Transcript THE ROLE OF THE KIDNEY IN GLUCOSE HOMEOSTASIS

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
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
SGLT-1
SGLT-2
Intestine, kidney
Kidney
Sugar specificity
Glucose or
galactose
Glucose
Glucose affinity
High
Km = 0.4 mM
Low
Km = 2 mM
Low
High
Dietary absorption of
glucose and galactose
Renal glucose
reabsorption
Renal glucose
reabsorption
Site
Glucose transport capacity
Role
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
S1 proximal
tubule
Glucose
GLUT2
Glucose
Glucose
Na+
Na+
ATPase
K+
Na+
K+
Lumen
Blood
S3 proximal
tubule
Glucose
GLUT1
Glucose
Glucose
SGLT-1
Low capacity
High affinity
Na+
Bakris GL, et al. Kidney Int, 2009;75:1272-1277.
Na+
ATPase
K+
Na+
K+
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
Glucose Reabsorption
and Excretion
TmG
Splay
Actual
threshold
Theoretic threshold
100
180
200
Plasma Glucose Concentration (mg/dL)
Abdul-Ghani MA, DeFronzo RA. Endocr Pract. 2008;14:782-790.
300
Renal Glucose Handling in Diabetes
Glucose Reabsorption
and Excretion
TmG
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
T2DM
Healthy
T2DM
*
AMG
Uptake
GLUT2
SGLT-2
Healthy
Healthy
0
2
4
*
T2DM
*
T2DM
Healthy
6
Normalized Glucose
Transport Levels
0
500
1000
1500
2000
CPM
*P <.05
Abbreviations: AMG, methyl--D-[U-14C]-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 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;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 Glucose
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
Urinary Glucose Excretion
(g/day)
150
Diabetes Threshold
SGLT-2 Inhibition
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
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
Phase III
Ertugliflozin
Phase III
Comparison of Selectivity of
SGLT-2 Inhibitors
SGLT-2 Inhibitor
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;14:782-790.
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
Placebo
(n = 192)
Canagliflozin
100 mg
(n = 195)
Canagliflozin
300 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;15:372-382.
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)
Least square
mean change
from baseline
(mg/dL)
Placebo
CANA 100 mg
CANA 300 mg
+5.2
-42.9*
-58.8*
*P <.001 vs placebo.
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
(%)
Fasting Plasma
Glucose
(mg/dL)
Body
Weight
(kg)
-0.22
+3.6
-1.1
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*
-25.2*
-3.4*
300 mg QD
-0.95*
-23.4*
-3.4*
-0.74*
-12.6
-0.6
Placebo (n = 65)
Canagliflozin (n = 321)
Sitagliptin (n = 65)
100 mg QD
*P <.001 vs placebo.
Rosenstock J, et al. Diabetes Care. 2012;35:1232-1238.
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
≥30 and <60
(n = 1085)
-0.38%*
≥45 and <60
(n = 721)
-0.47%
≥30 and <45
(n = 364)
-0.23%
CANA 300 mg
Difference vs Placebo
-0.47%*
-0.52%
-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 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 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
http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/204042s000lbl.pdf
Effect of Dapagliflozin on Renal Threshold
for Glucose in Diabetes
Glucose Excretion
T2DM +
dapagliflozin
(40 mg/dL)
40
100
Healthy
(180 mg/dL)
180
240
Plasma Glucose Concentration (mg/dL)
De Fronzo R, et al. Diabetes Care. Epub ahead of print. 6/4/13.
T2DM
(240 mg/dL)
300
Dapagliflozin—Mean Changes from
Baseline After 12 Weeks (N = 389)
HbA1c
(%)
Fasting Plasma
Glucose
(mg/dL)
Body Weight
Reduction
(%)
-0.18
-6
-1.2
2.5 mg
-0.71
-16
-2.7
5 mg
-0.72
-19
-2.5
10 mg
-0.85
-21
-2.7
20 mg
-0.55
-24
-3.4
50 mg
-0.90
-31
-3.4
-0.73
-18
-1.7
Placebo (n = 54)
Dapagliflozin (n = 279)
Metformin (n = 56)
750−1500 mg
List JF, et al. Diabetes Care. 2009;32:650-657.
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;32:650-657.
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;32:650-657.
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
-0.53 (P <.0001)
Dapagliflozin + metformin vs metformin
-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.
Change in HbA1c with Dapagliflozin Across
24-Week Studies
Monotherapy
(N = 558)
7.92
BL (%)
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
-0.13
 HbA1c -0.4
(%) with
95% CI -0.6
-0.8
-1.0
-0.23
-0.42
-0.30
-0.58*
-0.58
-0.77*
-0.75*
0.63*
-0.67*
-0.70*
-0.84*
-0.82*
-0.89*
0.82*
-0.82*
0.90*
-0.97*
-1.2
Dapa 2.5 mg
-0.30
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.
Placebo
Dapagliflozin—Change in FPG at Week 24
Across Studies
Monotherapy
(N = 558)
BL (mg/dL) 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
 FPG (mg/dL) with 95% CI
1.1
0.5
0
-1.1
-21.7
-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.
