocrinologists;
mellitus. Cairo, Egypt,CDA=Canadian Diabetes Association;
World Health Organization, WHO=World
2006. 2. The Health
Task Force Organization.
on Diabetes and
Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J. 2007;28:88-
136.
3. American Diabetes Association. Diabetes Care. 2012;35(suppl 1):S4-S10. 4. Handelsman Y, et al. American Association of Clinical Endocrinologists Medical
Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011;17(suppl 2):1-53. 5. Canadian Diabetes Association
Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2008;32(suppl 1):S1-S201. 6. Inzucchi SE, et al. ADA/EASD Position Statement. Diabetes Care.
2012;35:1-16.
Type 2 diabetesLOWERING HbA1c reduces risk for
macro- and microvascular complications

Stratton IM et al. BMJ. 2000;321:405-412.


Type 2 diabeteslowering HbA1c, blood pressure, and lipids
may reduce mortality

Schernthaner G. Wien Med Wochenschr. 2010;160(1-2):8-19.


The need for a pathway that acts
independently of insulin in
type 2 diabetes
Type 2 diabetescharacterized by insulin resistance and
-cell dysfunction1-4

1. Ramlo-Halsted BA, et al. Prim Care. 1999;26(4):771-789. 2. Piya MK, et al. Br J Clin Pharmacol. 2010;70(5):631-634. 3. DeFronzo RA. Med Clin N Am.
2004;88(4):787-835.
4. Stratton IM, et al. BMJ. 2000;321:405-412.
An insulin-independent pathwayrenal SGLT21,2

1. Rajesh R, et al. Int J Pharma Sci Res. 2010;1(2):139-147. 2. Marsenic O. Am J Kidney Dis. 2009;53(5):875883.
Insulin-independent pathways: SGLT system1-6
The role of the sodium-glucose cotransporter (SGLT) system
in glucose regulation

1. DeFronzo RA. Med Clin N Am. 2004;88(4): 787-835. 2. Rahmoune H, et al. Diabetes. 2005;54:3427-3434. 3. Marsenic O. Am J Kidney Dis. 2009;53(5):875-883.
4. Brown GK.
J Inherit Metab Dis. 2000;23(3):237-246. 5. Vallon V, Sharma K. Curr Opin Nephrol Hypertens. 2010;19(5):425-431. 6. Wright EM, et al. J Intern Med.
2007;261(1):32-43.
The role of the renal SGLT
pathway in glucose balance
Normal glucose homeostasis1,2
Net balance ~0 g/day
Glucose input ~250 g/day: Glucose uptake ~250 g/day:
Dietary intake ~180 g/day Brain ~125 g/day
Glucose production ~70 g/day Rest of the body ~125 g/day
Gluconeogenesis
Glycogenolysis

+ The kidney filters The kidney



circulating glucose reabsorbs
and recirculates
glucose

Glucose filtered Glucose reabsorbed


~180 g/day ~180 g/day

1. Wright EM. Am J Physiol Renal Physiol 2001;280:F1018;


2. Gerich, JE. Diabetes Obes Metab 2000;2:34550.
Glucose handling in Type 2 diabetes1,2

Glucose input >280 g/day: Glucose uptake >250 g/day:

Dietary intake >180 g/day Brain ~125 g/day


Glucose production ~100 g/day Rest of the body >125 g/day
Gluconeogenesis*
Glycogenolysis

+ Average blood glucose Increased



concentration 150 mg/dL reabsorption and
Kidney filters all recirculation of
circulating glucose glucose

Glucose filtered Above the renal threshold for


~270 g/day glucose (~200 mg/dL),
glucose is excreted in the
urine (glucosuria)
*Elevated glucose production in patients with Type 2 diabetes attributed to hepatic
and renal gluconeogenesis.2
1. Gerich JE. Diabet Med 2010;27:13642;
2. Abdul-Ghani MA, DeFronzo RA. Endocr Pract 2008;14:78290.
In normal renal glucose handling, 90% of glucose is
reabsorbed by SGLT214

Majority of glucose
is reabsorbed by
SGLT2 (90%)

Proximal tubule

Remaining
glucose is
SGLT2
Glucose reabsorbed by
Glucose filtration SGLT1 (10%)
Minimal to
no glucose
excretion

SGLT, sodium-glucose co-transporter 2.


Adapted from: 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F1018; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S2735; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C1421;
4. Marsenic O. Am J Kidney Dis 2009;53:87583.
SGLT and GLUT transporters facilitate insulin independent
reabsorption of filtered glucose in the proximal tubule

Tissue
S1 proximal
reabsorption
tubule lumen
(filtrate)
SGLT
SGLT 2
2
ATPase
SGLT2
Glucose
Low affinity
1 Na++
GLUT
GLUT 2
2
High capacity

Tissue
reabsorption
S3 proximal
tubule lumen
(filtrate) SGLT
SGLT 1
1
Glucose
ATPase
SGLT1
2 Na++ High affinity
GLUT
GLUT 1
1
Low capacity

GLUT, glucose transporter; SGLT, sodium-glucose co-transporter.


