Vivian Fonseca, MD
Professor, Medicine and Pharmacology
Tullis-Tulane Alumni Chair in Diabetes
Chief, Section of Endocrinology
Tulane University Health Sciences Center
New Orleans, Louisiana
Cyrus V. Desouza, MD, MBBS
Professor and Chief
Division of Diabetes, Endocrinology, and Metabolism
University of Nebraska Medical Center
Omaha, Nebraska

Renal Handling of Glucose —
A Potential New Drug Target?
“ Normal ” individuals
•Filtered glucose load ~180 g/day
•Urinary glucose <0.5 g/day
•Glucose reabsorption occurs in the proximal tubule through the action of sodium glucose cotransporter(SGLT)-1 and SGLT-2
Bakris GL, et al . Kidney Int. 2009;75:1272-1277.

SGLTs in the Kidney
Site
Sugar specificity
Glucose affinity
Glucose transport capacity
Role
SGLT-1
Intestine, kidney
Glucose or galactose
High
Km = 0.4 mM
Low
Dietary absorption of glucose and galactose
Renal glucose reabsorption
SGLT-2
Kidney
Glucose
Low
Km = 2 mM
High
Renal glucose reabsorption
Bakris GL, et al . Kidney Int. 2009;75:1272-1277.

Renal Handling of Glucose
162 g glucose filtered each day
Glomerulus 90% of glucose reabsorbed by
SGLT-2
10% of glucose reabsorbed by SGLT-1 *
Bakris GL, et al . Kidney Int. 2009;75:1272-1277.
Abdul-Ghani, et al. Endocr Rev. 2011;32:515-531.
No glucose excreted

Glucose Transport in Tubular Epithelial Cells
SGLT-2
High capacity
Low affinity
Glucose
Na +
S1 proximal tubule
Glucose GLUT2
Na +
K +
ATPase
Na +
K +
Glucose
Lumen Blood
S3 proximal tubule
Glucose GLUT1 Glucose
SGLT-1
Low capacity
High affinity
Glucose
Na +
Na +
K +
ATPase
Na +
K +
Bakris GL, et al. Kidney Int, 2009;75:1272-1277.

Familial Renal Glucosuria
• Autosomal recessive deficiency of SGLT-2
• Characterized by persistent urinary glucose excretion, with normal plasma glucose concentration
• Urinary glucose excretion varies from a few grams to >100 grams per day
Abdul-Ghani MA, et al. Endocrine Rev. 2011;32:515-531.

Familial Renal Glucosuria
• No evidence of renal glomerular or tubular dysfunction
• Usually asymptomatic
• Hypoglycemia and hypovolemia are rarely, if ever, observed
• Normal lifespan
• The large majority of patients have no clinical manifestations
– Both renal histology and renal function are normal
– The incidence of diabetes, chronic renal failure, and urinary tract infection are not increased

Renal Glucose Handling
Tm
G
Splay
Actual threshold
100 180 200
Theoretic threshold
300
Plasma Glucose Concentration (mg/dL)
Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14:782-790.

Renal Glucose Handling in Diabetes
Tm
G
100 200 240 300
Plasma Glucose Concentration (mg/dL)
De Fronzo RA, et al. Diabetes Care 2013. Epub ahead of print. 6/4/13.

Glucose Transporter Protein and Activity in
Human Renal Proximal Tubular Cells from the Urine of Patients with T2DM
Healthy T2DM
Healthy
T2DM *
Healthy
Healthy
T2DM
T2DM *
*
0 2 4
Normalized Glucose
Transport Levels
6 0 500 1000
CPM
1500 2000
*P <.05
Abbreviations: AMG, methyl-

-D-[U14 C]-glucopyranoside; T2DM, type 2 diabetes mellitus. Rahmoune H, et al.
Diabetes . 2005;54:3427-3434.

Renal Tubular Glucose Reabsorption in Diabetes
• In animal models of type 1 and type 2 diabetes mellitus, the maximum renal tubular reabsorptive capacity (Tm) for glucose is increased
• In human type 1 diabetes, the Tm for glucose is increased 1
• In human type 2 diabetes, the Tm for glucose has not been systematically examined
• Cultured human proximal renal tubular cells demonstrate increased SGLT-2/GLUT2 mRNA and protein, and increased glucose uptake (AMG)
Abbreviation: AMG, methyl-

-D-[U14 C]-glucopyranoside.
1. Mogensen CE. Scand J Clin Lab Invest . 1971;28-101-109.

Implications
• An adaptive response to conserve glucose
(ie, for energy needs) becomes maladaptive in diabetes
• Moreover, the ability of the kidney to conserve glucose may be augmented by an absolute increase in the renal Tm for glucose

Phlorizin —The “ Prototype ” SGLT Inhibitor
OH
HO
O
OH
O
HO
O
HO OH
HO
• First described in the mid-19th century
• Isolated from the root bark of the apple tree
• Utilized in the exploration of SGLT function
• Low selectivity for SGLT-2 over SGLT-1
• Poor oral bioavailability
– Hydrolyzed in small intestine to glucose + phloretin, an inhibitor of GLUT1
Ehrenkranz JLR. Diabetes Metab Res Rev. 2005;21:31-38.

