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SGLT2 Inhibitors:
2
SGLT2 Inhibitors: The New Approach to Treat Type 2
Diabetes
.

1-000-SPU-000-1106-01
2.0
: 17 ..2554
: 17 ..2556

1. SGLT2 inhibitors
2. dapagliflozin
3. dapagliflozin
4. dapagliflozin

Sodium glucose co-transporter subtype 2 (SGLT2) inhibitors

2

dapagliflozin SGLT2 inhibitors

 ()

(hematocrit)

: Diabetes, Sodium glucose co-transporter, SGLT2 inhibitors, Dapagliflozin

(insulin resistance)

1

Glucuretic Therapy1
Glucuretic therapy
( Diuretic therapy
)

Sodium glucose co-transporter (SGLT)

(glucose homeostasis)
3 1) renal gluconeogenesis 2)
3)
2

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glomerulus ( 180 )
sodium glucose co-transporter (SGLT) SGLT1 SGLT2
( 1)
1) SGLT1
proximal convoluted tubule (S3 segment) ( 1)
SGLT1 (high affinity) (low
capacity) ( 10
) SGLT1
2 1 (sodium : glucose coupling ratio = 2 : 1)
2) SGLT2 proximal convoluted tubule (S1 S2 segment)
( 1) SGLT2 (low affinity)
(high capacity) 90
SGLT2 1 1
(sodium : glucose coupling ratio = 1 : 1)
SGLT1 SGLT2 luminal epithelium
secondary active-transport


facilitated diffusion

glucose transporter-2 (GLUT2) basolateral membrane ( 2)1,2,3,4,5
1. SGLT subtype 2,5
Subtype
Substrates
SGLT1 Glucose & Galactose
SGLT2 Glucose
SGLT3 Glucose sensor
SGLT4 Glucose, mannose
SGLT5 Not known
SGLT6 Glucose, myo-inositol
*

Tissue Distribution
Intestine*, trachea, kidney, heart, brain, testis, prostate
Kidney*, brain, liver, thyroid, muscle and heart
Widely throughout the body in skeletal muscle, nervous system
Intestine, kidney, liver, brain, lung, trachea, uterus, pancreas
Kidney
Brain, kidney, intestine

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SGLT2 Inhibitors
Phlorizin ..
1835 SGLT
SGLT2 SGLT

SGLT2 sergliflozin remogliflozin
(result of
evaluating circumstances including the development status of SGLT2 inhibitors by
competitors) canagliflozin phase III BI10773
BI44847 1,2

1. 3

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2. SGLT1 SGLT2 2
Dapagliflozin
Dapagliflozin C-aryl glucoside (3)
flozin (selectivity)
SGLT2 1,2 ( 2) (acute in vivo
studies) (single oral dose) 0.01-10
1
(normal rats) (diabetic rats)
( 4), (Zucker diabetic fatty
rats) ( 5; )
(chronic in vivo studies) 0.01-1 1
2
(fasting) (fed) ( 5; )6

3. dapagliflozin4

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2. SGLT1 SGLT2 dapagliflozin 6

Human SGLT2
Dapagliflozin 1.12 0.065 (n=18)
Phlorizin
35.6 4.2 (n=11)

Human SGLT1

Rat SGLT2

1,391 7 (n=16) 3.0 0.5 (n=5)

330 50 (n=10) 75 8 (n=4)

Rat SGLT1
620 70 (n=6)
302 30 (n=4)

Data are mean EC50 SE (nmol/l)

4. dapagliflozin 6
[= vehicle, = 0.01 mg/kg, = 0.1 mg/kg,

= 1 mg/kg, = 10 mg/kg]

5. dapagliflozin 6
():
(): 1 15
[ = vehicle, = 0.01 mg/kg, = 0.1 mg/kg, = 1 mg/kg, *P < 0.0001, P < 0.05
vehicle]

dapagliflozin
List JF 2 389
glycosylated hemoglobin (HbA1C) 7-10 fasting plasma
glucose (FPG) 140 dapagliflozin
monotherapy 2.5-50 12
6

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52-85 HbA1C
FPG (placebo-subtracted) 0.37-0.72
10-25
(concentration-dependent) HbA1C 10
( 6)7

6. HbA1C dapagliflozin 2 7
Ferrannini E 2 485
HbA1C 7-10 dapagliflozin
monotherapy 2.5-10 24
HbA1C FPG 0.35-0.66
12-25 8
Bailey CJ 2 546
HbA1C 7-10 FPG 150
dapagliflozin 2.5, 5 10 add-on
therapy metformin 1,500 24
HbA1C FPG 0.370.54 12-18 9
Wilding JPH 2 71
HbA1C 7.5-10 FPG 150
dapagliflozin 10 20 add-on
therapy 12
7