Adapted from: Wright EM. Am J Physiol Renal Physiol 2001;280:F1018.

27
FORXIGA inhibits SGLT2 and removes excess glucose
in the urine independently of insulin
SGLT2
Reduced glucose
reabsorption
FORXIGA

Proximal tubule

Increased urinary
Increased urinary
excretion
excretion of excess
of excess
SGLT2
Glucose glucose
glucose (~70 g/day,
(~70 g/day,
Glucose filtration corresponding
corresponding toto
280kcal/day*
280 kcal/day*)1)
FORXIGA

By inhibiting SGLT2, FORXIGA removes glucose and associated calories


FORXIGA is >1400-times more selective for SGLT2 versus SGLT1

*Increases urinary volume by only ~1 additional void/day (~375 mL/day) in a 12-week study of healthy subjects and patients with Type 2 diabetes.
FORXIGA. Summary of product characteristics, 2015.
Impaired Regulation of

Renal Glucose Metabolism

in Type 2 Diabetes
Beyond a certain plasma glucose threshold,
saturation of glucose transporters results in glucosuria

Excretion Saturation Filtered glucose


threshold threshold Glucosuria starts Reabsorbed glucose
3 No excretion
to occur
reabsorption / excretion (mmol/min)

Excreted glucose
Rate of glucose filtration /

Glucose filtration
2 rate is normally
proportional to
plasma glucose
concentration
Splay

1 Transport
Maximum for Glucose
(TmG)

0
0 8.3 13.3 25 mmol/L Plasma glucose
0 149.6 239.6 450.5 mg/dL

Adapted from Chao EC, et al. Nat Rev Drug Discov 2010;9:551-559; Marsenic O. Am J Kidney Dis 2009;53:875-883.

30 732HQ10NP027
Increased Glucose Transporter
Proteins and Activity in Type 2 Diabetes

SGLT2
SGLT2 GLUT2
GLUT2 AMG
AMG Uptake
Uptake

8 P<0.05 2000
P<0.05
Transporter
Normalized

6 1500
Glucose

Levels

CPM
4 1000
P<0.05

2 500

0 0
NGT T2DM NGT T2DM NGT T2DM

AMG=methyl--D-[U14C]-glucopyranoside; CPM=counts per minute.


Rahmoune H, et al. Diabetes. 2005;54:34273434
Continued glucose reabsorption even at high glucose
levels induces sustained hyperglycaemia in diabetics 1,2

Paradoxically, SGLT2 reabsorbs glucose through an insulin-independent pathway,


even in the presence of hyperglycaemia

Filtered glucose
No excretion
3 Excretion
threshold Excreted glucose
reabsorption / excretion (mmol/min)
Rate of glucose filtration /

Reabsorbed glucose (diabetes)

Reabsorbed glucose (normal)


Saturation
threshold
1

0
0 8.3 13.3 25 mmol/L Plasma glucose
0 149.6 239.6 450.5 mg/dL
200 300
Adapted from Chao EC, et al. Nat Rev Drug Discov 2010;9:551-559; Marsenic O. Am J Kidney Dis 2009;53:875-883; Nairs S, et al. J Clin Endocrinol Metab 2010;95:34-42.

32
Patients with Diabetes Demonstrate
High Reabsorption of Filtered Glucose

TmG increased in Type 1 Diabetes TmG increased in Type 2 Diabetes

440 440
*
420

*P<0.05 Tm (mg/min)
Tm (mg/min)

419.1
400 420 423.9
380
360
352.2 400 404.0
340
320
300 380
Nondiabetic Type 1 diabetes Nondiabetic Type 2 diabetes
(n=9)1 (n=10)1 (n=9)2 (n=12)2

1. Mogensen CE. Scand J Clin Lab Invest. 1971 Sep;28(1):101-109. 2 Farber SJ, et al J Clin Invest. 1951;30(2):125-129.
Reabsorption
May Contribute to Hyperglycaemia in
Diabetes

Hyperglycaemia
An adaptive
response
to conserve
glucose
(i.e. for energy
Glucosuria Glucosuria
needs)
becomes
maladaptive
in diabetes
deFronzo 2009
SGLT2
SGLT2
and GLUT2
expression

1. Rahmoune H, et al. Diabetes. 2005;54:34273434; 2. Gerich JE. Diabet Med.


2010;27:136142
Sodium-glucose co-transporters (SGLTs)
are present throughout the body

Transporter Major site of action Function

SGLT1 Small intestine, heart, Co-transports sodium, glucose and galactose


trachea and kidneys across the brush border of the intestine and
proximal tubule of the kidneys

SGLT2 Kidney Co-transports sodium and glucose in the S1


segment of the proximal tubule of the kidneys

SGLT3 Small intestine, uterus, lungs, Transports sodium (not glucose)


thyroid and testis

SGLT4 Small intestine, kidneys, liver, Transports glucose and mannose


stomach and lung

SGLT5 Kidneys Unknown

SGLT6 Spinal cord, kidneys, brain Transports myoinositol and glucose


and small intestine

Bays H. Curr Med Res Opin 2009;25:671681; Abdul-Ghani MA, et al. Endocr Pract 2008;14:782-790.
Other conditions associated
with altered glucose transport