Treatment of Diabetic Rats with Phlorizin
Normalizes Plasma Glucos e
Fasting plasma glucose (mg/dL)
Fed plasma glucose (mg/dL)
Group 1 Group 2 Group 3 Group 4 Group 5
101 122 100 99 113
140 295 171 137 306
Group 1 (n = 14) — sham operated controls
Group 2 (n = 19) — partial (90%) pancreatectomy
Group 3 (n = 10) — 90% pancreatectomy + phlorizin
Group 4 (n = 7) — sham operated + phlorizin
Group 5 (n = 4) — 90% pancreatectomy/phlorizin → discontinue phlorizi
Rossetti L, et al. J Clin Invest. 1987;79:1510-1515.

Chronic SGLT-2 Inhibition Improves
Insulin Action in ZDF Rats
• Hyperinsulinemic-euglycemic clamp study
• T-1095 administered as diet admixture for
4 weeks
• Decreased hepatic glucose production, increased hepatic glucose uptake; improved glucokinase/glucose-6-phosphatase ratio
Abbreviation: ZDF, Zucker diabetic fatty.
Nawano M, et al. Am J Physiol Endocrinol Metab. 2000;278:E535-543.

Dapagliflozin Improves Islet Insulin Content in ZDF Rats
• Female Zucker diabetic fatty (ZDF) rats placed on a high-fat diet
• DAPA 1 mg/kg/d PO administered for 33 days
• DAPA improved insulin sensitivity index compared with obese controls (0.08 vs 0.02) ( P ≤.01)
• Variability of beta cell mass was markedly reduced and islet morphology index was maintained at level similar to lean controls
Macdonald FR, et al. Diabetes Obes Metab . 2010;12:1004-1012.

Chronic SGLT-2 Inhibition Led to
Weight Loss in Diet-Induced Obese Rats
Dapagliflozin-treated rats
•Increased water intake, urine volume, and total urine glucose
•Consumed more total kcals (12%) vs vehicle-treated animals
•Lost weight (4%–6%); rats pair-fed to the vehicle group lost more weight (10%)
•Showed increased utilization of fat as an alternate energy source to glucose (indirect calorimetry and plasma ketone data)
•Showed decreased fasting serum glucose concentration by 64% at the 5-mg/kg dose on day 27 of the study
Devenny J, et al. Obesity 2007;15(9 suppl):A121.

“Desirable” Properties of an SGLT-2 Inhibitor
• High potency and selectivity for SGLT-2, resulting in good efficacy in the treatment of diabetes
• Metabolic stability
• Oral bioavailability and convenient dosing
• Good tolerability
• Suitability for use in combination with other antidiabetic drugs

Selective SGLT-2 Inhibitors
Potential advantages
• Minimizes gastrointestinal side effects associated with SGLT-1 inhibition with nonselective agents
• Unique potential to cause negative energy balance
• Corrects effect of glucose toxicity on insulin secretion and action
Meng W, et al. J Med Chem . 2008;51:1145-1149. Katsuno K, et al. J Pharmacol Exp Ther . 2007;320:323-330.

Renal Glucose Handling After
SGLT-2 Inhibition
150
SGLT-2 Inhibition
Diabetes Threshold
100
Normal
Threshold
50
0
0 100 200 300 400
Plasma Glucose (mg/dL)
Farber SJ, et al.
J Clin Invest.
1951;30: 125-129. Mogensen CE. Scand J Clin Lab Invest. 1971;28:101-109.
Silverman M, Turner RJ. Handbook of Physiology . In: Windhager EE, ed. Oxford University Press. 1992:
2017-2038. Cersosimo E, et al. Diabetes.
2000;49:1186-1193. DeFronzo RA, et al. Endocr Pract. 2008;14:
782-790.

Approved and Emerging SGLT-2 Inhibitors
Compound
Canagliflozin
Dapagliflozin
Empagliflozin
Ipragliflozin
Status
Approved in United States (March 2013)
Submitted in Europe (June 2012)
Approved in United States (January 2014)
Approved in Europe (Nov. 2012)
Submitted to FDA (March 2013)
Submitted to Europe (March 2013)
Submitted in Japan (March 2013)
Luseogliflozin Phase III
Tofogliflozin Phase III
Ertugliflozin Phase III

Comparison of Selectivity of
SGLT-2 Inhibitors
Selectivity SGLT-1/2 IC
50
SGLT-2 Inhibitor
O-glycosides
Phlorizin
T-1095
Sergliflozin
Remogliflozin
C-glycosides
Canagliflozin
Dapagliflozin
Empagliflozin
10 1
30 1
~300 1
~360 2
220 3
>1200 1,3
>2500 3
1. Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14:782-790.
2. Fujimori Y, et al. J Pharmacol Exp Ther. 2008;327:268-276.
3. Grempler R, et al. Diabetes Obes Metab . 2012;14:83-90.

