: SGLT2

. MD,
MSc, PhD
-
. &

Gerich JE.
Diabet
Med
2010;27:13642.
G. Bolli,
presented
at EASD
7 September 2008

2025%*

~
70 g/
2530%*
4550%*

*post-absorptive state
Gerich JE. Diabet Med 2010;27:13642.


~0 g/
~250 g/:
~180 g/
~70 g/

~180 g/

~250 g/:

~125 g/
~125 g/

~180 g/

4
4

1. Wright EM. Am J Physiol Renal Physiol 2001;280:F1018; 2. Gerich JE. Diabetes Obes Metab 2000;2:34550.

>280 g/:
>180 g/
~100 g/
*

150
mg/dL

~270
g/

>250 g/:

~125 g/
>125 g/

(~200 mg/dL),

()

5
* 2 .2
5

1. Gerich JE. Diabet Med 2010;27:13642; 2. Abdul-Ghani MA, DeFronzo RA. Endocr Pract 2008;14:78290.


SGLTs

SGLT2

(90%)
S1

S2
S3

SGLT2

SGLT1


(10%)

Henle
6
6

SGLT, -.
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.

 SGLT GLUT

1
(S1)

()

SGLT2

ATPase

SGLT2

1 Na++
GLUT2

S3

ATPase

SGLT1

2 Na++
GLUT1

SGLT1

7
7

Hediger MA, Rhoads DB. Phsyiol Rev 1994;74:9931026.

 SGLTs , SGLT2

SGLT1

, ,

SGLT2

SGLT3

, , ,

( )

SGLT4

, , ,

SGLT5

S1

8
8

Bays H. Curr Med Res Opin 2009;25:67181.

 SGLT2

Reduced glucose

reabsorption

SGLT2

Proximal
tubule

SGLT2

SGLT2
Glucose

Glucose

filtration

Increased
urinary

excretion of

excess
glucose

(~70 g/day,
(~70g/,
corresponding
to
280
280
kcal/day*)
kcal/*)

* ~1 / (~375 mL/) 12
2.4

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. Dapagliflozin. Summary of product characteristics.
Bristol-Myers Squibb/AstraZeneca EEIG, 2012.

SGLT2 C-

OH

HO

HO
O

OH

OH
Cl

HO

HO

CH3

O
HO

HO

OH

HO

C-


Canagliflozin
S
F

OH

HO

CH3

HO
O

10

HO

10

Chao EC, et al. Nat Rev Drug Discov 2010;9:5519.

 HbA1c

SU3

N=70

10 mg

DPP4
4

OAD5

12
12

.
* placebo Dunnett (p<0.0001); placebo (p<0.0001); p<0.001.
OAD, oral antidiabetic drug.
1. Ferrannini E, et al. Diabetes Care 2010;33:221724; 2. Bailey CJ, et al. Lancet 2010;375:222333; 3. Strojek K, et al. Diabetes Obes Metab 2011;13:92838; 4. Jabbour SA, et al. Diabetes Care 2014;37:74050; 5. Wilding JPH, et al. Ann Intern Med 2012;156:40515.

 HbA1c
HbA1c 9%
1

SU2

10 mg

13
13

.
NR, .
1. Ferrannini E, et al. Diabetes Care 2010;33:221724; 2. Katz A, et al. Diabetes 2014;63(Suppl. 1):A284.

DPP4
2

OAD2


HbA1c (%)

:
HbA1c

24

+
HbA1c 8,13%)

(n=133)

+0,02%
(95% ,
0,20%, 0,23%,
n=28)

(n=132)

0,80%

10 mg +
HbA1c 7,95%)

0,78%
(95% ,
0,97%, 0,60%;
n=57)

16

24

37

50
63

76

89

102

37

50

63

76

89

102

10 mg

132

113

102

96

80

75

57

133

96

74

60

46

38

28

.
.
.
Bailey CJ, et al. Diabetes 2011;60(Suppl. 1):988-P.

