Emerging Type 2 Diabetes Treatment: Novel Therapy SGLT-2 Inhibitors Mark E. Molitch, MD Professor of...

Emerging Type 2Diabetes Treatment:

Novel TherapySGLT-2 Inhibitors

Mark E. Molitch, MDProfessor of Medicine

Division of Endocrinology, Metabolism,and Molecular MedicineNorthwestern University

Feinberg School of MedicineChicago, Illinois

Major Therapeutic Targets in Type 2 Diabetes Mellitus (T2DM)

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.

Glucose absorption

Hepatic glucoseoverproduction

Insulinresistance

Pancreas

Muscle and fat

Liver

MetforminThiazolidinedionesGLP-1 agonistsDPP-4 inhibitors

SulfonylureasMeglitinidesGLP-1 agonistsDPP-4 inhibitors

ThiazolidinedionesMetformin

Alpha-glucosidase inhibitorsGLP-1 agonists

GutGlucose

reabsorption

Kidney

Beta-celldysfunction

Glucose level

SGLT-2 inhibitors

Normal Glomerular Filtration and Renal Glucose Transport

Glomerular Filtration

• 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

• 162 g glucose filtered/24 h1

– Urine glucose excretion = 0 because reabsorption occurs

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.

1.5 L/24-h volume100 mEq Na+/24 h0 g/24-h glucose

180 L/24 h25000 mEq Na+/24 h

Reabsorption

Artery

Afferent Efferent Filtration

Tubular system

Secretion

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.

Nair S, et al. J Clin Endocrinol Metab. 2010;95:34-42. Lee YJ, et al. Kidney Int. 2007;72:S27-S35.

Active (SGLT-2) and Passive (GLUT2) Glucose Transport in S1 Renal

Proximal Tubule Cells

Abbreviations: GLUT2, glucose transporter 2; SGLT-2, sodium glucose cotransporter 2.

InterstitiumTubular lumen

Na+

GlucoseSGLT-2

ATPasepumpNa+ K+

GLUT2Glucose

Apical membrane Basolateral membrane

Na+

GlucoseSGLT-2

Na+K+

Glucose GLUT2

ATPasepump

With permission from Marsenic O. Am J Kidney Dis. 2009;53:875-883.

600

400

200

0

0 200 400 600 800

Reabsorbed

ExcretedFiltered

“Splay”

Tm

Plasma Glucose (mg/dL)

Glu

cose

(m

g/m

in)

Renal Glucose Handling

Abbreviation: Tm, transport maximum.

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

• 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

0 60 1200

50

100

150

200

250

300

350

Placebo

Placebo + phlorizin

Pancreatectomized

Pancreatectomized + phlorizin

Time After Meal (min)

Pla

sma

Glu

cose

(m

g/d

L)

Response to Meal Tolerance Test

Rossetti L, et al. J Clin Invest. 1987;79:1510-1515.

*

*

*

*Significantly different from other groups.

SGLT-2 Inhibition IsSafe 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

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

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.

SGLT-2 Inhibitors in Phase III Development

Dapagliflozin

Phase III Study of Dapagliflozin in Treatment-Naive T2DM

Ferrannini E, et al. Diabetes Care. 2010;33:2217-2224.

2-week single-blind lead-in phase: diet and exercise + placebo

T2DM Age 18–77 yTx-naive N = 591

24-week, double-blind phase

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

Placebo n = 75

Dapagliflozin 10 mg QD PM n = 76

Dapagliflozin 2.5 mg QD AM n = 65

Dapagliflozin 10 mg QD AM n = 70

Dapagliflozin 5 mg QD AM n = 64

Dapagliflozin 2.5 mg QD PM n = 67

Dapagliflozin 5 mg QD PM n = 68

HbA1c 7%–10%n = 485

HbA1c 10.1%–12%

n = 74

n = 35

n = 39


Glycemic Control at Week 24


Placebo

Dap 2.5 AM

Dap 5 AM

Dap 10 AM

Dap 2.5 PM

Dap 5 PM

Dap 10 PM

0

0.5

1

1.5

2

2.5

3

3.5

HbA1c <10.1%

HbA1c ≥10.1%

Red

uct

ion

in H

bA

1c (

%)


Fasting Plasma Glucose Level


Placebo Dap 2.5 AM

Dap 5 AM Dap 10 AM Dap 2.5 PM

Dap 5 PM Dap 10 PM0

10

20

30

40

50

60

70

80

90

Red

uct

ion

in F

PG

(m

g/d

L)

HbA1c <10.1%

HbA1c ≥10.1%

Phase III Study of Dapagliflozin in Treatment-Naive T2DMEffect on Body Weight at Week 24


Red

uct

ion

in W

eig

ht

(kg

)

Placebo Dap 2.5 AM

Dap 5 AM Dap 10 AM

Dap 2.5 PM

Dap 5 PM Dap 10 PM0

0.5

1

1.5

2

2.5

3

3.5

4

HbA1c <10.1%

HbA1c ≥10.1%

Phase III 24-Wk Study of Dapagliflozin in T2DM Patients on Metformin

Bailey CJ, et al. Lancet. 2010;375:2223-2233.