Clinical Efficacy with SGLT-2 Inhibitors
• Canagliflozin
• Dapagliflozin
• Empagliflozin
• Ipragliflozin

Canagliflozin Changes in HbA1C Over Time
(Week 26)
N = 584 (PBO = 192; CANA 100 = 195; CANA 300 = 197)
• Least squares mean changes from baseline compared with placebo at week 26
– CANA 100 mg: -0.915 ( P <.001)
– CANA 300 mg: -1.16% ( P <.001)
• Substantial reductions occurred at week 12, with modest progressive reductions and no apparent plateau through week 26
Stenlof K, et al. Diabetes Obes Metab. 2013;15:372-382.

Canagliflozin —Proportion of Subjects
Reaching A1C Goals at Week 26
A1c <7.0%
Placebo
(n = 192)
20.6%
Canagliflozin
100 mg
(n = 195)
44.5%*
Canagliflozin
300 mg
(n = 197)
62.4%*
28.4%
17.8% A1c <6.5%
†
5.3%
* P <.001 vs placebo.
†
Statistical comparison for CANA 100 and 300 mg vs placebo not performed (not prespecified).
Stenlof K, et al. Diabetes Obes Metab . 2013;15:372-382.

Canagliflozin Changes in Fasting Plasma
Glucose at Week 26
• Least squares mean changes from baseline at week 26
– Placebo: +8.3 mg/dL
– CANA 100 mg: -27.2 mg/dL
– CANA 300 mg/dL: -35.0 mg/dL
• Difference compared with placebo
– CANA 100 mg: -35.0 mg/dL ( P <.001)
– CANA 300 mg: -43.4 mg/dL ( P <.001)
• Reductions in fasting plasma glucose were near maximum by week 6, with a slight progressive decline through week
26, compared with a modest rise from baseline in placebo
Stenlof K, et al. Diabetes Obes Metab . 2013;15:372-382.

Canagliflozin —Change in Postprandial
Glucose After a Standardized Meal
(Week 26)
Placebo
Least square mean change from baseline
(mg/dL)
* P <.001 vs placebo.
+5.2
CANA 100 mg CANA 300 mg
-42.9* -58.8*
Stenlof K, et al. Diabetes Obes Metab . 2013;15:372-382.

Canagliflozin Add-On to Metformin
Changes from Baseline at Week 12 (N = 451)
HbA1c
(%)
-0.22
Placebo (n = 65)
Canagliflozin (n = 321)
50 mg QD
100 mg QD
200 mg QD
300 mg QD
300 mg QD
Sitagliptin (n = 65)
100 mg QD
-0.79*
-0.76*
-0.70*
-0.92*
-0.95*
-0.74*
* P <.001 vs placebo.
Rosenstock J, et al. Diabetes Care. 2012;35:1232-1238.
Fasting Plasma
Glucose
(mg/dL)
+3.6
-16.2*
-25.2*
-27.0*
-25.2*
-23.4*
-12.6
Body
Weight
(kg)
-1.1
-2.3*
-2.6*
-2.7*
-3.4*
-3.4*
-0.6

Change in HbA1c with Canagliflozin in Subjects with T2DM and Stage 3 Chronic Kidney Disease
( N = 2170)
Baseline eGFR mL/min/1.73m
2
≥30 and <60
(n = 1085)
≥45 and <60
(n = 721)
≥30 and <45
(n = 364)
CANA 100 mg
Difference vs Placebo
-0.38%*
-0.47%
-0.23%
CANA 300 mg
Difference vs Placebo
-0.47%*
-0.52%
-0.39%
Pooled analysis in patients with T2DM from placebocontrolled studies with eGFR ≥30 and
<60 mL/min/1.73m
2 (N = 1085) and in subgroups with eGFR ≥45 and <60 (n = 721) or ≥30
& <45 (n = 364).
* P <.001 vs placebo.
Woo V, et al. Presented at: ADA 2013. Abstract 73-LB. Chicago, Illinois.

Canagliflozin Dosage and Administration
• The recommended starting dose is 100 mg once daily, taken before the first meal of the day
• Dose can be increased to 300 mg once daily in patients tolerating canagliflozin 100 mg once daily who have an epidermal growth factor receptor (eGFR) of ≥60 mL/min/1.73 m 2 and require additional glycemic control
• Canagliflozin is limited to 100 mg once daily in patients who have an eGFR of 45 to <60 mL/min/1.73 m 2
• Assess renal function before initiating canagliflozin; do not initiate canagliflozin if eGFR is <45 mL/min/1.73 m 2
• Discontinue canagliflozin if eGFR falls below 45 mL/min/1.73 m 2 http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204042s000lbl.pdf

Effect of Dapagliflozin on Renal Threshold for Glucose in Diabetes
T2DM + dapagliflozin
(40 mg/dL)
Healthy
(180 mg/dL)
T2DM
(240 mg/dL)
40 100 180 240
Plasma Glucose Concentration (mg/dL )
De Fronzo R, et al. Diabetes Care . Epub ahead of print. 6/4/13.
300

