1. Does SGLT-2 Inhibition Have a Role in the Management of Diabetes?
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

2. 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:

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

4. 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*
No glucose excreted
Bakris GL, et al. Kidney Int. 2009;75: Abdul-Ghani, et al. Endocr Rev. 2011;32:

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

6. 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:

7. 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

8. Renal Glucose Handling
Plasma Glucose Concentration (mg/dL)
300
200
100
Glucose Reabsorption and Excretion
180
Splay
Actual threshold
TmG
Reabsorption
Excretion
Theoretic threshold
Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14:

9. Renal Glucose Handling in Diabetes
Plasma Glucose Concentration (mg/dL)
300
200
100
Glucose Reabsorption and Excretion
240
Excretion
Reabsorption
TmG
De Fronzo RA, et al. Diabetes Care Epub ahead of print. 6/4/13.

10. Normalized Glucose Transport Levels
Glucose Transporter Protein and Activity in Human Renal Proximal Tubular Cells from the Urine of Patients with T2DM
Healthy
T2DM
Healthy
T2DM
Healthy
T2DM
2000
1000
1500
500 *
CPM
AMG Uptake
SGLT-2 *
Healthy
T2DM
GLUT2 * 2 4 6
Normalized Glucose Transport Levels
*P <.05
Abbreviations: AMG, methyl--D-[U-14C]-glucopyranoside; T2DM, type 2 diabetes mellitus. Rahmoune H, et al. Diabetes. 2005;54:

11. 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 increased1
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-[U-14C]-glucopyranoside.
1. Mogensen CE. Scand J Clin Lab Invest. 1971;

12. 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

13. Phlorizin—The “Prototype” SGLT InhibitorOH O 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.

14. Treatment of Diabetic Rats with Phlorizin Normalizes Plasma Glucose
Group 1
Group 2
Group 3
Group 4
Group 5
Fasting plasma glucose (mg/dL)
101
122
100 99
113
Fed plasma glucose (mg/dL)
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:

15. 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:E

16. 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:

17. 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.

18. “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

19. 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: Katsuno K, et al. J Pharmacol Exp Ther. 2007;320:

20. Renal Glucose Handling After SGLT-2 Inhibition
150
Diabetes Threshold
SGLT-2 Inhibition
100
Urinary Glucose Excretion
(g/day)
Normal
Threshold 50
This graph then summarizes the anticipated effect of 30 to 50% blockade of the proximal tubular glucose reabsorption capacity using chemicals that promote competitive inhibition of the SGLT-2 specific in the kidney.
Again, the y axis represents the rate of filtration, reabsorption and excretion of glucose by the kidney versus plasma glucose concentration in the x axis. The blockade shifts the curve to your left and the new threshold is reached when plasma glucose is at or around glucose. Thus, glucose is lost in the urine at a lower concentration level [Tm]. Note that the starting threshold is shown at a higher value since these are diabetic conditions. The selective inhibition of SGLT-2 lowers plasma glucose in an insulin-independent manner without the risk of hypoglycemia and accomplishes body weight loss due to an average urinary loss of calories per day.
100
200
300
400
Plasma Glucose (mg/dL)
Farber SJ, et al. J Clin Invest. 1951;30: Mogensen CE. Scand J Clin Lab Invest. 1971;28:
Silverman M, Turner RJ. Handbook of Physiology. In: Windhager EE, ed. Oxford University Press. 1992: Cersosimo E, et al. Diabetes. 2000;49: DeFronzo RA, et al. Endocr Pract. 2008;14: 20 20

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

22. Comparison of Selectivity of SGLT-2 Inhibitors
Selectivity SGLT-1/2 IC50
O-glycosides
Phlorizin
101
T-1095
301
Sergliflozin
~3001
Remogliflozin
~360 2
C-glycosides
Canagliflozin
2203
Dapagliflozin
>12001,3
Empagliflozin
>25003
1. Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14:
2. Fujimori Y, et al. J Pharmacol Exp Ther. 2008;327:
3. Grempler R, et al. Diabetes Obes Metab. 2012;14:83-90.

23. Clinical Efficacy with SGLT-2 Inhibitors
Canagliflozin
Dapagliflozin
Empagliflozin
Ipragliflozin

24. 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: (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:

25. Canagliflozin—Proportion of Subjects Reaching A1C Goals at Week 26
Placebo
(n = 192)
Canagliflozin 100 mg (n = 195)
Canagliflozin mg (n = 197)
A1c <7.0%
20.6%
44.5%*
62.4%*
A1c <6.5%†
5.3%
17.8%
28.4%
*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:

26. 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: mg/dL
CANA 300 mg/dL: mg/dL
Difference compared with placebo
CANA 100 mg: mg/dL (P <.001)
CANA 300 mg: 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:

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

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

29. CANA 100 mg Difference vs Placebo
Change in HbA1c with Canagliflozin in Subjects with T2DM and Stage 3 Chronic Kidney Disease (N = 2170)
Baseline eGFR mL/min/1.73m2
CANA 100 mg Difference vs Placebo
CANA 300 mg
Difference vs Placebo
≥30 and <60 (n = 1085)
-0.38%*
-0.47%*
≥45 and <60
(n = 721)
-0.47%
-0.52%
≥30 and <45
(n = 364)
-0.23%
-0.39%
Pooled analysis in patients with T2DM from placebo-controlled studies with eGFR ≥30 and <60 mL/min/1.73m2 (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 Abstract 73-LB. Chicago, Illinois.

