Transcript Slides - Projects In Knowledge

Emerging Type 2
Diabetes Treatment:
Novel Therapy
SGLT-2 Inhibitors
Mark E. Molitch, MD
Professor of Medicine
Division of Endocrinology, Metabolism,
and Molecular Medicine
Northwestern University
Feinberg School of Medicine
Chicago, Illinois
Major Therapeutic Targets in Type 2
Diabetes Mellitus (T2DM)
Pancreas
Liver
Hepatic glucose
overproduction
Beta-cell
dysfunction
Sulfonylureas
Meglitinides
GLP-1 agonists
DPP-4 inhibitors
Muscle and fat
Metformin
Thiazolidinediones
GLP-1 agonists
DPP-4 inhibitors
Kidney
Glucose
reabsorption
Glucose level
Gut
Glucose
absorption
Insulin
resistance
Thiazolidinediones
Metformin
Alpha-glucosidase inhibitors
GLP-1 agonists
SGLT-2 inhibitors
DeFronzo RA. Ann Intern Med. 1999;131:281-303. Buse JB, et al. In: Williams Textbook of Endocrinology. 10th ed. WB
Saunders; 2003:1427-1483.
Normal Glomerular Filtration and
Renal Glucose Transport
Glomerular Filtration
Artery
• 125 mL of filtrate formed/min
(180 L/24 h)1
– Urine output 1.5 L/24 h
• 25000 mEq of Na+ filtered2
– Urine Na+ excretion
100 mEq/L
180 L/24 h
25000 mEq Na+/24 h
Efferent
Afferent
Filtration
Tubular system
• 162 g glucose filtered/24 h1
Reabsorption
– Urine glucose excretion = 0
because reabsorption occurs
Secretion
1.5 L/24-h volume
100 mEq Na+/24 h
0 g/24-h glucose
1. Abdul-Ghani M, et al. Endocr Pract. 2008;14:782-790. 2. Mount DB, et al. In: Brenner and Rector’s The Kidney. 8th ed.
Elsevier Saunders; 2007:156-200.
Renal Glucose Transport
• GLUTs
– Facilitative or passive transporters, work along a glucose gradient
– Expressed in all cells—GLUT2 in kidney
• SGLTs
– Active transport across membranes on lumenal side of cell using the Na+
gradient produced by Na+/K+ ATPase pumps
– SGLT-2
 S1 and S2 segments of proximal convoluted tubule
 Low affinity but high capacity for glucose
 Responsible for 90% of tubular reabsorption of glucose
– SGLT-1
 S3 segment of proximal convoluted tubule
 Responsible for 10% of tubular reabsorption of glucose
Nair S, et al. J Clin Endocrinol Metab. 2010;95:34-42. Marsenic O. Am J Kidney Dis. 2009;53:875-883.
Active (SGLT-2) and Passive (GLUT2)
Glucose Transport in S1 Renal
Proximal Tubule Cells
Apical membrane
Na+
Glucose
SGLT-2
Basolateral membrane
Na+
Glucose
ATPase
pump
GLUT2
Interstitium
Tubular lumen
Na+
Na+
Glucose
K+
SGLT-2
Glucose
ATPase
pump
GLUT2
Abbreviations: GLUT2, glucose transporter 2; SGLT-2, sodium glucose cotransporter 2.
Nair S, et al. J Clin Endocrinol Metab. 2010;95:34-42. Lee YJ, et al. Kidney Int. 2007;72:S27-S35.
K+
Renal Glucose Handling
Filtered
40
0

Glucose (mg/min)
60
0
“Splay
”
20
0
Excreted
Reabsorbed
T
m
0
0
40
60
20
0
0
0
Plasma
Glucose (mg/dL)
Abbreviation: Tm, transport maximum.
With permission from Marsenic O. Am J Kidney Dis. 2009;53:875-883.
80
0
Rationale for SGLT-2 Inhibition in
Type 2 Diabetes
SGLT-2 Expression and Glucose
Uptake Are Increased in T2DM
• Human exfoliated proximal tubular epithelial cells (HEPTECs)
– Can be isolated from urine
– Express a variety of proximal tubular markers, including
SGLT-2
• In HEPTECs isolated from individuals with T2DM
– SGLT-2 levels are 3-fold higher than in individuals with
normal glucose tolerance (NGT)
– Renal glucose uptake is also 3-fold higher than with NGT
• Increases in renal glucose transport expression and activity
seem to be associated with T2DM
Rahmoune H, et al. Diabetes. 2005;54:3427-3434.
