Sodium-Glucose

Cotransporters (SGLT) Type 2

Inhibitors: New Tools in the
Fight Against Diabetes?

Edward Chao, DO
Endocrine Grand Rounds
April 8, 2009
Outline
 Challenges and a potential solution
 Renal glucose handling
 SGLT2 inhibitors: Some history and the latest
 Safety
 Potential clinical utility
 Unresolved questions
 Normal Glucose
Homeostasis
Pancreas

Fat Insulin Insulin Glucagon

Liver

Skeletal 90 mg/dL
muscle
Normal fasting glucose Kidney
homeostasis involves the Fasting
hormonal regulation of glucose plasma
utilization and production and glucose
the filtration and reabsorption
of glucose by the kidney.
DeFronzo RA. Ann Intern Med. 1999;131:281-303. Wright EM. Am J Physiol Renal Physiol. 2001;280:F10-F18.
 Pathophysiology of T2DM
Impaired Insulin Secretion Gluconeogenes
Pancreas is

Insulin Insuli Glucagon

Fat
n Liver
+ - +

+
Insulin resistance 180 mg/dL
Skeletal
muscle Kidney
Fasting
plasma
glucose
DeFronzo RA. Ann Intern Med. 1999;131:281-303. Wright EM. Am J Physiol Renal Physiol. 2001;280:F10-F18.
Challenges with Current Treatment

Hyperglycemia:
– Leads to microvascular complications
– Can facilitate beta-cell failure in the pancreas and
worsen insulin resistance, thus triggering a cycle
of impaired metabolism (glucotoxicity)
Traditional focus: developing agents that improve
insulin sensitivity and/or enhance endogenous
insulin secretion
But hypoglycemia and weight gain are major
obstacles to optimizing glycemic control
 SGLT2 Inhibitors: A Potential
Solution?
Paradoxically, there can be an increased glucose
reabsorptive capacity by the kidney in diabetes
Inhibition of SGLT2-mediated glucose reabsorption in
the renal proximal tubule leads to increased
glycosuria
Results in: reduced plasma glucose levels, enhanced
insulin sensitivity, suppressed hepatic glucose
production, and improved insulin secretion
Mechanism of action is independent of insulin
resistance or the severity of beta-cell dysfunction
 The Renal Corpuscle and Glomerular
Filtration
Afferent arteriole Efferent arteriole
• Glucose, water, salts,
small metabolites, and
other small molecules are
filtered and collect in
Bowman’s space
• Filtration is a process of
passive diffusion
• The total amount of a
substance (glucose)
filtered is proportional to
its plasma concentration
Bowman’s space Proximal tubule

Fawcett.DW. A Textbook of Histology. 11th ed. WB Saunders Co.; 1986:757-759.

 Renal Handling of Glucose in a Non-
Diabetic Individual
Volume of plasma kidneys filter/day = 180 L
Normal glucose concentration = 1000 mg/L (100 mg/dl)
Glucose filtered/day = (180 L/day) (1000 mg/L) = 180 g
Under normal
circumstances, virtually
Glucose SGLT2 all the glucose filtered is
reabsorbed and glucose
does not appear in the
S1 segment of
S urine.
proximal tubule
~90% G Collecting
Reabsorption L duct
T
~10%
1
Distal S2 / S3
segment of
proximal tubule NO GLUCOSE

Wright EM. Am J Physiol Renal Physiol. 2001;280:F10-F18. Thorens B. Am J Physiol. 1996;270:G541-G553.

Cellular Glucose Transport
Glucose is a polar compound to which cell
membranes are impermeable
Movement across lipid-rich cell membranes thus
requires membrane-associated carrier protein
transport
2 classes of glucose transporters:
- Sodium-linked active glucose transporters:
6 isoforms (SGLT1-6)
- Facilitative passive glucose transporters:
12 isoforms (GLUT1-12)
 Comparison of Sodium-Glucose
Cotransporters
SGLT1 SGLT2

Site Mostly small intestine, Almost exclusively

some in kidney, heart kidney
Renal Location Late proximal straight Early proximal
tubule (S3 segment) convoluted tubule (S1
segment)
Affinity for Glucose High Low
Km = 0.4 mM Km = 2 mM
Capacity for Low High
Glucose Transport

% of Renal Glucose 10% 90%

Reabsorption

Lee YJ. et al. Kidney Int Suppl. 2007;72:S27-S35.