Dapagliflozin —Mean Changes from
Baseline After 12 Weeks (N = 389)
HbA1c
(%)
-0.18
Fasting Plasma
Glucose
(mg/dL)
-6
Body Weight
Reduction
(%)
-1.2
Placebo (n = 54)
Dapagliflozin (n = 279)
2.5 mg
5 mg
10 mg
20 mg
50 mg
Metformin (n = 56)
750−1500 mg
-0.71
-0.72
-0.85
-0.55
-0.90
-0.73
-16
-19
-21
-24
-31
-18
-2.7
-2.5
-2.7
-3.4
-3.4
-1.7
List JF, et al. Diabetes Care. 2009;32:650-657.

Dapagliflozin —Mean Postprandial Glucose
AUC Changes from Baseline After 12 Week s
DAPA 2.5 mg
DAPA 5 mg
DAPA 10 mg
DAPA 20 mg
DAPA 50 mg
Placebo
Metformin 1500 mg
Postprandial Glucose AUC
(mg* min -1 /dL -1 )
-9382
-8478
-10,149
-7053
-10,093
-3182
-5891
List JF, et al. Diabetes Care. 2009;32:650-657.

Dapagliflozin Adjusted Mean Urinary
Glucose Excretion
Changes from Baseline After 12 Weeks
DAPA 2.5 mg
DAPA 5 mg
DAPA 10 mg
DAPA 20 mg
DAPA 50 mg
Placebo
Metformin 1500 mg
* P <.001 vs placebo at 12 weeks.
24-Hour Urinary Glucose/
Creatinine (g/g)
32*
49*
51*
65*
60*
-0.2
-1.4
List JF, et al. Diabetes Care. 2009;32:650-657.

Dapagliflozin Initial Combination with Metformin XR
Change in HbA1c at 24 Weeks (N = 638)
Regimen
Dapagliflozin 10 mg (n = 219)
Metformin extended release (XR) (n = 208)
Dapagliflozin + metformin (n = 211)
Dapagliflozin + metformin vs dapaglifloxin
Dapagliflozin + metformin vs metformin
Change from Baseline
-1.45
-1.44
-1.98
-0.53 (P <.0001)
-0.54 (P <.0001)
• Dapagliflozin was noninferior to metformin
• Combination therapy was superior to monotherapy
Henry R, et al. Int J Clin Pract. 2012;66:446-456 .

BL (%)
Change in HbA1c with Dapagliflozin Across
Monotherapy
(N = 558)
7.92
24-Week Studies
Add-on to
MET
(N = 546)
8.06
Add-on to SU
(N = 596)
8.11
Add-on to PIO
(N = 420)
8.38
Add-on to Insulin
(N = 807)
8.53
0.0
-0.2

HbA1c
(%) with
95% CI
-0.4
-0.6
-0.23
-0.30
-0.13
-0.8
-0.58
-0.58*
0.63*
-1.0
-0.77*
-0.89*
-0.84*
-0.82*
0.82*
-0.97*
-1.2
Dapa 2.5 mg Dapa 5 mg Dapa 10 mg
* P <.05 vs placebo.
Abbreviations: BL, baseline; MET, metformin; PIO, pioglitazone; SU, sulfonylurea.
FDA Advisory Committee 19th July 2011: http://www.fda.gov
.
-0.42
-0.75*
-0.82*
0.90*
Placebo
-0.30

Dapagliflozin —Change in FPG at Week 24
Across Studies
BL (mg/dL)
Monotherapy
(N = 558)
162.7
Add-on to
MET
(N = 546)
163.3
Add-on to SU
(N = 596)
172.9
Add-on to PIO
(N = 420)
164.8
Add-on to Insulin
(N = 807)
177.6
-21.7
1.1
0.5
0
-0.5
-1.1
-1.6
-2.2
* P <.05 vs placebo.
Abbreviations: BL, baseline; MET, metformin; PIO, pioglitazone; SU, sulfonylurea.
FDA Advisory Committee 19th July 2011: http://www.fda.gov
.

Change in HbA1c at 52 Weeks in Dapagliflozin vs
Sulfonylurea Add-on to Metformin Study (N = 801)
Regimen
Dapagliflozin + metformin
(n = 400)
Glipizide + metformin
(n = 401)
Baseline HbA1c
7.69%
7.74%
HbA1c Week 52
-0.52%
-0.52%
• Initial drop in HbA1c during the titration period was greater with glipizide + metformin than with dapagliflozin + metformin
• Efficacy during the maintenance period waned with glipizide but remained stable for dapagliflozin
• This resulted in equivalent efficacy at week 52
• Percent patients with ≥1 hypoglycemic events
− Dapagliflozin: 3.5%
− Glipizide: 40.8%
Nauck M, et al. Diabetes Care. 2011; 34:2015-2022.