Phlorizin
• Nonselective SGLT-2 inhibitor1
• Development deterred by its other activities
– SGLT-1 inhibition—associated with GI effects/diarrhea2
– GLUT1 inhibition by active metabolite (phloretin)—may
affect glucose uptake in the GI tract1
• Effect in rodent diabetes model provided proof-of-concept
for SGLT as a therapeutic target in diabetes1
1. Chao EC, et al. Nat Rev. 2010;9:551-559. 2. Wright EM. J Intern Med. 2007;261:32-43.
Phlorizin as Proof-of-Concept for
SGLT Inhibition
Response to Meal Tolerance Test
Plasma Glucose (mg/dL)
350
*
300
*
250
Placebo
200
Placebo + phlorizin
150
*
Pancreatectomized
100
50
Pancreatectomized
+ phlorizin
0
0
60
120
Time After Meal (min)
• Phlorizin also restored fasting plasma glucose, fed plasma glucose, and glucose
uptake in pancreatectomized rats
• Glucosuria: 8–9 g/dL in phlorizin vs 0.7–0.8 g/dL in pancreatectomy groups
*Significantly
different from other groups.
Rossetti L, et al. J Clin Invest. 1987;79:1510-1515.
SGLT-2 Inhibition Is
Safe and Well Tolerated
• Familial renal glucosuria
– Rare kidney disorder associated with SGLT-2 gene mutations
– Absence of glucose reabsorption indicated by higher urinary
glucose excretion (1–170 g/d)
– Benign, with no corresponding kidney complications
• Intestinal glucose-galactose malabsorption
– Due to SGLT-1 gene mutations
– Severe diarrhea
■ Suggests major role for SGLT-1 in intestinal reabsorption
■ Corrected by removing glucose, galactose, and lactose from the diet
– Mild glucosuria consistent with minor SGLT-1 role in renal
reabsorption
Wright EM. J Intern Med. 2007;261:32-43.
SGLT-2 Inhibitors in Development
Oral SGLT-2 Inhibitors in Development
SGLT-2 Inhibitor
Development Phase
Dapagliflozin1
3
Canagliflozin1
3
BI107732
3
ASP19412
3
GSK1890751
2
R72011
2
TS-0713
2
CSG4524
2
LX42112
2/1*
ISIS 3886262
1
BI 448472
1
GSK16142352
1
Discontinued: YM543,5 AVE2268,1 T-1095,1 TS-033,1 remogliflozin,1 sergliflozin1
*LX4211 phase II efficacy study completed; phase I dosage forms study ongoing.
1. Patel AK, et al. Curr Diab Rep. 2010;10:101-107. 2. ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov. Accessed
on: October 2010. 3. Kakinuma H, et al. J Med Chem. 2010;53:3247-3261. 4. JAPIC Clinical Trials Information. Available at:
http://www.clinicaltrials.jp/user/showCteDetailE.jsp?japicId=JapicCTI-090859. Accessed on: November 8, 2010. 5. Astellas
pipeline. Available at: http://www.astellas.com/en/ir/library/pdf/4q2009_rd_en.pdf. Accessed on: November 9, 2010
SGLT-2 Inhibitors in Phase III
Development
Dapagliflozin
Phase III Study of Dapagliflozin in
Treatment-Naive T2DM
T2DM Age 18–77 y
Tx-naive N = 591
2-week single-blind lead-in phase:
diet and exercise + placebo
24-week, double-blind phase
Dapagliflozin 2.5 mg QD AM n = 65
HbA1c
10.1%–12%
n = 74
HbA1c
7%–10%
n = 485
Dapagliflozin 5 mg QD AM n = 64
n = 35
Dapagliflozin 10 mg QD AM n = 70
n = 39
Dapagliflozin 2.5 mg QD PM n = 67
Dapagliflozin 5 mg QD PM n = 68
Dapagliflozin 10 mg QD PM n = 76
Placebo n = 75
Open-label metformin was allowed for patients with fasting plasma glucose >270 mg/dL at
week 4, >240 mg/dL at week 8, or >200 mg/dL at weeks 12–24
Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224.
Phase III Study of Dapagliflozin in
Treatment-Naive T2DM
Reduction in HbA1c (%)
Glycemic Control at Week 24
3.5
3
HbA1c <10.1%
2.5
2
HbA1c ≥10.1%
1.5
1
0.5
0
Placebo Dap 2.5 Dap 5 Dap 10 Dap 2.5 Dap 5 Dap 10
AM
AM
AM
PM
PM
PM
Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224.
Phase III Study of Dapagliflozin in
Treatment-Naive T2DM
Reduction in FPG (mg/dL)
Fasting Plasma Glucose Level
90
80
70
60
50
40
30
20
10
0
HbA1c <10.1%
HbA1c ≥10.1%
Placebo Dap 2.5 AM Dap 5 AM Dap 10 AM Dap 2.5 PM Dap 5 PM Dap 10 PM
Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224.
