program editors ralph anthony defronzo, md professor of medicine and chief of the diabetes division...

Program Editors

Ralph Anthony DeFronzo, MD Professor of Medicine and

Chief of the Diabetes Division

University of Texas Health

Science Center

Audie L. Murphy Memorial Veterans Hospital

San Antonio, Texas, USA

Jaime A. Davidson, MD President, Worldwide Initiative

for Diabetes Education

Clinical Professor of Internal Medicine

Division of Endocrinology

University of Texas Southwestern

Medical School

Dallas, Texas, USA

Jaime A. Davidson, MD President, Worldwide Initiative

for Diabetes Education

Clinical Professor of Internal Medicine

Division of Endocrinology

University of Texas Southwestern

Medical School

Dallas, Texas, USA

Faculty

Professor Rury HolmanProfessor of Diabetic Medicine

Honorary Consultant Physician

Diabetes Trials Unit

University of Oxford

Oxford, United Kingdom

Professor Stefano Del PratoProfessor of Endocrinology and Metabolism

School of Medicine

University of Pisa

Pisa, Italy

Professor Allan VaagChief Physician

Steno Diabetes Center

Gentofte, Denmark

SGLT2 InhibitionSGLT2 Inhibition

A Novel Treatment Strategy for Type 2 DiabetesA Novel Treatment Strategy for Type 2 Diabetes

The Ominous OctetThe Ominous Octet

Islet -cell

ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion

NeurotransmitterNeurotransmitterDysfunctionDysfunction

Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake

Islet -cell

IncreasedIncreasedGlucagon SecretionGlucagon SecretionIncreasedIncreasedGlucagon SecretionGlucagon Secretion

IncreasedIncreasedLipolysisLipolysisIncreasedIncreasedLipolysisLipolysis

Increased GlucoseIncreased GlucoseReabsorptionReabsorptionIncreased GlucoseIncreased GlucoseReabsorptionReabsorption

IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP

DecreasedDecreasedIncretin EffectIncretin Effect

DecreasedDecreasedIncretin EffectIncretin Effect

Renal Glucose Reabsorption Renal Glucose Reabsorption in Type 2 Diabetesin Type 2 Diabetes

• Sodium-glucose cotransporter 2 (SGLT2) plays a role in renal glucose reabsorption in proximal tubule

• Renal glucose reabsorption is increased in type 2 diabetes

• Selective inhibition of SGLT2 increases urinary glucose excretion, reducing blood glucose

Wright EM, et al. J Intern Med. 2007;261:32-43.

SGLT1SGLT1

(180 L/day) (900 mg/L)=162 g/day(180 L/day) (900 mg/L)=162 g/day

10%10%

GlucoseGlucose

No GlucoseNo Glucose

S1S1

S3S3

Renal Handling of GlucoseRenal Handling of Glucose

SGLT2

90%

GLUT2GLUT2 AMG UptakeAMG Uptake

NGT T2DM NGT T2DM

AMG=methyl--D-[U14C]-glucopyranoside; CPM=counts per minute.

Rahmoune H, et al. Diabetes. 2005;54:3427-3434.

SGLT2SGLT2

NGT T2DM0

2

6

8

0

500

1000

1500

2000

No

rmal

ized

Glu

cose

T

ran

spo

rter

Lev

els

CP

M

Increased Glucose Transporter Proteins Increased Glucose Transporter Proteins and Activity in Type 2 Diabetesand Activity in Type 2 Diabetes

P<0.05

4

P<0.05

P<0.05

5 mmol/L5 mmol/L

FastingFastingPlasma GlucosePlasma Glucose

MuscleMuscle

Normal Glucose HomeostasisNormal Glucose Homeostasis

FatFat

LiverLiver

PancreasPancreas


Pathophysiology of Type 2 DiabetesPathophysiology of Type 2 Diabetes

10 mmol/L10 mmol/L

Islet -cell

Impaired Insulin Impaired Insulin SecretionSecretionImpaired Insulin Impaired Insulin SecretionSecretion