Red

uct

ion

in H

bA

1c (

%)

†

*

Red

uct

ion

in F

PG

(m

g/d

L)

Dapagliflozin groups averaged 2.2–3.0 kg weight loss

N = 534

Placebo Dap 2.5 Dap 5 Dap 100

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

*P <.0002; †P <.0001; ‡P = .0019.

†


5

10

15

20

25

30

‡

†

†

Phase III 24-Wk Study of Dapagliflozin in T2DM Patients on Glimepiride

*Measured 2 h after ingestion of 75 g glucoseStrojek K, et al. 46th EASD; Sept 20-24, 2010. Abstract 870.

Red

uct

ion

in H

bA

1c (

%)

Red

uct

ion

in P

ost

pra

nd

ial

OG

TT

(m

g/d

L)*

Dapagliflozin groups averaged 1.18–2.26 kg weight loss

N = 597


0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9


5

10

15

20

25

30

35

40

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; DPP-4, 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

451 patients with T2DM

inadequately controlled on

metformin

Canagliflozin 50 mg QD n = 64


Placebo n = 65



Canagliflozin 300 mg BID n = 64

Sitagliptin 100 mg QD 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

Glycemic Control at Week 12

Can 50 QD

Can 100 QD

Can 200 QD

Can 300 QD

Can 300 BID

Sit 65 QD

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8


Pla

ceb

o-A

dju

sted

Red

uct

ion

in

Hb

A1c

(%

) vs

Bas

elin

e

Can 50 QD

Can 100 QD

Can 200 QD

Can 300 QD

Can 300 BID

Sit 65 QD

0

5

10

15

20

25

30

35

Pla

ceb

o-A

dju

sted

Red

uct

ion

in F

PG

(m

g/d

L)

vs B

asel

ine

P vs placebo ≤.001 for all groups P vs placebo ≤.001 for all groups

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 (dose-

dependent effect) Significant differences at all doses vs placebo

– Sitagliptin group gained 0.4 kg


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

Phase III Trials of CanagliflozinResults 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

80 patients with T2DM

BI10773 10 mg QD

BI10773 25 mg QD

Placebo

BI10773 100 mg QD


Heise T, et al. 70th ADA; June 25-29, 2010. Abstract 629-P.

Phase II Study of BI10773Effect on Glucose Levels

Placebo BI10773 10 mg

BI10773 25 mg

BI10773 100 mg

0

10

20

30

40

50

60

70

80

90

Heise T, et al. 70th ADA; June 25-29, 2010. Abstract 629-P.

Uri

nar

y G

luco

se E

xcre

tio

n (

g)

Placebo BI10773 10 mg

BI10773 25 mg

BI10773 100 mg

0

5

10

15

20

25

30

35

40

45

50

Red

uct

ion

in F

PG

(m

g/d

L)

Phase IIa Study of ASP1941 in T2DM

61 patients with T2DM:

either tx naive,on monotherapy,

or onlow-dose

combination therapy

ASP1941 50 mg QD n = 12

ASP1941 100 mg QD n = 12

Placebo n = 13

ASP1941 200 mg QD n = 12

ASP1941 300 mg QD n = 12

28-day, double-blind phase

Schwartz S, et al. 70th ADA; June 25-29, 2010. Abstract 0566-P.

2-wk washout

for patients already on treatment

Phase IIa Study of ASP1941 in T2DMEffects on Glucose Levels

Placebo

ASP 50

ASP 100

ASP 200

ASP 300

0

100

200

300

400

500

600

Schwartz S, et al. 70th ADA; June 25-29, 2010. Abstract 0566-P.

24-h

Uri

nar

y G

luco

se E

xcre

tio

n (

mm

ol)

Placebo

ASP 50

ASP 100

ASP 200

ASP 300

0

10

20

30

40

50

60

70

80

Red

uct

ion

in F

PG

(m

g/d

L)

*

**

†

*P <.001; †P <.005.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 StudiesResults 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 ASP1941Results 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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