Phase III Study of Dapagliflozin in
Treatment-Naive T2DM
Effect on Body Weight at Week 24
Reduction in Weight (kg)
HbA1c <10.1%
4
3.5
3
2.5
2
1.5
1
0.5
0
HbA1c ≥10.1%
Placebo
Dap 2.5
AM
Dap 5 AM Dap 10 AM Dap 2.5
PM
Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224.
Dap 5 PM Dap 10 PM
Phase III 24-Wk Study of Dapagliflozin
in T2DM Patients on Metformin
N = 534
30
0.9
Reduction in HbA1c (%)
0.7
†
†
Reduction in FPG (mg/dL)
†
0.8
*
0.6
0.5
0.4
0.3
0.2
25
†
20
‡
15
10
5
0.1
0
0
Placebo Dap 2.5
Dap 5
*P <.0002; †P <.0001; ‡P = .0019.
Bailey CJ, et al. Lancet. 2010;375:2223-2233.
Dap 10
Placebo Dap 2.5
Dap 5
Dap 10
Dapagliflozin groups averaged
2.2–3.0 kg weight loss
Phase III 24-Wk Study of Dapagliflozin
in T2DM Patients on Glimepiride
0.9
40
0.8
35
Reduction in Postprandial
OGTT (mg/dL)*
Reduction in HbA1c (%)
N = 597
0.7
0.6
0.5
0.4
0.3
0.2
30
25
20
15
10
5
0.1
0
0
Placebo Dap 2.5
Dap 5
Dap 10
*Measured 2 h after ingestion of 75 g glucose
Strojek K, et al. 46th EASD; Sept 20-24, 2010. Abstract 870.
Placebo Dap 2.5
Dap 5
Dap 10
Dapagliflozin groups averaged
1.18–2.26 kg weight loss
Dapagliflozin
Adverse Events
•
•
•
•
Nasopharyngitis (~3%–12%)
Diarrhea (~1%–10%)
Headache (~3%–15%)
Hypoglycemia (0%–3% in treatment-naive;
~2%–4% in patients on metformin, ~7%–8% in
patients on glimepiride)
• Urinary tract infection (~4%–15%)
• Genital infection (~3%–18%)
• Hypotensive events (0%–5%)
Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224. Bailey CJ, et al. Lancet. 2010;375:2223-2233. Strojek K, et al.
46th EASD; Sept 20-24, 2010. Abstract 870.
.
Additional Phase III Trials of
Dapagliflozin
Results Pending
• Add-on therapy
– To thiazolidinedione
– To DPP-4 inhibitor
– To insulin
• Special populations;
patients with T2DM and
– CVD
– CVD + hypertension
– Hypertension
inadequately controlled
on ACE inhibitor or ARB
– Moderate renal
impairment
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CVD, cardiovascular disease; DPP4, dipeptidyl peptidase-4.
ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov. Accessed on: November 2010.
SGLT-2 Inhibitors in Phase III
Development
Canagliflozin
Phase IIb Study of Canagliflozin Added
to Metformin in Patients with T2DM
12-week, double-blind phase
Canagliflozin 50 mg QD n = 64
Canagliflozin 100 mg QD n = 64
451 patients
with T2DM
inadequately
controlled on
metformin
Canagliflozin 200 mg QD n = 65
Canagliflozin 300 mg QD n = 64
Canagliflozin 300 mg BID n = 64
Sitagliptin 100 mg QD n = 65
Placebo n = 65
Rosenstock J, et al. 70th ADA; June 25-29, 2010. Abstract 77-OR.
Phase IIb Study of Canagliflozin in
T2DM Patients on Metformin
P vs placebo ≤.001 for all groups
Placebo-Adjusted Reduction in
HbA1c (%) vs Baseline
0.8
0.7
Placebo-Adjusted Reduction in FPG
(mg/dL) vs Baseline
Glycemic Control at Week 12
35
P vs placebo ≤.001 for all groups
30
0.6
25
0.5
20
0.4
15
0.3
10
0.2
0.1
0
Can Can
50 QD 100
QD
Can
200
QD
Can
300
QD
Can Sit 65
300 QD
BID
Rosenstock J, et al. 70th ADA; June 25-29, 2010. Abstract 77-OR.
5
0
Can Can
50 QD 100
QD
Can
200
QD
Can
300
QD
Can Sit 65
300 QD
BID
Phase IIb Study of Canagliflozin in
T2DM Patients on Metformin
Effect on Body Weight at Week 12
• Placebo-adjusted change in body weight
– Canagliflozin groups lost 1.3–2.3 kg (dosedependent effect)
 Significant differences at all doses vs placebo
– Sitagliptin group gained 0.4 kg
Rosenstock J, et al. 70th ADA; June 25-29, 2010. Abstract 77-OR.