 SGLT2 Mediates Glucose
Reabsorption in the Kidney

Lumen Blood
Glucos
Na+ e GLUT Glucos
Na+ and Glucose S1 Proximal 2 e
at 1:1 SGLT2
stoichiometry
Tubule
Glucos
K+
e Na+
Na+
ATPase

Adapted from Dr. Robert Henry, New Classes of Pharmacologic Agents for the Treatment of Hyperglyce
on the Horizon: Sodium Glucose Cotransporter (SGLT) - Type 2 Inhibitors, June 2008.
 Renal Glucose Handling
Filtration/Reabsorption/Excretion 300
Tmax Tm
Rate of Glucose

ti
200
(mg/min)

rp
so
b
on ea
R

100

Actual Threshold Theoretical threshold

180 200 300

Plasma Glucose (mg/dL)

chematic representation of the typical titration curve for renal glucose reabsorption in man.
dapted and modified from Silverman M, Turner RJ. Handbook of Physiology. In: Windhager EE, ed. Oxford University Press; 1992:2017-2038.
 Renal Glucose Handling After
SGLT2 Inhibition
Filtration/Reabsorption/Excretion 300
Tmax Tm
Rate of Glucose

ti
200
(mg/min)

rp
bso
on ea
R

100

Actual Threshold Theoretical threshold

180 200 300

Plasma Glucose (mg/dL)

chematic representation of the typical titration curve for renal glucose reabsorption in man.
dapted and modified from Silverman M, Turner RJ. Handbook of Physiology. In: Windhager EE, ed. Oxford University Press; 1992:2017-2038.
 A Model of SGLT2 Inhibition
from Nature
Concern due to increasing excretion of urinary
glucose – paradigm shift

Could renal glycosuria exacerbate diabetic

nephropathy?

Familial renal glycosuria: rare autosomal recessive

d/o; mutations in the SGLT2 gene: persistent
isolated glycosuria 10-120 g/day in the face of
normal fasting serum glucose

Calado, et al. Nephrol Dial Transplant. 2008;23:3874-3879.

 Familial Renal Glycosuria Pts
Typically:
Have no evidence of renal tubular dysfunction
Are asymptomatic
Hypoglycemia and hypovolemia rarely, if ever,
observed
– Some with mutational variations with renal Na wasting
and/or mild volume depletion
Renal biopsies: normal histology
No increased incidence of UTI
No increased incidence of chronic renal
insufficiency
No increased incidence of diabetes
No obesity observed
 Phlorizin
First SGLT inhibitor
First isolated in 1835 from the root bark of the apple
tree by French chemists
Non-selective
Used in research to establish that hyperglycemia
contributes to the insulin resistance that
characterizes T2DM
Insulinopenic model of T2DM: diabetic rats with 90%
of their pancreases resected
 Effect of Phlorizin on insulin
(mg/kg min) sensitivity
Glucose
uptake
Phlorizin was never developed
Due to poor intestinal absorption and resultant low
bioavailability

Non-selective

Easily degraded in vivo to phloretin, which inhibits

facilitative glucose transporters, such as GLUT1

An analogue, T-1095, is rapidly converted in the liver

to an active metabolite, T-1095A – has a high affinity
and selectivity for human kidney SGLT2
 After Phlorizin
By the early 1950s, phlorizin was demonstrated to block
facilitated glucose transport into erythrocytes and inhibit
transport of glucose in both the kidney and small
intestine

Interest in the mechanisms and potential significance of

phlorizin-induced renal glycosuria did not develop until
the early 1990s, when SGLT2 was fully characterized
 Clinical Development of SGLT2 Inhibitors
Kipnes, M. Expert Opin Investig. Drugs. 2009 ;18(3) 335-348.