30. 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 m2 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 m2
Assess renal function before initiating canagliflozin; do not initiate canagliflozin if eGFR is <45 mL/min/1.73 m2
Discontinue canagliflozin if eGFR falls below 45 mL/min/1.73 m2

31. Effect of Dapagliflozin on Renal Threshold for Glucose in Diabetes40
Glucose Excretion
Plasma Glucose Concentration (mg/dL)
300
180
100
240
Healthy (180 mg/dL)
T2DM +
dapagliflozin
(40 mg/dL)
Excretion
T2DM
(240 mg/dL)
De Fronzo R, et al. Diabetes Care. Epub ahead of print. 6/4/13.

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

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

34. 24-Hour Urinary Glucose/ Creatinine (g/g)
Dapagliflozin Adjusted Mean Urinary Glucose Excretion Changes from Baseline After 12 Weeks
24-Hour Urinary Glucose/ Creatinine (g/g)
DAPA 2.5 mg
32*
DAPA 5 mg
49*
DAPA 10 mg
51*
DAPA 20 mg
65*
DAPA 50 mg
60*
Placebo
-0.2
Metformin 1500 mg
-1.4
*P <.001 vs placebo at 12 weeks.
List JF, et al. Diabetes Care. 2009;32:

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

36. Change in HbA1c with Dapagliflozin Across 24-Week Studies
7.92
Mono- therapy
(N = 558)
8.06
Add-on to MET
(N = 546)
8.11
Add-on to SU
(N = 596)
8.38
Add-on to PIO
(N = 420)
Add-on to Insulin
(N = 807)
8.53
BL (%)
 HbA1c (%) with 95% CI
Urinary glucose:creatinine ratio results were also dose dependent across all Phase 3 studies
Placebo-corrected adjusted mean change at Week 24 for urinary glucose creatinine ranges
11.16 to 17.0 in the 2.5 mg groups; to 35.6 in the 5 mg groups; to 41.5 in the 10 mg groups
*P <.05 vs placebo.
Abbreviations: BL, baseline; MET, metformin; PIO, pioglitazone; SU, sulfonylurea.
FDA Advisory Committee 19th July 2011: 36 36

37. Dapagliflozin—Change in FPG at Week 24 Across Studies
Mono- therapy
(N = 558)
Add-on to MET
(N = 546)
Add-on to SU
(N = 596)
Add-on to PIO
(N = 420)
Add-on to Insulin
(N = 807)
162.7
163.3
172.9
164.8
BL (mg/dL)
177.6
1.1
0.5
 FPG (mg/dL) with 95% CI
(mmol/L)
-0.5
-1.1
-1.6
-21.7
-2.2
*P <.05 vs placebo.
Abbreviations: BL, baseline; MET, metformin; PIO, pioglitazone; SU, sulfonylurea.
FDA Advisory Committee 19th July 2011:

38. Change in HbA1c at 52 Weeks in Dapagliflozin vs Sulfonylurea Add-on to Metformin Study (N = 801)
Regimen
Baseline HbA1c
HbA1c Week 52
Dapagliflozin + metformin
(n = 400)
7.69%
-0.52%
Glipizide + metformin
(n = 401)
7.74%
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:

39. Change in HbA1c to 104 Weeks in Dapagliflozin vs Sulfonylurea Add-On to Metformin Study
Regimen
HbA1c Week 521
HbA1c Week 1042
Dapagliflozin + metformin (n = 400)
-0.52%
-0.32%
Glipizide + metformin
(n = 401)
-0.14%
1. Nauck K, et al. Diabetes Care. 2011;34: Del Prato S, et al. Presented at: EASD September 12-16, 2011 (presentation 852).