Insulin Insulin ResistanceResistance

Increased Increased HGPHGP

5 mmol/L5 mmol/L

Rationale for SGLT2 InhibitorsRationale for SGLT2 Inhibitors

• Inhibit glucose reabsorption in the renal proximal tubule

• Resultant glucosuria leads to a decline in plasma glucose and reversal of glucotoxicity

• This therapy is simple and nonspecific

• Even patients with refractory type 2 diabetes are likely to respond



10 mmol/L10 mmol/L

Islet -cell




GlucosuriaGlucosuria



10 mmol/L10 mmol/L

Islet -cell




5 mmol/L5 mmol/L

GlucosuriaGlucosuria

SGLT1SGLT1

(180 L/day) (900 mg/L)=162 g/day(180 L/day) (900 mg/L)=162 g/day

10%10%

GlucoseGlucose

No GlucoseNo Glucose

S1S1

S3S3

Renal Handling of GlucoseRenal Handling of Glucose

SGLT2

90%

Sodium-Glucose CotransportersSodium-Glucose Cotransporters

SGLT1 SGLT2

SiteSite Intestine, kidney Kidney

Sugar specificitySugar specificity Glucose or galactose Glucose

Glucose affinityGlucose affinityHigh

Km=0.4 mM

Low

Km=2 mM

Glucose transport Glucose transport capacitycapacity

Low High

RoleRole

Dietary absorption of glucose and galactose

Renal glucose reabsorption

Renal glucose reabsorption

Major transporter of glucose in the kidney• Low affinity, high capacity for glucose• Nearly exclusively expressed in the kidney• Responsible for ~90% of renal glucose reabsorption in the proximal tubule

Hediger MA, Rhoads DB. Physiol. Rev. 1994;74:993-1026.

S1 Proximal Tubule

NaNa++

K+

AT

Pase

Glucose

GLUT2

Glucose

SGLT2

BloodBloodLumenLumen

Na+

SGLT2 Mediates GlucoseSGLT2 Mediates GlucoseReabsorption in the KidneyReabsorption in the Kidney

Plasma Glucose Concentration (mmol/L)

155

Glucose Reabsorptionand Excretion

Splay

Excre

tion

TmG

10

Actual Threshold

Reabso

rptio

n

Theoretical threshold

Renal Glucose HandlingRenal Glucose Handling

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

Effect of Phlorizin on Insulin Sensitivity Effect of Phlorizin on Insulin Sensitivity in Diabetic Rats: Study Designin Diabetic Rats: Study Design

Rat Rat GroupGroup

Pancreatectomy / Pancreatectomy / Diabetic StatusDiabetic Status PhlorizinPhlorizin Meal Tolerance TestMeal Tolerance Test

I (n=14)Sham

Control– +

II (n=19)90%

Diabetes– +

III (n=10)

90%

Diabetes+ +

IV (n=4)90%

Diabetes+ / –

10-12 days after discontinuation of

phlorizin

• Phlorizin treatment period: 4-5 weeks

• Diet was same for all groups; body weight was similar across groups at end of study

Fas

tin

g G

luco

se (

mm

ol/

L)

Diabetes +/-

Phlorizin

Diabetes +

Phlorizin

Diabetes

Control

*

Fed

Glu

cose

(m

mo

l/L

)

Diabetes +/-

Phlorizin

Diabetes +

Phlorizin

Diabetes

Control

*P<0.05 vs control and phlorizin. †P<0.001 vs control and phlorizin.Rossetti L, et al. J Clin Invest. 1987;79:1510-1515.

Effect of Phlorizin on Fed and Fasting Effect of Phlorizin on Fed and Fasting Plasma Glucose in Diabetic RatsPlasma Glucose in Diabetic Rats

†

†

0

5

10

15

20

0

2

4

6

8

Glucose Uptake

(mg/kg ∙ min)

*P<0.001 vs control and phlorizin.