Drug Development Company Phase of Development

Dapagliflozin BMS / AstraZeneca III
Remogliflozin GSK / Kissei II
AVE-2268 Sanofi-Aventis II (discontinued)

TA-7284 JNJ/Mitsubishi Tanabe II

TS-033 Taisho II (discontinued)
YM-543, ASP-1941 Astellas IIa

T-1095 J & J / Tanabe Seiyaku II (discontinued)

Sergliflozin GSK / Kissei II (discontinued)
R-7201 Roche/Chugai II
BI 10773, BI 44847 Boehringer Ingelheim II, I

DSP-3235 Dainippon Sumitomo/Kissei I

SAR7226 Sanofi-Aventis I
Dapagliflozin: the structure
Contains a C-glucoside for increased in-
vivo
stability, thus longer t1/2 (~17 hr)
Can be administered PO QD in an
unmodified form

A selective inhibitor of SGLT2

(~1200-fold more than SGLT1)
 Dapagliflozin in Type 2
Diabetes: Phase II Study
47 subjects, 55-60 years of age with T2DM and
unimpaired renal function (eGFR 60-136
ml/min/1.73m m2) , drug naïve or on a stable dose
metformin
Baseline characteristics were similar
Randomized to: QD for 14 days
– placebo (n = 8)
– 5 mg (n = 11)
– 25 mg (n = 12)
- 100 mg (n = 16)

Komoroski et al. Clinical Pharm and Therap 2009 Epub

Jan 7, 2009; 1-7.
 Dapagliflozin Increases Urinary
Glucose Excretion
120
urinary glucose (g/day)
Mean (SD) Cumulative

100

80 81.3
75.3 Day -1
70.1 69.9
60 Day 1
Day 14
40
45.2
36.6
1
20
2 2 2 2 4
0
5 25 100
Placebo
Dapagliflozin dose (mg)
• Constant rate of glucosuria over 24 hrs
– ~2 g/h (5 mg) ~3 g/h (25 and 100 mg)
Komoroski et al. Clinical Pharm and Therap 2009 Epub Jan 7,
Dapagliflozin decreases mean fasting
serum glucose
Dapagliflozin Improves Postprandial
Glucose
Komoroski et al. Clinical Pharm and Therap 2009 Epub Jan 7, 2009; 1-7.
Dapagliflozin dose

Day 2

-2.5
Day 13
-5.2
* * P< 0.001
-9.6 *
* -
-13.7 11.7
*
- -18.8
*
17.6
*
-22.6
 Dapagliflozin: Effect on Renal Glucose
Reabsorption
100 % Inhibition of Excreted
= × 100
Glucose reabsorption* Filtered
Mean (SD) % Inhibition of
glucose reabsorption

75

Placebo (n=8)
44%
41% 5 mg (n=11)
50 34%36%
25 mg (n=12)
20% 20% 100 mg (n=16)

25

0.1% 0.9%
0
Day 1 Day 14
* Measured over 0-4h post-dose
Komoroski et al. Clinical Pharm and Therap 2009 Epub Jan 7,
interval
 Adverse Events
No deaths or discontinuations due to serious
adverse events

Adverse events did not appear to be dose-related

with either dapagliflozin or metformin

Most frequent adverse events were GI

Komoroski et al. Clinical Pharm and Therap 2009 Epub Jan 7, 2009; 1-7
Komoroski B et al 2009 Clin Pharm Ther 2009 Jan 7
Another Dapagliflozin Trial: Phase
IIb
389 drug-naïve T2DM pts (348 completed) in a
randomized, prospective, double-blind, placebo-
controlled study
18-79 years, A1c >7 and <10%, BMI <40 kg/m2, GFR
>60 ml/min/1.73m2, SCr <1.5 mg/dL in men and <1.4
mg/dL in women; urine MAU/Cr <300 mg/g
Assigned to:
Dapagliflozin Metformin XR 750 mg
2.5 mg QD QD titrated at week 2 to
5 mg QD 1500 mg QD
10 mg QD Placebo
20 mg QD
50 mg QD