Condition leading
Transporter Symptoms of condition
to defective glucose transport

Most patients do not develop significant


SGLT2 Familial renal glucosuria
clinical problems over time

Numerous symptoms, including enlarged


GLUT2 FanconiBickel syndrome liver, abdominal bloating and vitamin
D-resistant rickets

Glucosegalactose
SGLT1 Severe diarrhoea
malabsorption syndrome

Numerous symptoms, including


GLUT1 De Vito disease microcephaly and delayed mental and
motor development

Adapted from Bays H. Curr Med Res Opin 2009;25:671


681.
Development of SGLT2
inhibitors

The search for a potent, selective SGLT2


inhibitor.from apple trees
to candidate drugs
Discovery of phlorizin
by French chemists in the early 1800s

Isolated from apple tree bark


(1835)
Glycosuric effect revealed
(1865)
Renal effects identified in rat
(1903) and man (1933)
Antidiabetic effect discovered
(1987)
Found to inhibit SGLT1
and SGLT2
Ehrenkranz JRL, et al. Diabetes Metab Rev 2005;21:3138.
In the 1880s-1890s,
phlorizin was shown to induce glycosuria

In 1886, Von Mering observed that dogs In a diabetic with 2.857 g of glucose per litre
receiving doses of phlorizin above 1.0 g of blood, the injection of 50 mg of phlorizin
developed glycosuria was also followed by a slight decrease,
to 2.706 g, while glycosuria increased by
115 to 140 g (Emile) Charles Achard, 1899
Cited in Joel RL, et al. Diabetes Metab Res Rev 2005;21:3138.
In 1987, phlorizin was found to prevent hyperglycaemia and
restore insulin sensitivity in partially pancreatectomised rats

Rats treated with phlorizin (0.13 g/kg) every 8 h for 45 weeks


after 90% partial pancreatectomy:

Glycosuria increased Fasting blood Fed blood


400
10-fold glucose glucose
**

Blood glucose (mg/dL)


**
Oral glucose tolerance 300

test and meal tolerance


200
test responses *

normalised 100

Insulin sensitivity 0
(reduced by onset Sham Diabetic Diabetic + Sham + Phlorizin
phlorizin phlorizin stop
of hyperglycaemia)
restored *p<0.05; **p<0.001

Rossetti L, et al. J Clin Invest 1987;79:15101515.


Proof of concept of SGLT2 inhibition
in type 2 DM

In experimental models and in humans, inhibition of SGLT2:

1
Komoroski BJ, et al. Clin Pharmacol Ther 2009;85:520526; 2Han S, et al. Diabetes 2008;57:17239; 3Jurczak et al. Diabetes 2011;60:890-8.
FORXIGA lowers HbA1c with the additional benefits of
weight loss and blood pressure reduction1

Glycaemic control Weight loss Blood pressure reduction

FORXIGA:11 Urinary excretion of ~70 g FORXIGA increases


Acts independently of glucose/day with diuresis and is associated
insulin mechanisms to FORXIGA corresponds to with significant reductions
reduce HbA1c1c
via the loss of 280 Kcal/day*11 in systolic blood pressure11
kidney (1 g glucose = ~4 Kcal)

1 lb of body fat equates to


Has a low propensity for ~3500 calories22
hypoglycaemia
FORXIGA can result in
loss of 1 lb of body fat in
under 2 weeks

FORXIGA is not indicated for the management of obesity or high blood pressure.1 Weight change was a secondary endpoint in clinical trials.1,3
*Increases urinary volume by only ~1 additional void/day (~375 mL/day) in a 12-week study of healthy subjects and patients with Type 2 diabetes. 1
1. FORXIGA. Summary of product characteristics, 2014;
2. Calories per hour.com. Available at: http://www.caloriesperhour.com/tutorial_pound.php. Last accessed August 2014;
Summary
Renal glucose reabsorption and gluconeogenesis are increased in T2DM
SGLT2 is responsible for 90% of glucose reabsorption
Inhibition of SGLT2 increases glucose excretion with the potential to reduce
hyperglycaemia

FORXIGA is not indicated for the management of obesity or high blood pressure.1 Weight change was a secondary endpoint in clinical trials.1,5
*This information is an estimate derived from the use of information under licence from the following IMS Health information service: NPA Market Dynamics for period February April 2014. IMS
expressly reserves the rights of copying, distribution and republication.
1. FORXIGA. Summary of product characteristics, 2014; 2. Del Prato S, et al. Presented at the 73rd American Diabetes Association Scientific Sessions, Chicago, USA. 2125 June
2013.
Abstract 62-LB; 3. Data on file (Cegedim Strategic Data, Longitudinal Patient Databases, October 2014); 4. Marsenic O. Am J Kidney Dis 2009;53:87583; 5. Bailey CJ, et al. Lancet
2010;375:222333.
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