Insulin-Mediated Glucose Uptake in DiabeticInsulin-Mediated Glucose Uptake in DiabeticRats Following Phlorizin TreatmentRats Following Phlorizin Treatment

Diabetes+/- Phlorizin

Diabetes+ Phlorizin

DiabetesControl20

25

30

35

40

**

Mechanism of Action of Mechanism of Action of SGLT2 InhibitorsSGLT2 Inhibitors

Inhibition of SGLT2 Reversal of glucotoxicity

Insulin sensitivity in muscle• ↑ GLUT4 translocation• ↑ Insulin signaling• Other

Insulin sensitivity in liver• ↓ Glucose- 6-phosphatase

Gluconeogenesis• Decreased Cori cycle• ↓ PEP carboxykinase

-Cell function

Effect of Phlorizin on Effect of Phlorizin on -Cell Function -Cell Function in Diabetic Rats: Study Designin Diabetic Rats: Study Design

Rat GroupRat Group Pancreactomy / Diabetic StatusPancreactomy / Diabetic Status PhlorizinPhlorizin

ISham

Control–

II90%

Diabetes–

III90%

Diabetes0.4 g/kg/day

• Sprague-Dawley male rats weighing 80-100 g

• Phlorizin treatment period: 3 weeks

• Arginine clamp (2 mM); hyperglycemic clamp (≥5.5 mmol/L)


First PhaseFirst Phase Second PhaseSecond Phase

Control ControlDiabetes+ Phlorizin

Diabetes+ Phlorizin

Diabetes Diabetes

6

0

4

*

*2

Plasma Insulin(ng/mL ∙ min / g

Pancreas)

Plasma Insulin Response to GlucosePlasma Insulin Response to Glucose

*P<0.001 vs control.


Starke A, et al. Proc Natl Acad Sci. 1985;82:1544-1546.

Glucagon (pg/mL)

Glucose Infusion Rate (mg/kg • min)

Diabetic +Phlorizin

Diabetic

-400

-200

0241612862

Plasma Glucagon Concentration in DiabeticPlasma Glucagon Concentration in DiabeticDogs Before and After PhlorizinDogs Before and After Phlorizin

Familial Renal Glucosuria: A Genetic Model of SGLT2 Inhibition

Familial Renal GlucosuriaFamilial Renal Glucosuria

PresentationPresentation• Glucosuria: 1-170 g/dayGlucosuria: 1-170 g/day

• AsymptomaticAsymptomatic

BloodBlood• Normal glucose concentration

• No hypoglycemia or hypovolemiaNo hypoglycemia or hypovolemia

Kidney / bladderKidney / bladder• No tubular dysfunction

• Normal histology and function

ComplicationsComplications

• No increased incidence of

– Chronic kidney disease

– Diabetes

– Urinary tract infection

Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882;Wright EM, et al. J Intern Med. 2007;261:32-43.

Familial Renal GlucosuriaFamilial Renal Glucosuria

Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882.


155

Glucose Reabsorption

10

Type A

Type B

NormalTheoretical

Observed

Analysis of SGLT2 Gene in Patients Analysis of SGLT2 Gene in Patients With Renal GlucosuriaWith Renal Glucosuria

Santer R, et al. J Am Soc Nephrol. 2003;14:2873-2882.

• 23 families analyzed for mutations• In 23 families, 21 different mutations were detected

in SGLT2• Cause of glucosuria in other 2 families remains

unknown

GLUT2GLUT2 AMG UptakeAMG Uptake

NGT T2DM NGT T2DM

Rahmoune H, et al. Diabetes. 2005;54:3427-3434.