Change in HbA1c to 104 Weeks in
Dapagliflozin vs Sulfonylurea
Add-On to Metformin Study
Regimen
Dapagliflozin + metformin
(n = 400)
Glipizide + metformin
(n = 401)
HbA1c Week 52 1
-0.52%
-0.52%
HbA1c Week 104 2
-0.32%
-0.14%
1. Nauck K, et al. Diabetes Care . 2011;34:2015-2022.
2.Del Prato S, et al. Presented at: EASD 2011. September 12-16, 2011 (presentation 852).

Weight Loss Characterization with
Dapagliflozin (N = 182)
• Dapagliflozin 10 mg/d or placebo added to open-label metformin (182 diabetics on metformin, A1c 7.17, BMI
31.0 kg/m 2 )
• At 24 weeks, dapagliflozin reduced (vs placebo):
– Total body weight (-2.08 kg, P <.0001)
– Waist circumference (-1.52 cm, P = .0143)
– Fat mass by DEXA (-1.48 kg = 2/3 of weight loss attributed to reduction in fat mass, P = .0001)
– Visceral adipose tissue by MRI (-258.4 cm 3 , nominal
P = .0084)
– Subcutaneous adipose tissue by MRI (-184.9 cm 3 , nominal
P = .0385)
Bolinder J, et al. J Clin Endocr Metab . 2012;97:1020-1031.

Dapagliflozin Adjusted Mean Change from
Baseline in Body Weight in Phase III Studies
Dapagliflozin 10 mg
24-week monotherapy 1
Add-on to metformin 2
Add-on to sulfonylurea 3
Add-on to insulin (24 wk) 4
Add-on to insulin (48 wk) 4
Head to head 5
Dapagliflozin + metformin vs
Glipizide + metformin
†
Adjusted Mean Change from Baseline (kg)
-3.2
-2.9*
-2.26*
-1.61*
-1.61*
-3.4
+1.4
* P <.001;
†
Difference between the two, -4.7 ( P <.0001).
1. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. 2. Bailey CJ, et al. Lancet.
2010;375:2223-2233.
3. Strojek K, et al. Diabetes Obes Metab . 2011;13:928-938. 4. Wilding J, et al. Ann Intern Med . 2012;156:
405-415. 5. Nauck MA, et al . Diabetes Care. 2011;34: 2015-2022.

Dapagliflozin Adjusted Mean Change from
Baselinein Blood Pressure in Phase III Studies
Dapagliflozin 10 mg Adjusted Mean Change (mm Hg)
Systolic blood pressure (mm Hg)
24-week monotherapy 1
Add-on to metformin 2
Add-on to sulfonylurea 3
-3.6
-5.1
-5.0
Diastolic blood pressure (mm Hg)
24-week monotherapy 1 -2.0
Add-on to metformin 2 -1.8
Add-on to sulfonylurea 3 -2.8
Statistical significance not reported.
1. Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. 2. Bailey CJ, et al. Lancet.
2010;375:2223-2233.
3. Strojek K, et al. Diabetes Obes Metab . 2011;13:928-938.

Plasma Lipid Changes in Pooled
Dapagliflozin Studies at 24 Weeks
HDL-C (n)
Mean BL (mg/dL)
Mean change
LDL-C (n)
Mean BL (mg/dL)
Mean change
TC (n)
Mean BL (mg/dL)
Mean change
TG (n)
Mean BL (mg/dL)
Mean change
FFA (n)
Mean BL (mg/dL)
Mean change
Dapagliflozin 5 mg
(n = 1145)
889
44.79
+6.5%
884
113.24
+0.6%
888
194.48
+1.1%
886
190.40
-3.2%
732
0.58
-0.5%
Dapagliflozin 10 mg
(n = 1193)
834
45.04
+5.5%
828
114.09
+2.7%
834
195.88
+1.4%
831
194.21
-5.4%
694
0.56
+1.2%
Placebo
(n = 1393)
990
44.54
+3.8%
985
114.72
-1.9%
989
195.22
-0.4%
984
187.46
-0.7%
838
0.56
-5.7%
Hardy E, et al. Presented at: ADA 2013. Chicago, Illinois. Abstract 1188-P.

Dapagliflozin Dosage and Administration
• Recommended starting dose is 5 mg daily, taken in the morning, with or without food
• Dosage can be increased to 10 mg daily in patients requiring additional glycemic control
• Assess renal function before initiating dapagliflozin. Do not initiate if eGFR
<60 mL/min/1.73 m 2
• Discontinue if eGFR persistently falls
<60 mL/min/1.73 m 2
Dapagliflozin PI. Bristol-Myers Squibb Company: Princeton, NJ. January 2014.