(mmol/L)
-0.5
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%
-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
HbA1c Week 521
HbA1c Week 1042
Dapagliflozin + metformin
(n = 400)
-0.52%
-0.32%
Glipizide + metformin
(n = 401)
-0.52%
-0.14%
Regimen
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/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 (-258.4 cm3, nominal
P = .0084)
– Subcutaneous adipose tissue by MRI (-184.9 cm3, 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
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
-1.61*
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;33:2217-2224. 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 monotherapy1
-3.6
Add-on to metformin2
-5.1
Add-on to sulfonylurea3
-5.0
Diastolic blood pressure (mm Hg)
24-week monotherapy1
-2.0
Add-on to metformin2
-1.8
Add-on to sulfonylurea3
-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
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)
Mean BL (mg/dL)
Mean change
884
113.24
+0.6%
828
114.09
+2.7%
985
114.72
-1.9%
TC (n)
Mean BL (mg/dL)
Mean change
888
194.48
+1.1%
834
195.88
+1.4%
989
195.22
-0.4%
TG (n)
Mean BL (mg/dL)
Mean change
886
190.40
-3.2%
831
194.21
-5.4%
984
187.46
-0.7%
FFA (n)
Mean BL (mg/dL)
Mean change
732
0.58
-0.5%
694
0.56
+1.2%
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 m2
• Discontinue if eGFR persistently falls
<60 mL/min/1.73 m2
Dapagliflozin PI. Bristol-Myers Squibb Company: Princeton, NJ. January 2014.
Empagliflozin Monotherapy Change
From Baseline at Week 12
(N = 406)
HbA1c (%)
FPG
(mmol/L)
Body Weight (kg)
+0.1
+0.04
-0.75
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*
-0.7*
-1.66*
-1.32
Regimen
Placebo (n = 82)
Empagliflozin (n = 244)
Metformin (n = 80)
1000 QD
1000 BID
*P
<.0001 vs placebo. †P <.001 vs placebo.
Ferrannini E, et al. Diabetes Obes Metab. 2013;15:721–728.
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
-0.58d
-17.5b
+0.3
Sitagliptin (n = 71)
100 mg qd
(open label)
*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)
Least Squares Mean
Difference from Placebo
% Patients with
HbA1c <7.0%
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%†
-0.72%*
34.8%
Regimen
Ipragliflozin (n = 273)
Metformin (n = 69)
Initial 1000 mg/d;
1500 mg/d after 2 wk
*P <.001 vs placebo. †P =.002 vs placebo (test for trend).
Fonseca VA, et al. J Diabetes Complications. 2013;27:268-273.
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
*P = .006 vs placebo.
+0.12 kg
†P
<.001 vs placebo.
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
HbA1c (%)
FPG (mmol/L)
-0.31
-0.06
-0.48
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
-0.79*
-1.54*
-2.21*
Placebo (n = 65)
Body Weight (kg)
Ipragliflozin (n = 272)
*P <.05, compared with placebo.
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)
Patients
Placebo
(n = 34)
Sitagliptin
(n = 27)
Pooled
Canagliflozin
(n = 154)
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;28:1173-1178.
Infections in the Setting of
Pharmacologically Induced Glucosuria
in Women on Dapagliflozin
Short- and Long-Term Trials Combined
14.2
11.5
% Patients
10.8
1.9
Placebo
DAPA
10 mg
Genital Infections
Placebo
DAPA
10 mg
Urinary Tract Infections
Statistical significance not reported.
FDA Advisory Committee 19th July 2011:http://www.fda.gov.
Infections in the Setting of
Pharmacologically Induced Glucosuria
in Men on Dapagliflozin
% Patients
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)
1 mg
—
2.8
5 mg
—
2.8
10 mg
—
4.2
25 mg
—
5.7
50 mg
—
4.3
4.0*
4.0*
0
2.8
2.8
4.2
Treatment Arm
Empaglifozin
Total (n = 353)
Placebo (n = 71)
Sitagliptin (open-label) (n = 71)
*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
Agent
Comparator Rate
SGLT-2 Rate
Dapagliflozin
8%−13%
24 weeks1
5*
52 weeks2
3†
12%
102 weeks3
5*
12%−15%
2*
3%−8%
0*
4%
Canagliflozin
12 weeks4
Empagliflozin
12 weeks5
*Placebo. †Glimepiride.
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
Comparator Rate
SGLT-2 Rate
Dapafliglozin
24 weeks1
8*
4%−8%
52 weeks2
6†
11%
102 weeks3
8*
8%−13%
6*
3%−9%
3*
4%
Canafliglozin
12 weeks4
Empagliflozin
12 weeks5
*Placebo. †Glimepiride.
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
Number (%) of Patients
Dapa 2.5 mg
(N = 814)
Dapa 5 mg
(N = 1145)
Dapa 10 mg
(N = 1193)
Placebo
N = 1393
10 (1.2)
7 (0.6)
9 (0.8)
5 (0.4)
6 (0.7)
5 (0.4)
5 (0.4)
2 (0.1)
0
0
2 (0.2)
1 (<0.1)
3 (0.4)
0
1 (<0.1)
0
Urine flow decreased
0
0
1 (<0.1)
0
Blood pressure decreased
0
0
0
1 (<0.1)
Orthostatic hypotension
1 (0.1)
2 (0.2)
0
0
Urine output decreased
1 (0.1)
0
0
1 (<0.1)
Total Subjects with an event
Hypotension
Syncope
Dehydration
Pooled data from placebo-controlled dapagliflozin studies.
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
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)
5/4281 (0.1)
3/1942 (0.2)
Combined Elevations
AST or ALT >3x ULN and
Bilirubin >2x ULN within 14 days
Bailey CJ, et al. BMC Med. 2013;11:43;
FDA Advisory Committee 19th July 2011: http://www.fda.gov.
Summary of Ongoing Cardiovascular
Outcomes Trials with SGLT-2 Inhibitors
Canagliflozin
Dapagliflozin
Empagliflozin
Name
NCT-01032629
NCT-01730534
NCT-01131676
Status
Ongoing
Recruiting
Ongoing
4330
17,150
7000
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
June 2018
April 2019
No. patients
Primary
outcome
Estimated
completion
www.clinical trials.gov. Accessed January 26, 2014.
March 2018
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/m2
• 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 m2
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