Part 1 of 4

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

FastingFastingPlasma GlucosePlasma Glucose

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