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HbA1C FPG 0.70-0.78

15-27 10
dapagliflozin
dapagliflozin
osmotic diuresis (
osmotic pressure lumen
) 2-3
6
1 dapagliflozin
metformin 12-24
dapagliflozin 10 systolic blood pressure
(SBP) 3-5 mmHg diastolic blood pressure (DBP) 2 mmHg1,7,9,10

(fainting) 1,7 1
dapagliflozin
dapagliflozin
(Tmax) 1 ( 0.5-4 )
Tmax 4 (AUC)
dapagliflozin (metabolize)
glucuronosyl transferase subtype UGT1A9 (inactive metabolite)
(renal clearance 3-6 ml/min)
(unchanged drug) 2.5 (halflife) 16 2
dapagliflozin

dapagliflozin 2,7 2.5-20
8

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12 urine output 107-375

(dehydration) (electrolyte
imbalance) 7 osmotic diuresis
( 1-2 )1
(microbial growth)
( 5-12 7 8-13
9 )
1


1

dapagliflozin
dapagliflozin
cytochrome P450 1,2

SGLT2 inhibitors
2
SGLT2
dapagliflozin HbA1C

2

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1. Bailey CJ, Day C. SGLT2 inhibitors: Glucuretic treatment for type 2 diabetes. Br
J Diabetes Vasc Dis 2010;10:193-9.
2. White JR. Apple trees to sodium glucose co-transporter inhibitors: A review of
SGLT2 inhibition. Clin Diabetes 2010;28:5-10.
3. Wilding JPH. SGLT2 inhibitors for the treatment of diabetes. Medscape Diabetes
& Endocrinology 2008. Available: http://cme.medscape.com/viewarticle/578176
(accessed 2010 Sep 8).
4. Boldys A, Okopien B. Inhibitors of type 2 sodium glucose co-transporters-a new
strategy for diabetes treatment. Pharmacol Rep 2009;61:778-84.
5. Gerich JE. Role of the kidney in normal glucose homeostasis and in the
hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med 2010;
27:13642.
6. Han S, Hagan D, Taylor JR, et al. Dapagliflozin, a selective SGLT2 inhibitor,
Improves glucose homeostasis in normal and diabetic rats. Diabetes
2008;57:1723-9.
7. List JF, Woo V, Morales E, et al. Sodium-glucose cotransport inhibition with
dapagliflozin in type 2 diabetes. Diabetes Care 2009;32:650-7.
8. Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2
diabetic patients with inadequate glycemic control by diet and exercise: a
randomized, double-blind, placebo-controlled, phase III trial. Diabetes Care (in
press) doi:10.2337/dc10-0612.
9. Bailey CJ, Gross JL, Pieters A, et al. Effect of dapagliflozin in patients with type
2 diabetes who have inadequate glycaemic control with metformin: a
randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223-33.
10. Wilding JPH, Norwood P, Tjoen C, et al. A study of dapagliflozin in patients with
type 2 diabetes receiving high doses of insulin plus insulin sensitizers.
Applicability of a novel insulin-independent treatment. Diabetes Care
2009;32:1656-62.
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1. (glucose homeostasis)

1) Distal convoluted tubule

2) Proximal convoluted tubule
3) Ascending limb Henles loop
4) Descending limb Henles loop
5) Collecting tubule
2. Sodium glucose co-transporter subtype 2 (SGLT2)

1) (high affinity) (low
capacity)
2) (low affinity) (low
capacity)
3) proximal convoluted tubule (high affinity)
(low capacity)
4) proximal convoluted tubule (low
affinity) (high capacity)
5) proximal convoluted tubule (high affinity)
(high capacity)
3. dapagliflozin
1) SGLT2
2) SGLT2
3) SGLT2
4) SGLT1
5) SGLT1

11

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4. dapagliflozin
(selectivity) humanSGLT2 humanSGLT1
1) 10
2) 50
3) 100
4) 1200
5) 2000
5. dapagliflozin HbA1C
1) 2.5
2) 5
3) 10
4) 15
5) 20
6. dapagliflozin HbA1C
1) <1
2) 1-1.5
3) >1.5-2
4) >2-2.5
5) >2.5
7. dapagliflozin
1)
2) glucuronosyl transferase (UGT1A9)
3) (unchanged drug) 2.5
4) (Tmax)
5) (AUC)

12

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8. dapagliflozin
1)
2)

3)
4)

5)

9. dapagliflozin
1)
2)
3)
4)
5)
10.
1) SGLT2 10
glomerulus
2) SGLT2 passive diffusion
3) dapagliflozin
(dose-independent)
4) dapagliflozin
5) dapagliflozin
cytochrome P450

13