SGLT2SGLT2

NGT T2DM0

2

6

8

0

500

1000

1500

2000

No

rmal

ized

Glu

cose

T

ran

spo

rter

Lev

els

CP

M

Increased Glucose Transporter Proteins Increased Glucose Transporter Proteins and Activity in Type 2 Diabetesand Activity in Type 2 Diabetes

P<0.05

4

P<0.05

P<0.05

• An adaptive response to conserve glucose (ie, for energy needs) becomes maladaptive in diabetes

• Moreover, the ability of the diabetic kidney to conserve glucose may be augmented in absolute terms by an increase in the renal reabsorption of glucose

ImplicationsImplications

SGLT2 Inhibitors for the Treatment SGLT2 Inhibitors for the Treatment of Type 2 Diabetesof Type 2 Diabetes

Effect of SGLT2 Inhibition on Effect of SGLT2 Inhibition on Renal Glucose HandlingRenal Glucose Handling


155

Glucose Reabsorptionand Excretion

Splay

Excre

tion

TmG

10

Actual Threshold

Reabso

rptio

n

Theoretical threshold

FPG (mg/dL)

Baseline Day 8 Day 15

Vehicle (n=6)0.01 mg/kg (n=6)0.1 mg/kg (n=6)1 mg/kg (n=6)10 mg/kg (n=6)

0

100

200

300

400

*P<0.05; †P<0.0001 vs vehicle. ZDF=Zucker diabetic fatty.

Han S, et al. Diabetes. 2008;57:1723-1729; Whaley J, et al. Diabetes. 2007;56(suppl 2). Abstract 0559-P.

Effects of SGLT2 on Fasting Effects of SGLT2 on Fasting Plasma Glucose in ZDF RatsPlasma Glucose in ZDF Rats

*

*

*

†

†* †

Hep

atic Glu

cose P

rod

uctio

n(m

g/kg

• min

)G

luco

se I

nfu

sio

n R

ate

(mg

/kg

• m

in)

0

1.0

2.0

3.0

4.0

0

2.0

4.0

6.0

8.0

CON DAPA CON DAPA

P<0.01

P<0.01

CON=controls; DAPA=dapagliflozin.

Han S, et al. Diabetes. 2008;57:1723-1729.

Effect SGLT2-I on Insulin-Stimulated Glucose Effect SGLT2-I on Insulin-Stimulated Glucose Disposal and Hepatic Glucose Disposal and Hepatic Glucose Production in ZDF RatsProduction in ZDF Rats

SGLT-2 Inhibitor GlucosuriaSGLT-2 Inhibitor GlucosuriaReduces HbAReduces HbA1c1c: A Dose-Ranging Trial: A Dose-Ranging Trial

Study designStudy design

• 12 week, double-blind, placebo-controlled12 week, double-blind, placebo-controlled

– Dapagliflozin: 2.5, 5, 10, 50 mg/dayDapagliflozin: 2.5, 5, 10, 50 mg/day

– Metformin XR: 1500 mg/dayMetformin XR: 1500 mg/day

– PlaceboPlacebo

PatientsPatients• 389 drug-naive T2DM patients

• HbA1c >7.0%

MeasurementsMeasurements • FPG, PPG, HbA1c

List JF, et al. Diabetes Care. 2009;32:650-657.

Baseline HbA1c (%) 7.7 8.0 8.0 7.8 7.9 7.7

All comparisons vs placebo; no statistical comparisons with metformin were made.

List JF, et al. Diabetes Care. 2008;2009;32:650-657.

P<0.01 P<0.01

P<0.01

Effect of Dapagliflozin on HbAEffect of Dapagliflozin on HbA1c1c

Δ HbA1c (%)

P<0.01 -1

-0.8

-0.6

-0.4

-0.2

0DAPA

2.5DAPA

5DAPA

10DAPA

50PBO MET MET

XRXR15001500

SGLT2-I: Glucosuric and SGLT2-I: Glucosuric and Metabolic EffectsMetabolic Effects

