Program Editors Ralph Anthony DeFronzo, MD Professor of Medicine and Chief of the Diabetes Division University of Texas Health Science Center Audie L.

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

Educational Objectives

Upon completion of this activity, participants will be able to

• Name 5 current challenges for glycemic control in individuals with type 2 diabetes

• List the key physiologic, biochemical, and molecular events involved in the renal regulation of glucose metabolism

• Understand the effects of inhibiting glucose reuptake by the kidney in individuals with type 2 diabetes

Magnitude of the Diabetes EpidemicMagnitude of the Diabetes Epidemic

28.3 M40.5 M43.0%

16.2 M32.7 M102%

53.2 M64.164.1 M20%

67.0 M 99.4 M 48%

10.4 M18.7 M80%

46.5 M

80.3 M

M=million; AFR=Africa; EMME=Eastern Mediterranean and Middle East; EUR=Europe; NA=North America; SACA=South and Central America; SEA=South-East Asia; WP=Western Pacific.

International Diabetes Federation. Diabetes Atlas. 3rd ed. Available at: http://www.eatlas.idf.org/index.asp.

2007=246 M2025=380 M

WP24.5 M44.5 M82%

2007 2025

Global Projections for theGlobal Projections for theDiabetes Epidemic: 2007-2025Diabetes Epidemic: 2007-2025

Global Increase in Obesity

Overweight, BMI ≥25 kg/m2; obese, BMI >28 kg/m2 (Asian) or >30 kg/m2.

James WP. J Intern Med. 2008;263:336-352.

USAUSA

AustraliaAustraliaFinlandFinland

SwedenSwedenNorwayNorwayBrazilBrazilCubaCuba

JapanJapan

19701970 19751975 19801980 19851985 19901990 19951995 20002000 20052005

20022002 20072007 20152015

Obese 356 million 523 million 704 million

Overweight 1.4 billion 1.5 billion 2.3 billion

Increasing Problem of Obesity Increasing Problem of Obesity and Diabetes: United Statesand Diabetes: United States

*BMI ≥30 kg/m2.

Centers for Disease Control and Prevention. National diabetes fact sheet. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2008;Mokdad AH, et al. JAMA. 1999;282:1519-1522; Mokdad AH, et al. Diabetes Care. 2000;23:1278-1283; Ogden CL, et al. NCHS data brief no 1. Hyattsville, MD: National Center for Health Statistics, 2007.

Obesity*Obesity* DiabetesDiabetes

US Population

(%)6.5

10 20% increase

1998 2007

40 92% increase

1998 2006

Increasing Problem of Obesity Increasing Problem of Obesity and Diabetes: Mexicoand Diabetes: Mexico

ObesityObesity DiabetesDiabetes

Mexican Population

Aguilar-Salinas CA, et al. Am J Med. 2002;113:569-574; Aguilar-Salinas CA, et al. Diabetes Care. 2003;26:2021-2026; Sánchez-Castillo CP, et al. Public Health Nutr. 2005;8:53-60.

25.129.0

1993 2000

Men MenWomen Women

21% increase

17% increase

1993 2000

1991 1999-2000

Men MenWomen Women

169% increase

Increasing Problem of Obesity Increasing Problem of Obesity and Diabetes: Chinaand Diabetes: China

Obesity*Obesity* DiabetesDiabetes

Chinese Population

*Asian-specific obesity cut-point: BMI ≥28 kg/m2.

Gu D, et al. Diabetologia. 2003;46:1190-1198; Wildman RP, et al. Obesity (Silver Spring). 2008;16:1448-1453.

1994 2000-2001

120% increase

Increasing Problem of WeightIncreasing Problem of WeightGain and Diabetes: IndiaGain and Diabetes: India

Rural Indian Population

*BMI ≥25 kg/m2.

Ramachandran A, et al. Diabetologia. 2004;47:860-865.

Overweight*Overweight* DiabetesDiabetes

8 191% increase

1989 2003

20 750% increase

1989 2003

HyperglycemiaHyperglycemia

• Biochemical marker by which the diagnosis of diabetes is made

– Assessed with HbA1c, daily SMBG, and eAG

• Major and treatable risk factor for microvascular disease (DCCT, UKPDS 33 and 35)

• Independent and treatable risk factor for macrovascular disease (DCCT-EDIC, UKPDS 35 and 80)

• Self-perpetuating cause of diabetes

– Glucotoxicity → insulin resistance and impaired insulin secretion

eAG=estimated average glucose.SMBG=self-monitoring of blood glucose.