Empagliflozin Monotherapy Change
From Baseline at Week 12
(N = 406)
Regimen HbA1c (%)
FPG
(mmol/L) Body Weight (kg)
-0.75
Placebo (n = 82)
Empagliflozin (n = 244)
5 mg/d
10 mg/d
25 mg/d
Metformin (n = 80)
+0.1
-0.4*
-0.5*
-0.6*
+0.04
-1.29*
-1.61*
-1.72*
1000 QD
1000 BID -0.7*
* P <.0001 vs placebo. † P <.001 vs placebo.
Ferrannini E, et al. Diabetes Obes Metab . 2013;15:721 –728.
-1.66*
-1.81
-2.33*
-2.03*
-1.32
†

Empagliflozin Add-on to Metformin
Change from Baseline at Week 12
N = 495 (PBO = 71, EMPA = 353, SITA = 71 )
Regimen
Empagliflozin (n = 353)
HbA1c (%)* FPG mmol/l* Body Weight (kg)*
1 mg QD -0.24
a -6.5
-0.4
5 mg QD
10 mg QD
25 mg QD
50 mg QD
-0.39
c
-0.71
d
-0.70
d
-0.64
d
-20.6
-26.9
-31.6
-32.7
d d d d
-1.1
-1.6
-1.4
-1.7
b c b d
Sitagliptin (n = 71)
100 mg qd
(open label)
-0.58
d -17.5
b +0.3
*Placebo corrected. a. P <.05; b. P <.01; c. P <.001; d. P <.0001 vs placebo.
Rosenstock J, et al. Diabetes Obes Metab . 2013;15:1154 –1160.

Ipragliflozin Monotherapy
Change from Baseline in HbA1c at Week 12
N = 411 (PBO = 69, IPRA = 273, MET = 69)
Regimen
Ipragliflozin (n = 273)
12.5 mg/d
50 mg/d
150 mg/d
300 mg/d
Metformin (n = 69)
Initial 1000 mg/d;
1500 mg/d after 2 wk
Least Squares Mean
Difference from Placebo
-0.49%*
-0.65%*
-0.73%*
-0.81%*
-0.72%*
* P <.001 vs placebo.
†
P =.002 vs placebo (test for trend).
Fonseca VA, et al. J Diabetes Complications . 2013;27:268-273.
% Patients with
HbA1c <7.0%
20.0%
22.4%
23.5%
38.2%
34.8%
†
†
†
†

Ipragliflozin Monotherapy Change in
Body Weight from Baseline Weight at Week 12
Regimen
Ipragliflozin (n = 273)
12.5 mg/d
50 mg/d
150 mg/d
300 mg/d
Metformin (n = 69)
Initial 1000 mg/d;
1500 mg/d after 2 wk
LS Mean Difference from Placebo
* P = .006 vs placebo.
†
P <.001 vs placebo.
-0.50 kg
-0.66 kg
-1.08 kg*
-1.67 kg
+0.12 kg
†
Fonseca VA, et al. J Diabetes Complications. 2013;27:268-273.

Ipragliflozin
Changes from Baseline in 12-Week
Add-On to Metformin Study (N = 342)
Regimen
Placebo (n = 65)
Ipragliflozin (n = 272)
HbA1c (%)
-0.31
12.5 mg/d
50 mg/d
150 mg/d
300 mg/d
-0.53*
-0.65*
-0.72*
-0.79*
*P <.05, compared with placebo.
FPG (mmol/L) Body Weight (kg)
-0.06
-0.48
-0.47
-0.79*
-1.35*
-1.54*
-0.92
-2.10*
-1.99*
-2.21*
Wilding JPH, et al. Diabetes Obes Metab. 2013;15:403-409.

Adverse Events with SGLT-2 Inhibitors
• Genital/urinary tract infections
• Hypotension/hypovolemia/dehydration
• Elevated liver tests
• Cardiovascular effects

Incidence of Vulvovaginal Candidiasis in
Female Patients on Canagliflozin
(N = 215)
Placebo
(n = 34)
2.9%
Sitagliptin
(n = 27)
3.7%
Pooled
Canagliflozin
(n = 154)
10.4% Patients
Pooling all adverse event terms consistent with this event.
Statistical significance not reported.
An increase in vulvovaginal candidiasis in female patients was observed with canagliflozin
Nyirjesy P, et al. Curr Med Res Opin . 2012;28:1173-1178 .

Infections in the Setting of
Pharmacologically Induced Glucosuria in Women on Dapagliflozin
Short- and Long-Term Trials Combined
14.2
11.5
10.8
1.9
Placebo DAPA
10 mg
Placebo DAPA
10 mg
Genital Infections
Statistical significance not reported.
FDA Advisory Committee 19th July 2011:http://www.fda.gov.
Urinary Tract Infections

Infections in the Setting of
Pharmacologically Induced Glucosuria in Men on Dapagliflozin
Short- and Long-Term Trials Combined
4.9
4.5
3.0
0.3
Placebo DAPA
10 mg
Genital Infections
Statistical significance not reported.
FDA Advisory Committee 19th July 2011:http://www.fda.gov.
Placebo DAPA
10 mg
Urinary Tract Infections