List, J.F. et al Diabetes Care 2009;32:4:650-657

 Outcome Measures
Primary outcome measure: compare mean A1c
change from baseline for each dapagliflozin group
vs placebo after 12 weeks

Secondary outcome measures – comparisons of

dapagliflozin vs placebo for:
– FSG change from baseline
– Dose-dependent trends in glycemic efficacy
– Proportion of pts achieving A1c < 7%
– Change in 24-hr urinary glucose to creatinine ratio

List, J.F. et al Diabetes Care 2009;32:4:650-657

 Table 1— Baseline patient
characteristics
Data are means ± SD. Dapagliflozin dose Placebo Met
2.5 mg 5 mg 10 mg 20 mg 50 mg

Age (years) 55 ± 11 55 ± 12 54 ± 9 55 ± 10 53 ± 10 53 ± 11 54 ± 9

A1C (%) 7.6 ± 0.7 8.0 ± 0.9 8.0 ± 0.8 7.7 ± 0.9 7.8 ± 1.0 7.9 ± 0.9 7.6 ± 0.8

FPG (mg/dl) 145 ± 34 153 ± 48 148 ± 38 149 ± 41 153 ± 42 150 ± 46 143 ± 33

Weight (kg) 90 ± 20 89 ± 17 86 ± 17 88 ± 18 92 ± 19 89 ± 18 88 ± 20

BMI (kg/m2) 32 ± 5 32 ± 5 31 ± 5 31 ± 5 32 ± 4 32 ± 5 32 ± 5

sBP (mmHg) 127 ± 14 126 ± 13 127 ± 16 127 ± 15 126 ± 16 126 ± 16 126 ± 13

dBP (mmHg) 78 ± 8 76 ± 8 77 ± 8 77 ± 8 77 ± 9 77 ± 8 78 ± 8

Creatinine (mg/dl) 0.85 ± 0.83 ± 0.85 ± 0.88 ± 0.84 ± 0.2 0.85 ± 0.82 ±
0.15 0.19 0.17 0.19 0.19 0.17

List, J.F. et al Diabetes Care 2009;32:4:650-657

Mean change in A1c at Week 12

* P <0.001
^P
=0.007

^
* *
2.5 mg 5 10 20
mg mg* mg *
List, J.F. et al Diabetes Care 2009;32:4:650-657
 % Mean Change from Baseline in
Weight after 12 wks of Dapagliflozin

List, J.F. et al Diabetes Care 2009;32:4:650-657

 Dapagliflozin Dose-Ranging 12 Week
Monotherapy Study of Treatment-Naïve T2D

Dapagliflozin dose (mg)

2.5 5 10 20 50 PBO Met
n=59 n=58 n=47 n=59 n=56 n=54 n=56
Baseline 145 153 148 149 153 150 143
FPG
Change -16.2* -19.3* -21.1* -24.4* -30.5* -5.8 -18.0
FPG
(mg/dL)

Change -9382 -8478 -10,149 -7053 -10,093 -3182 -5891

PPG [-11420, -7344] [-10200, -6756] [-12215, -8082] [-8913, -5194] [-12024, -8162] [-5086, -1277] [-7775, -4008]

(mg•min/dL)

List JF et al. Diabetes (Suppl 1), A94, 2008 * p<0.01 Baseline to Week 12; [95% CIs]
 Summary of List et al Results
Decreases in A1c, FPG, and PPG after 12 weeks, with
reduced FPG apparent by week 1

Changes in FPG were dose-related

There was little evidence of a dose response for either

A1c or PPG

Greater impact on PPG than FPG

List, J.F. et al Diabetes Care 2009;32:4:650-657.