HbAHbA1c1c Is Correlated With Is Correlated With

Average GlucoseAverage Glucose

AG=average glucose.

Nathan DM, et al. Diabetes Care. 2008;31:1473-1478.

03 5 7 9 11 13 15

HbA1c (%)

Diabetes Report Card: HbADiabetes Report Card: HbA1c1c Levels Levels

in the United Statesin the United States

Hoerger TJ, et al. Diabetes Care. 2008;31:81-86.

Patients(%)

6.0-6.9

7.0-7.9

8.0-8.9

9.0-9.9>10.0

22%22%

35%35%

20%20%

11%11%

6%6%6%6%

NHANESNHANES1988-19941988-1994

Advances in Therapy, Advances in Therapy, but Falling Short of Goalsbut Falling Short of Goals

1980s1980s 1990s1990s 2000s 2000s

1c1c (

SU / InsulinSU / InsulinSU / InsulinSU / Insulin Metformin (1995)Metformin (1995)Metformin (1995)Metformin (1995) TZDs (1998)TZDs (1998)TZDs (1998)TZDs (1998) Incretins (2004)Incretins (2004)Incretins (2004)Incretins (2004)

Pre-DCCTPre-DCCT9.0%9.0%

FutureFuture6.0% ?6.0% ?

1997: ADA lowered T2DM diagnosis from

FPG ≥7.8 mmol/Lto ≥7.0 mmol/L

1997: ADA lowered T2DM diagnosis from

FPG ≥7.8 mmol/Lto ≥7.0 mmol/L

2003: ADA eliminated HbA1c “action point” of <8% from guidelines

SU=sulfonylurea; TZDs=thiazolidinediones; T2DM=type 2 diabetes.

Koro CE, et al. Diabetes Care. 2004;27:17-20; Hoerger TJ, et al. Diabetes Care. 2008;31:81-86.

2005: ADA added HbA1c goal of <6% for

“individual patients” to guidelines

2005: ADA added HbA1c goal of <6% for

“individual patients” to guidelines

General ADA Target: <7%

1998: UKPDS results published

2008: ACCORD, ADVANCE, VADT,

and UKPDS 80 published

2008: ACCORD, ADVANCE, VADT,

and UKPDS 80 published

2009: ADA added “less stringent” HbA1c goal for patients with

significant comorbidities or risk of hypoglycemia, or short life expectancy

2009: ADA added “less stringent” HbA1c goal for patients with

significant comorbidities or risk of hypoglycemia, or short life expectancy

WeightManagement

Type 2Diabetes

Multiple Defects in Type 2

Diabetes

Adverse Effectsof Therapy

Hyperglycemia

Unmet Needs in Diabetes CareUnmet Needs in Diabetes Care

CVD Risk(Lipid and

HypertensionControl)

Relationship Between Hyperglycemia and Relationship Between Hyperglycemia and Microvascular and Macrovascular ComplicationsMicrovascular and Macrovascular Complications

IGT (HbA1c=5.9%) IGT………..…7.9%

IGT (HbA1c=6.1%) T2DM………12.6%

Neuropathy (%)Neuropathy (%)

IGT………..…13%*

*Prevalence.

Diabetes Prevention Program Research Group. Diabet Med. 2007;24:137-144; Singleton JR, et al. Diabetes Care. 2001;24:1448-1453; Ziegler D, et al. Diabetes Care. 2008;31:464-469.

Diabetic Retinopathy (%)Diabetic Retinopathy (%)

Incidence of Microvascular Incidence of Microvascular Complications in IGTComplications in IGT

Diabetes Is a Cardiovascular DiseaseDiabetes Is a Cardiovascular DiseaseRisk EquivalentRisk Equivalent

DM=diabetes mellitus; MI=myocardial infarction.Haffner SM, et al. N Engl J Med. 1998;339:229-234.