40. 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 kg/m2)
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 ( cm3, nominal P = .0084)
Subcutaneous adipose tissue by MRI ( cm3, nominal P = .0385)
Bolinder J, et al. J Clin Endocr Metab. 2012;97:

41. Adjusted Mean Change from Baseline (kg)
Dapagliflozin Adjusted Mean Change from Baseline in Body Weight in Phase III Studies
Dapagliflozin 10 mg
Adjusted Mean Change from Baseline (kg)
24-week monotherapy1
-3.2
Add-on to metformin2
-2.9*
Add-on to sulfonylurea3
-2.26*
Add-on to insulin (24 wk)4
-1.61*
Add-on to insulin (48 wk)4
Head to head5
Dapagliflozin + metformin vs
-3.4
Glipizide + metformin†
+1.4
*P <.001; †Difference between the two, -4.7 (P <.0001).
1. Ferrannini E, et al. Diabetes Care. 2010;33: Bailey CJ, et al. Lancet. 2010;375:
3. Strojek K, et al. Diabetes Obes Metab. 2011;13: Wilding J, et al. Ann Intern Med. 2012;156: Nauck MA, et al. Diabetes Care. 2011;34:

42. Adjusted Mean Change (mm Hg)
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 monotherapy1
-3.6
Add-on to metformin2
-5.1
Add-on to sulfonylurea3
-5.0
Diastolic blood pressure (mm Hg)
-2.0
-1.8
-2.8
Statistical significance not reported.
1. Ferrannini E, et al. Diabetes Care. 2010;33: Bailey CJ, et al. Lancet. 2010;375:
3. Strojek K, et al. Diabetes Obes Metab. 2011;13:

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

44. 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 m2
Discontinue if eGFR persistently falls <60 mL/min/1.73 m2
Dapagliflozin PI. Bristol-Myers Squibb Company: Princeton, NJ. January 2014.

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

46. Empagliflozin Add-on to Metformin Change from Baseline at Week 12 N = 495 (PBO = 71, EMPA = 353, SITA = 71)
Regimen
HbA1c (%)*
FPG mmol/l*
Body Weight (kg)*
Empagliflozin (n = 353)
1 mg QD
-0.24a
-6.5
-0.4
5 mg QD
-0.39c
-20.6d
-1.1b
10 mg QD
-0.71d
-26.9d
-1.6c
25 mg QD
-0.70d
-31.6d
-1.4b
50 mg QD
-0.64d
-32.7d
-1.7d
Sitagliptin (n = 71)
100 mg qd
(open label)
-0.58d
-17.5b
+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.

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

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

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

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

51. Incidence of Vulvovaginal Candidiasis in Female Patients on Canagliflozin (N = 215)
Placebo
(n = 34)
Sitagliptin
(n = 27)
Pooled Canagliflozin
(n = 154)
Patients
2.9%
3.7%
10.4%
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:

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

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

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

55. SGLT-2 Inhibitors with Metformin Genital Infections
Agent
Comparator Rate
SGLT-2 Rate
Dapagliflozin
24 weeks1 5*
8%−13%
52 weeks2 3†
12%
102 weeks3
12%−15%
Canagliflozin
12 weeks4 2*
3%−8%
Empagliflozin
12 weeks5 0* 4%
*Placebo. †Glimepiride.
1. Bailey CJ, et al. Lancet. 2010;375: Nauck M, et al. Diabetes Care. 2011;34:
3. Bailey CJ, et al. BMC Med. 2013;11: Rosenstock J, et al. Diabetes Care. 2012;35:
5. Rosenstock J, et al. Diabetes Obes Metab. 2013, Aug 1. (Epub ahead of print)

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

57. Urinary Tract Infections— SGLT-2 Inhibitors with Metformin (% Patients)
Agent
Comparator Rate
SGLT-2 Rate
Dapafliglozin
24 weeks1 8*
4%−8%
52 weeks2 6†
11%
102 weeks3
8%−13%
Canafliglozin
12 weeks4 6*
3%−9%
Empagliflozin
12 weeks5 3* 4%
*Placebo. †Glimepiride.
1. Bailey CJ, et al. Lancet. 2010;375: Nauck M, et al. Diabetes Care. 2011;34: Bailey CJ, et al. BMC Med. 2013;11: Rosenstock J, et al. Diabetes Care. 2012;35: Rosenstock J, et al. Diabetes Obes Metab Aug 1. (Epub ahead of print)

58. 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

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

60. 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
62/4281 (1.4)
17/4281 (0.4)
4/4281 (0.1)
2/4281 (<0.1)
31/1943 (1.6) 11/1943 (0.6)
3/1943 (0.2)
1/1943 (0.1)
Total Bilirubin Elevation
>2x ULN
18/4281 (0.4)
5/1942 (0.3)
Combined Elevations
AST or ALT >3x ULN and
Bilirubin >2x ULN within 14 days
5/4281 (0.1)
3/1942 (0.2)
Bailey CJ, et al. BMC Med. 2013;11:43;
FDA Advisory Committee 19th July 2011: 60

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

62. Perspectives on SGLT-2 Inhibition
Potential Advantages
Concerns
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
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

63. 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

64. 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

65. Physical Examination Height: 5 ft, 7 in Body mass index: 33.9 kg/m2
Blood pressure: 125/75

66. 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 m2

67. 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

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

69. 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

70. 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?

71. 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

72. 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%

73. 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?

74. 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

75. 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