 List et al
Likely reflects an intrinsic property of dapagliflozin:
greater impact on PPG – a “relief valve” to blunt
postprandial hyperglycemia

Diuretic effect:
– small dose-dependent increases in urine volume,
– small increases in BUN
– small dose-dependent increase in Hct
– No evidence of dehydration
Polyuria in 1.4% of pts, and no nocturia was noted

.
List, J.F. et al Diabetes Care 2009;32:4:650-657
 Weight Loss
All doses induced progressive weight reductions
consistent with steady caloric loss via glycosuria

– Weight loss was more pronounced in week 1,

especially at higher doses

– Acute weight loss during week 1 ? due to fluid loss,

then ?decreased adiposity represented by continued
gradual weight loss

List, J.F. et al Diabetes Care

2009;32:4:650-657.
 Dapagliflozin Induced Weight Loss
After 12 weeks in T2D Patients
Dapagliflozin dose (mg)

Measurement 2.5 5 10 20 50 PBO Met

n=59 n=58 n=47 n=59 n=56 n=54 n=56
Baseline Wt 90 (20) 89 (17) 86 (17) 88 (18) 91 (19) 89 (19) 88 (20)
kg (SD)
Mean Wt -2.7 -2.5 -2.7 -3.4 -3.4 -1.2 -1.7
Reduction [-3.4, -1.9] [-3.3, -1.8] [-3.5, -1.8] [-4.1, -2.6] [-4.1, -2.6] [-2.0, -0.4] [-2.4, -0.9]

kg [95% Cl]
Baseline BMI 31 (5) 31 (5) 30 (5) 31 (5) 32 (4) 32 (6) 32 (5)
kg/m2 (SD)
Mean BMI -0.9 -0.8 -0.8 -1.0 -1.1 -0.3 -0.5
Reduction [95% [-1.1, -0.7] [-1.2, -0.4] [-1.1, -0.5] [-1.2, -0.8] [-1.3, -0.9] [-0.5, 0.0] [-0.8, -0.3]
Cl]
List JF et al. Diabetes (Suppl 1), A138, 2008
 Adverse Events
2.5 mg 5 mg 10 mg 20 mg 50 mg Placebo Metformin

UTI 3 5 5 (11%) 4 4 (7%) 3 4

(5%) (9%) (7%) (6%) (7%)
Hypoglycemia 4 6 3 4 4 (7%) 2 5
(7%) (10%) (6%) (7%) (4%) (9%)

Genital 2 1 1 4 4 (7%) 0 1
infection (3%) (2%) (2%) (7%) (0%) (2%)

Nausea 3 4 3( 2 3 (5%) 3 6
(5%) (7%) 6%) (3%) (6%) (11%)
Diarrhea 1 1 1 4 1 1 4
(2%) (2%) (2%) (7%) (2%) (2%) (7%)
Hypotension 0 0 0 0 1 (2%) 1 2
(2%) (4%)

List, J.F. et al Diabetes Care 2009;32:4:650-657

 ISIS 388625 and 388626 Inhibit SGLT2
RNA Levels in Kidney of ZDF RATS
120

100
% Saline Control

80

60

40
> 80%
20 reduction
0
PBS 388625 388626 ctrl ASO

p<0.0001 p<0.0001 p<0.05

ZDF rats were administered 1.6 mg/kg
compound weekly by ip administration for 26 weeks
 SGLT2 ASO Treatment Caused Significant
and Sustained Reduction in Plasma
Glucose Levels in ZDF Rats
Fasted Plasma Glucose (wk
Fed Plasma Glucose
22)
900 PBS 500
800 388625 450
388626
700 400
ctrl ASO
600 350
mg/dL

mg/dL
500 300
250
400
200
300
150
200
100
100
50
0
0
0 50 100 150 200
PBS 388625 388626 ctrl
Study Day ASO
p<0.05
p<0.05ns
 ISIS 388625 and 388626 Promote
Glucosuria in ZDF Rats
Total Glucose Excreted (3 hrs) Normalized Glucose Excretion