GlucosuriaGlucosuria ↑ 52-85 g/day52-85 g/day

FPGFPG ↓ 16-30 mg/dL

PPGPPG ↓ 23-29 mg/dL

Body weightBody weight ↓ 2.2-3.2 kg (↓ 2.5%-3.4%)

Urine volumeUrine volume ↑ 107-470 mL/day


Adverse Events With DapagliflozinAdverse Events With Dapagliflozin

PBO(n=54)

Met 1500 mg QD(n=56)

Dapa 2.5 mg QD(n=59)

Dapa 5 mg QD(n=58)

Dapa 10 mg QD(n=47)

Dapa 20 mg QD(n=59)

Dapa 50 mg QD(n=56)

Hypoglycemia, n (%)

2 (4) 5 (9) 4 (7) 6 (10) 3 (6) 4 (7) 4 (7)

UTIs, n (%) 3 (6) 5 (9) 3 (5) 5 (9) 5 (11) 7 (12) 5 (9)

Genital infection, n (%)

0 (0) 1 (2) 2 (3) 1 (2) 1 (2) 4 (7) 4 (7)

Hypotensive event, n (%)

1 (2) 2 (4) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2)

UTI=urinary tract infection.


• Highly specific for the kidney and SGLT2 transporter

• ~80% reduction in SGLT2 mRNA/protein in Sprague- Dawley rats, ZDF rats, and dogs without any effect on SGLT1

• Marked reduction in FPG, PPG, and HbA1c in all three species

• No changes in plasma or urine electrolytes

Wancewicz EV, et al. Diabetes. 2008;57(suppl 2). Abstract 334-OR.

ISIS 388626 – A Specific SGLT2ISIS 388626 – A Specific SGLT2Antisense OligonucleotideAntisense Oligonucleotide

Unanswered Questions About Unanswered Questions About SGLT2 InhibitionSGLT2 Inhibition

DurabilityDurabilityThe efficacy of SGLT2 inhibition may wane once blood glucose falls into the normal range

Safety and Safety and tolerabilitytolerability

The long-term safety of this class remains to be proven

Risk of nocturia and genitourinary infections may limit use in some patients

Renal Renal impairmentimpairment

SGLT2 inhibition may not be effective in patients with renal impairment

SGLT2 Inhibition: Meeting UnmetSGLT2 Inhibition: Meeting UnmetNeeds in Diabetes CareNeeds in Diabetes Care

WeightManagement

Type 2Diabetes

Multiple Defects in Type 2

Diabetes

Adverse Effectsof Therapy

Hyperglycemia

CVD Risk(Lipid and

HypertensionControl)

Improvements inImprovements inGlucose and WeightGlucose and Weight

Support OtherSupport OtherCVD InterventionsCVD Interventions

ComplementsAction of Other

AntidiabeticAgents

PromotesPromotesWeight LossWeight Loss

Corrects a NovelCorrects a NovelPathophysiologicPathophysiologic

DefectDefectNo HypoglycemiaNo Hypoglycemia

ImprovesImprovesGlycemicGlycemicControlControl

ConclusionsConclusions

• SGLT2 inhibition represents a novel approach to the treatment of type 2 diabetes

• Studies in experimental models of diabetes have demonstrated that induction of glucosuria reverses glucotoxicity

– Restores normoglycemia– Improves -cell function and insulin sensitivity

ConclusionsConclusions

• Genetic mutations leading to renal glucosuria support the long-term safety of SGLT2 inhibition in humans

• Early results with dapagliflozin provide proof of concept of the efficacy of SGLT2 inhibition in reducing both fasting and postprandial plasma glucose concentrations in type 2 diabetes

Overall ConclusionsOverall Conclusions

• Understanding of the pathophysiology of type 2 diabetes is an evolving process

• As new concepts emerge, there is potential for new treatment modalities

• Optimal management of type 2 diabetes requires a multifaceted approach that targets multiple defects in glucose homeostasis

program editors ralph anthony defronzo, md professor of medicine and chief of the diabetes division...

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