Canagliflozin Added to Metformin
Adverse Effects
Canagliflozin
(All Doses)
Sitagliptin
Placebo
Genital infections
3%–8%
2%
2%
Urinary tract
infections
3%–9%
2%
6%
Hypoglycemia
0%–6%
5%
2%
No safety signals in laboratory abnormalities, echocardiogram, or vital signs
with canagliflozin
Rosenstock J, et al. 70th ADA; June 25-29, 2010. Abstract 77-OR.
Phase III Trials of Canagliflozin
Results Pending
•
•
•
•
•
•
•
Monotherapy
Add-on to metformin
Add-on to metformin and sulphonylurea
Add-on to metformin and pioglitazone
Patients with cardiovascular risk factors
Elderly patients
Patients with moderate renal impairment
ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov. Accessed on: November 2010.
Other SGLT-2 Inhibitors in Phase III
Development
BI10773 and ASP1941
Phase II Study of BI10773
4-week, double-blind phase
BI10773 10 mg QD
BI10773 25 mg QD
80 patients with
T2DM
BI10773 100 mg QD
Placebo
Heise T, et al. 70th ADA; June 25-29, 2010. Abstract 629-P.
Phase II Study of BI10773
90
50
80
45
Reduction in FPG (mg/dL)
Urinary Glucose Excretion (g)
Effect on Glucose Levels
70
60
50
40
30
20
40
35
30
25
20
15
10
10
5
0
0
Placebo BI10773 BI10773 BI10773
10 mg 25 mg 100 mg
Heise T, et al. 70th ADA; June 25-29, 2010. Abstract 629-P.
Placebo BI10773 BI10773 BI10773
10 mg 25 mg 100 mg
Phase IIa Study of ASP1941
in T2DM
28-day, double-blind phase
ASP1941 50 mg QD n = 12
61 patients with
T2DM:
either tx naive,
on monotherapy,
or on
low-dose
combination
therapy
2-wk
washout
for patients
already on
treatment
Schwartz S, et al. 70th ADA; June 25-29, 2010. Abstract 0566-P.
ASP1941 100 mg QD n = 12
ASP1941 200 mg QD n = 12
ASP1941 300 mg QD n = 12
Placebo n = 13
Effects on Glucose Levels
600
500
400
300
200
100
80
Reduction in FPG (mg/dL)
24-h Urinary Glucose Excretion (mmol)
Phase IIa Study of ASP1941 in T2DM
0
*P <.001; †P <.005.
Schwartz S, et al. 70th ADA; June 25-29, 2010. Abstract 0566-P.
*
70
60
50
*
*
†
40
30
20
10
0
Weight loss: 3.2–4.2 kg with
ASP1941, 1.8 kg with placebo
Most Frequent Adverse Events
BI107731
• Frequent urination
• Nasopharyngitis
• Constipation
• Headache
ASP19412
• Constipation
• Nausea
• Xerosis
• Headache
1. Heise T, et al. 70th ADA; June 25-29, 2010. Abstract 629-P. 2. Schwartz S, et al. 70th ADA; June 25-29, 2010. Abstract
0566-P.
BI10773 Phase III Studies
Results Pending
•
•
•
•
•
Monotherapy in treatment-naive T2DM
Monotherapy in T2DM pretreated with metformin
Add-on to metformin or metformin/sulfonylurea
Add-on to pioglitazone or pioglitazone/metformin
Add-on to usual care in patients at high
cardiovascular risk
• Add-on to pre-existing therapy in patients with renal
impairment
ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov. Accessed on November 2010.
Phase III Trials of ASP1941
Results Pending
• Monotherapy in Japanese patients with T2DM
• Add-on to metformin
• Add-on to thiazolidinedione
• Add-on to sulfonylurea
• Add-on to DPP-4 inhibitor
• Add-on to alpha-glucosidase inhibitor
ClinicalTrials.gov. Available at: http://www.clinicaltrials.gov. Accessed on November 2010.
Where Will SGLT-2 Inhibitor
Therapy Fit?
• Combination therapy
– Novel mechanism of action
– Complementary to available agents
• Second-line therapy
• Monotherapy
– Possibly in cases of metformin intolerance
• Use in T1DM and T2DM?
Summary
• SGLT-2 is a low-affinity high-capacity glucose
transporter located in the proximal tubule and is
responsible for 90% of glucose reabsorption
• Mutations in SGLT-2 transporter linked to hereditary
renal glycosuria, a benign condition
• Oral selective SGLT-2 inhibitors in development
reduce blood glucose levels by increasing renal
excretion of glucose
• Selective SGLT-2 inhibition results in loss of
200–300 kcal/d, associated with weight loss
• SGLT-2 inhibitors are generally well tolerated
Brooks AM, et al. Ann Pharmacother. 2009;43:1286-1293.
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