Empagliflozin Genital Infections and Urinary Tract Infections (N = 495)
Genital Infections
(% Patients)
Urinary Tract Infections
(% Patients) Treatment Arm
Empaglifozin
1 mg
5 mg
10 mg
25 mg
50 mg
Total (n = 353)
Placebo (n = 71)
Sitagliptin (open-label) (n = 71)
—
—
—
—
—
4.0*
0
2.8
2.8
2.8
4.2
5.7
4.3
4.0*
2.8
4.2
*7 males, 7 females. Statistical significance not reported.
Rosenstock J et al. Diabetes Obes Metab . 2013 Aug 1. (Epub ahead of print)

SGLT-2 Inhibitors with Metformin
Genital Infections
Comparator Rate SGLT-2 Rate Agent
Dapagliflozin
24 weeks 1
52 weeks 2
102 weeks 3
Canagliflozin
12 weeks 4
Empagliflozin
12 weeks 5
*Placebo.
†
Glimepiride.
5*
3
†
5*
2*
0*
8%−13%
12%
12%−15%
3%−8%
4%
1. Bailey CJ, et al. Lancet . 2010;375:2223-2233. 2. Nauck M, et al. Diabetes Care . 2011;34: 2015-2022.
3. Bailey CJ, et al. BMC Med. 2013;11:43. 4. Rosenstock J, et al. Diabetes Care.
2012;35:1232-1238.
5. Rosenstock J, et al. Diabetes Obes Metab . 2013, Aug 1. (Epub ahead of print)

SGLT-2 Inhibitors with Metformin
Genital Infections
• Most events were mild to moderate
• Most resolved with conventional intervention
• Rarely led to study discontinuation

Urinary Tract Infections —
SGLT-2 Inhibitors with Metformin
(% Patients)
Agent
Dapafliglozin
24 weeks 1
52 weeks 2
102 weeks 3
Canafliglozin
12 weeks 4
Empagliflozin
12 weeks 5
*Placebo.
†
Glimepiride.
Comparator Rate
8*
6
8*
6*
3*
†
SGLT-2 Rate
4%−8%
11%
8%−13%
3%−9%
4%
1. Bailey CJ, et al. Lancet . 2010;375:2223-2233. 2. Nauck M, et al. Diabetes Care . 2011;34: 2015-2022.
3. Bailey CJ, et al. BMC Med . 2013;11:43. 4. Rosenstock J, et al. Diabetes Care. 2012;35: 1232-1238.
5. Rosenstock J, et al. Diabetes Obes Metab . 2013 Aug 1. (Epub ahead of print)

Urinary Tract Infections —
SGLT-2 Inhibitors with Metformin
• Occurrence of signs and symptoms suggestive of urinary tract infection was similar across treatments
• Reports indicate that urinary tract infections
– Were generally mild to moderate and not recurrent
– Responded to standard treatments
• Rarely led to discontinuation

Events of Hypotension/Hypovolaemia/Dehydration in Dapagliflozin Studies (N = 4545)
Placebo-Controlled Pool —Short-Term Period
Total Subjects with an event
Hypotension
Syncope
Dehydration
Urine flow decreased
Blood pressure decreased
Dapa 2.5 mg
(N = 814)
10 (1.2)
6 (0.7)
0
3 (0.4)
0
0
Number (%) of Patients
Dapa 5 mg
(N = 1145)
7 (0.6)
5 (0.4)
0
0
0
0
Orthostatic hypotension 1 (0.1) 2 (0.2)
Urine output decreased 1 (0.1) 0
Pooled data from placebo-controlled dapagliflozin studies.
Dapa 10 mg
(N = 1193)
9 (0.8)
5 (0.4)
2 (0.2)
1 (<0.1)
1 (<0.1)
0
0
0
Placebo
N = 1393
5 (0.4)
2 (0.1)
1 (<0.1)
0
0
1 (<0.1)
0
1 (<0.1)
FDA Advisory Committee 19th July 2011: http://www.fda.gov
.

Dapagliflozin —Proportion of Patients with
Elevated Liver Tests (N = 6272)
All Phase IIb and III Pool – Short-Term + Long-Term Treatment Period, 4MSU n/N (% of Patients)
All Dapagliflozin
N = 4310
All Control
N = 1962
ALT Elevation
>3x ULN
>5x ULN
>10x ULN
>20x ULN
Total Bilirubin Elevation
>2x ULN
Combined Elevations
AST or ALT >3x ULN and
Bilirubin >2x ULN within 14 days
62/4281 (1.4)
17/4281 (0.4)
4/4281 (0.1)
2/4281 (<0.1)
18/4281 (0.4)
5/4281 (0.1)
Bailey CJ, et al. BMC Med. 2013;11:43;
FDA Advisory Committee 19th July 2011: http://www.fda.gov
.
31/1943 (1.6)
11/1943 (0.6)
3/1943 (0.2)
1/1943 (0.1)
5/1942 (0.3)
3/1942 (0.2)

Summary of Ongoing Cardiovascular
Outcomes Trials with SGLT-2 Inhibitors
Name
Status
No. patients
Primary outcome
Estimated completion
Canagliflozin Dapagliflozin Empagliflozin
NCT-01032629 NCT-01730534 NCT-01131676
Ongoing Recruiting Ongoing
4330
Major cardiovascular
(CV) events,
CV death, nonfatal MI, nonfatal stroke
17,150
Time to CV death, MI, or ischemic stroke
7000
Time to CV death, nonfatal
MI, nonfatal stroke
June 2018 April 2019 March 2018 www.clinical
trials.gov. Accessed January 26, 2014.