 OADs:
HbA1c 104
+
( HbA1c = 8,47%)
10 mg +
HbA1c = 8,57%)

0
N

8 12 16 20 24
24

32

40

48 52

65

78

91

104

16

20

32

40

48

52

65

78

91

104

10 mg + 193

188

184 183

179

176 173

175

173

164

148

145

144

140

139

183

173 169

167

164 166

163

159

157

122

116

114

109

107

193

12

LT 2

LT 1

ST

* , 95%
15
.
15

OADs, , LT, , ST, .

Wilding J, et al. ADA 2012: Poster 1042-P.

 OADs:
48
+
( : 73,7 U/)
10 mg +
( : 78,0 U/)

8 12 16 20 24

10 mg +

194

189

191

185

12

LT 2

LT 1

ST

24

32

40

48 52

65

78

91

104

32

40

48

52

65

78

91

104

16

20

185 183

180

178 177

175

173

166

145

146

144

142

140

176 171

170

165 168

164

158

157

121

118

114

110

104

*
95%
16
.
16

Wilding J, et al. ADA 2012: Poster 1042-P.

17
17

18
18

 HbA1c (%) placebo

19
19

(%)

10 mg (n=1193)

(n=1193)

.
Food & Drug Administration. Endocrinologic and Metabolic Drugs Advisory Committee: Dapagliflozin BMS-512148. Available at: http://tinyurl.com/7kjf5j7.
Last accessed October 2012.

 -
SGLT2 :
ZDF -

,
(),

1
:

-

Zucker (ZDF)
SGLT2
82

24
24

1. Macdonald FR, et al. Diabetes, Obesity and Metabolism 2010;12:100412; 2. Jelsing J, et al. ADA 2012: Poster 1018-P.

 -
SGLT2 :
clamp 12
26 (ISR)
(MMTT)
III 2 HOMA (
SGLT2)

25
HOMA, , ISR, , LOCF, . MMTT, ,
SE, .
25
1. Mudaliar S. EASD 2011: Poster 854; 2. Polidori D, et al. ADA 2012: Poster 1032-P; 3. Langkilde AM. EASD 2012: Poster 750.

SU3
DPP4
4

10 mg

27
27
1. Ferrannini E, et al. Diabetes Care 2010;33:221724; 2. Bailey CJ, et al. Lancet 2010;375:222333; 3. Strojek K, et al. Diabetes Obes Metab 2011;13:92838; 4. Jabbour SA, et al. Diabetes Care 2014;37:74050; 5. W ilding JPH, et al. Ann Intern Med 2012;156:40515; 6. Dapagliflozin 10mg. Summary of product characteristics, 2014.

OAD5

(kg)

+
(n=401)
87,6 kg

+1,36 kg
(95% ,
0,88 1,84 kg;
n=211)

5,06 kg
(95% , 5,73 4,4 kg)

+
(n=400)
88,4 kg

3,70 kg
(95% ,
4,16 3,24
kg, n=234)

12 18

26

42

34

65

52

104

91

78

12

18

26

34

42

52

65

78

91

104

400

386

368

369

355

340

335

323

314

271

243

234

401

380

367

361

355

343

332

315

304

248

224

211

95%
.
1. Nauck MA, et al. Diabetes 2011;60(Suppl. 1):Poster 40-LB.


DXA

10 mg
10 mg

+
+
+
+
(n=89)
(n=89)
(n=91)
(n=91)
0,65
0,40
1,46

2,16

0,90

2,80
1,00

1,30
24

102

29

*
.
29

Bolinder J, et al. EASD 2012: Poster 751.


12 placebo, dapagliflozin 10 mg
24
Systolic blood pressure

Mean change in
blood pressure (mmHg)

Dapagliflozin 10 mg Control groups

Diastolic blood pressure

Dapagliflozin 10 mg Control groups

0.5 mmHg
0.9 mmHg

(n=1096)

(n=1096)

2.1 mmHg
(n=949)

4.4 mmHg
(n=949)
Baseline blood pressure2

130 mmHg

130 mmHg

79 mmHg

80 mmHg

1. Dapagliflozin. Summary of product characteristics. Bristol-Myers Squibb/AstraZeneca EEIG, 2012; 2. BMS/AZ data on file.