Glucose/Creatinine (mg/mg)
800 350
700 300
Urine Glucose (mg)

600
250
500
200
400
150
300
200 100

100 50
0 0
PBS 388625 388626ctrl ASO PBS 388625 388626ctrl ASO

p<0.05
p<0.001ns p<0.01
p<0.001ns
 Phase III Study of Dapagliflozin as
Monotherapy
Multicenter, randomized, double-blind, placebo-
controlled trial
T2DM subjects ages 18-77 with inadequate glycemic
control; drug-naïve or treated with medication for < 24
weeks
Randomized to dapagliflozin 2.5, 5,10 mg, or placebo
Primary outcome measure: change in A1c at week 24
vs baseline
Secondary outcome measures include: changes at
week 24 vs. baseline in:
– FPG
– total body weight
– proportion of pts at A1c < 7.0%
US National Institutes of Health,
http://www.clinicaltrials.gov/ct2/show/NCT00528372?term=dapagliflozin&rank=3. Accessed
March 30, 2009.
 Phase III Study of Dapagliflozin: Pts with
T2DM Inadquately Controlled on Metformin
Alone
Multicenter, randomized, double-blind, placebo-
controlled trial

T2DM subjects on Metformin total daily dose > 1500 mg

for at least 8 weeks

Same primary and secondary outcome measures

US National Institutes of Health,

http://www.clinicaltrials.gov/ct2/show/NCT00528879?
term=dapagliflozin&rank=4. Accessed March 30, 2009.
 A Novel Approach
Antisense oligonucleotides can selectively target the
kidney epithelial cells in the proximal tubule
Reduces SGLT2 expression – transcription, and
ultimately, translation – by up to 80% with once-weekly
administration
There were increases in glucosuria, improvements in
blood glucose control, and lowering of A1C in rodent
models, such as the Zucker Diabetic Fatty rat
Highly selective, with no cross-reactivity with SGLT1 or
GLUT 2 gene expression – in mouse, dog, monkey, rat
No compensatory increase in gene expression has been
seen, even after 6 months of administration
 How might SGLT2 inhibitors
potentially be used?
T1DM: added on to insulin

T2DM : add-on to other oral agents

add-on to injectables

As an obesity treatment

In individuals with pre-diabetes for prevention

 Unresolved Questions
Would urinary excretion of calories as glucose lead to a
compensatory increase in eating?

Will adverse effects such as UTI and genitourinary

infections be found with significantly increased frequency
in long-term trials with large numbers of subjects? If so,
would increased surveillance be needed?

What are the long-term effects on renal function?

Are the weight loss effects sustained?

 Unresolved Questions

Are there any effects on bone metabolism? On lipids?

To what extent do the diuretic effect and reduced

adiposity contribute to weight loss?

How will glycemic control/weight loss be affected when

SGLT2 inhibitors are combined with other currently
used diabetes agents?
Potential Advantages of SGLT2
Inhibitors
Novel mechanism of action: no effect on insulin
secretion or gluconeogenesis – should not cause
hypoglycemia
– Could continue to be effective as diabetes progresses

Potential for negative energy balance and thus

weight loss

Minimizing GI side effects by not inhibiting SGLT1

Osmotic diuretic effect - ?use with TZDs, ?useful for

pts with htn
 Summary
SGLT2 inhibitors reduces both preprandial and
postprandial blood glucose

May decrease glucotoxicity and can consequently lead to

sustained, long-term glycemic control

May have broad indications, including potentially

prevention of diabetes, obesity, and both T1DM and
T2DM

Further studies in large numbers of human subjects will

be needed to determine how best to utilize these agents
in the treatment of diabetes
 Acknowledgments:
Dr. Daniel Porte
Dr. Robert Henry
Dr. Steve Edelman
Dr. Richard Daly