Perspectives on SGLT-2 Inhibition
Potential Advantages
• Once daily administration
• Decreases FPG, PPG, A1c
• Weight loss (60g urine glucose
= 240 kcal/day = ½ lb/week)
• No/low risk of hypoglycemia
• Modest blood pressure lowering
• Effect independent of insulin secretion or insulin resistance
• Use complementary with other
T2D Rx?T1D,? Pre-diabetes?
• Potential for use in Type 1
Diabetes
Concerns
• Bacterial urinary tract infections
• Fungal genital infections
• May not be as effective in patients with renal impairment
• Transient initial period of dehydration, polyuria, thirst
• No known long-term effects on kidney and on CV outcomes
• Added cost to diabetes therapy

Conclusions
The Emerging Role of the Kidney in Diabetes Treatment —
SGLT-2 Inhibitors Address Unmet Needs
• Good efficacy in lowering A1C
– Equivalent to metformin or sulfonylurea
• No increased risk of hypoglycemia
• Weight loss
• Once-daily dosing, irrespective of meals
• Oral
• Effective in the full spectrum of patients
– Independent of background therapy
– Independent of duration of diabetes
• Safety/tolerability on par with other approved agents

Case Presentation
• Black male, 65 years old
• Diagnosed with type 2 diabetes mellitus
10 years ago
• Switched from oral antihyperglycemic agents
(pioglitazone, glimepiride, metformin) to insulin treatment (maintained on metformin and glimepiride)
1 year ago when he had an acute MI
• Gained ~10 pounds over the past year
• Had 2−3 episodes of mild hypoglycemia over the past year

Physical Examination
• Height: 5 ft, 7 in
• Body mass index: 33.9 kg/m 2
• Blood pressure: 125/75

Biochemistry
• Fasting plasma glucose: 130 mg/dL
• 2-hour plasma glucose: 210 mg/dL
• A1C: 9.2%
• Low-density lipoprotein cholesterol: 68 mg/dL
• High-density lipoprotein cholesterol: 41 mg/dL
• Triglycerides: 151 mg/dL
• Total cholesterol: 159 mg/dL
• Creatinine: 1.3 mg/dL
• Estimated glomerular filtration rate:
52 mL/min/1.73 m 2

Medications
• Metformin 1000 mg BID
• Glimepiride 4 mg BID
• Insulin glargine: Previously 30 U at bedtime uptitrated to 55 U at bedtime
• Aspirin 81 mg once daily
• Losartan 50 mg once daily
• Amlodipine 5 mg once daily
• Metoprolol succinate 200 mg
• Atorvastatin 80 mg

Determining HbA1C Goal
• In customizing treatment for this particular patient, what would be an appropriate
A1C goal?
• What patient factors would influence your decision?

Determining HbA1C Goal
• Factors indicating an A1C goal closer to 8% for this particular patient
– Cardiovascular comorbidity (previous acute MI)
– Long duration of disease
– Mild renal disease
– Propensity for hypoglycemia
• In contrast, a lower A1C goal would be appropriate for a newly diagnosed patient with no other complications

Treatment
• What should be the next step in managing this patient ’ s hyperglycemia?
– Increase basal insulin dose
– Add prandial insulin
– Add GLP-1 RA
– Add DPP-4 inhibitor
– Add SGLT-2 inhibitor
– Make no changes to treatment
• Why would this be your choice?

Treatment Considerations
• Insulin has already been uptitrated; increasing it further will increase the risk of hypoglycemia
• GLP-1 receptor agonist should lower insulin requirement and may help the patient to lose weight

Treatment Response
• Liraglutide added (0.6 mg uptitrated to 1.8 mg)
• Insulin glargine initiated reduced to 40 U but now uptitrated to 60 U
• 3 months later on his office visit his A1C is 8.3%

Further Treatment
• At this point, what would be your next step in attempting to reduce this patient ’ s HbA1c?
– Add DPP-4 inhibitor
– Add SGLT-2 inhibitor
– Make no changes to treatment
• Why would you choose this alternative?

Treatment Considerations
• The mechanism of action (MOA) of DPP-4 inhibitors is similar to that of GLP-1 receptor agonists
• SGLT-2 inhibitors have a different MOA and also result in weight loss

Treatment Response
• An SGLT-2 inhibitor was added. The patient ’ s insulin dose was decreased to 40 U but now titrated up to 60 U
• 6 months later at follow-up
– AIC 7.4
– No episodes of hypoglycemia since his last visit
– Weight loss of 3 pounds