24

(mg/dL)

888

834

989

194,5 195,9 195,2

(mg/dL)

HDL
(mg/dL)

889 834

990

44,8 45,0 44,5

5 mg (n=1145)

LDL
(mg/dL)

884 828

(mg/dL)

985

113,2 114,1 114,7

10 mg (n=1193)

886

831

984

190,4 194,2 187,5

(mEq/L)

732

694

838

0,58 0,56 0,56

(n=1393)

, - ,
. : .
, , HDL, , LDL,
BMS. Data on file.

 24 102
24

(%)

10

7,7

8
6

102

6,3

4,3

3,7

2
0

10 mg

10 mg

(0,3%)
102
74,6% 86,4%

: 0,1% 0,2%

Parikh S, et al. EASD 2011; Dapagliflozin. Summary of product characteristics. Bristol-Myers Squibb/AstraZeneca EEIG, 2012;
Food & Drug Administration. Endocrinologic and Metabolic Drugs Advisory Committee Background Document


24 102
(%)

10

24

102
8,2

8
6

4,8

4
2
0

1,3

0,9

10 mg

10 mg

(0,2%)

102
74,6% 77,8%

, . Bristol-Myers Squibb/AstraZeneca EEIG, 2012;

Food & Drug Administration. Endocrinologic and Metabolic Drugs Advisory Committee Background Document. Available at:
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM262996.pdf.

10 mg (n=1193)
(%)

(n=1193)

*p<0,1%.
, , .
Food & Drug Administration. Endocrinologic and Metabolic Drugs Advisory Committee: Dapagliflozin BMS-512148. Available at: http://tinyurl.com/7kjf5j7.
Last accessed October 2012.

eGFR:

102

eGFR (mL/min/1,73m2)

24
4.0
2.0
0.0

10 mg

2.0
4.0
6.0
8.0
10.0
0

12

24

48

64

80

96

112

()
N

12

24

50

63

76

89

102

10 mg

785

627

682

617

305

271

242

164

859

719

758

717

405

372

338

249

, . .

Ptaszynska A, et al. EASD 2012: Oral presentation 242.


10 mg

S-

S-

S-

24 (SE)

S- (mEq/L)

0,07

1,71

S- (mEq/L)

0,17

3,58

S-

S- (mg/dL)

0,57 (0,03)

5,28

(%)

2,15 (0,08)

42,51

, . 10 mg 911 938.
SE, .
Food & Drug Administration. Endocrinologic and Metabolic Drugs Advisory Committee: Dapagliflozin BMS-512148. Available at: http://tinyurl.com/7kjf5j7.
Last accessed
October 2012.
42
42


(n)

(N=5501)

(N=3184)

95%
1.0

: ~1,8

81

43

( )

10

( )

10

15

10

0,001
43
43

0,01

0,1

10

100

1000

* = 1,047 (95% , 0,702 1,579)

Johnsson K, et al. EASD 2012. Poster 743; Wilding J. Presented at the Congress on Controversies to Consensus in Diabetes, Obesity and
Hypertension (CODHy)-Latin America, 2nd Congress. 2012, Rio de Janeiro, Brazil.



2*
0,82
(95% 0,58, 1,15)
1,99 %

1,64%

* 19 -
mg . , , .
. . Bristol-Myers Squibb/AstraZeneca EEIG, 2012.

2,510

47
47

48
48

49
49

Dual Add-on Therapy in Type 2 Diabetes Poorly Controlled With Metformin

Monotherapy: A Randomized Double-Blind Trial of Saxagliptin Plus
Dapagliflozin Addition Versus Single Addition of Saxagliptin or Dapagliflozin to
Metformin

1.5%
0.9%
1.2%

52
52

 SGLT2


SGLT2

1. eGFR <60 mL/min/1.73 m2

2.
3.
4.
5.

6. 75 <18
7.

 2 - ADA 2015

Diabetes Care 2015;38(Suppl. 1):S41S48

57
57