7-Year Incidence Rate of MI

DiabeticDiabeticn=1059n=1059

P<0.001

18.8 20.2

DMNo MI

No DMMI

No DM No MI

NondiabeticNondiabeticn=1373n=1373

Microvascular Disease

5 6 7 8 9 10 11

Mean HbA1c (%)

Stratton IM, et al. BMJ. 2000;321:405-412.

Estimated 37% decrease in microvascular risk for each 1% decrement in HbA1c (P<0.0001)

Historic Rationale for Improving Glycemia: Historic Rationale for Improving Glycemia: Microvascular Risk ReductionMicrovascular Risk Reduction

Incidence per 1000 Person-

Years(%)

Stratton IM, et al. BMJ. 2000;321:405-412.

Macrovascular Disease

Estimated 14% decrease in myocardial infarction riskfor each 1% decrement in HbA1c (P<0.0001)

Less Strong Association Between Less Strong Association Between Hyperglycemia and Macrovascular Hyperglycemia and Macrovascular Risk in Type 2 DiabetesRisk in Type 2 Diabetes

Estimated 37% decrease in microvascular risk for each 1% decrement in HbA1c (P<0.0001)

5 6 7 8 9 10 11

Mean HbA1c (%)

Incidence per 1000 Person-

Years(%)

Optimizing Glycemia in Advanced Type 2Optimizing Glycemia in Advanced Type 2Diabetes Exerts Unclear Macrovascular BenefitDiabetes Exerts Unclear Macrovascular Benefit

ACCORD Study Group. N Engl J Med. 2008;358:2545-2559; ADVANCE Collaborative Group.N Engl J Med. 2008;358:2560-2572; Duckworth W, et al. N Engl J Med. 2009;360:129-139.

EndpointHbA1c (%)

Primary EndpointMacro

P=0.37

↓10%

P=0.16

Intensive therapy

Conventional therapy

ADVANCEADVANCEN=11,140N=11,140

ACCORACCORDD

N=10,251N=10,251

VADTVADTN=1791N=1791

↓13%

P=0.12

-13-15

Lasting Benefits of Early, Intensive Intervention: UKPDS “Legacy” Effect

P=0.029

P=0.040

P=0.0099

P=0.001

P=0.052

P=0.014

P=0.44

P=0.007

Any Diabetes Endpoint

Myocardial Infarction

All-cause Mortality

Holman RR, et al. N Engl J Med. 2008;359:1577-1589; UKPDS Study Group. Lancet. 1998;352:837-853.

ACCORD Study Group. N Engl J Med. 2008;358:2545-2559; ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572; Duckworth W, et al. N Engl J Med. 2009;360:129-139; Holman RR, et al. N Engl J Med. 2008;359:1577-1589.

Early vs Late Intervention in Type 2 Diabetes

TrialTrialIntensive ArmIntensive Arm

HbAHbA1c1c Reduction ReductionNo Patients / No Patients / Trial DurationTrial Duration Disease SeverityDisease Severity MacrovasculaMacrovascula

r Benefitr Benefit

ACCORD

Goal: <6.0%

Endpoint: 6.4%

↓1.4% from BL in 4 months

N=10,251

3.4 yr

CVD or 2 risk factors

10 yr from T2DM diagnosis

NoADVANCE

Goal: <6.5%

Endpoint: 6.5%

N=11,140

5.0 yr

Vascular disease or 1 risk factor

Goal: ↓1.5% vs standard

Endpoint: 6.9%

N=1791

5.6 yr

UKPDS 80

Goal: FPG <6.0 mmol/L (108 mg/dL)

Intervention endpoint: 7.0%

Follow-up: 7.7%

N=4209

Newly diagnosed with T2DM

Steno-2: Time to Cardiovascular EventsSteno-2: Time to Cardiovascular Events

Gaede P, et al. N Engl J Med. 2008;358:580-591.

0 2 4 6 8 10 12

Cumulative Incidence of

Any CV Event (%)

YearsNo. at RiskConventional 80 70 60 46 38 29 25 14Intensive 80 72 65 61 56 50 47 31

P<0.001

Conventional Treatment

Intensive Treatment

InterventionIntervention Follow-upFollow-up

Steno-2: Goal AttainmentSteno-2: Goal Attainment

BP=blood pressure.

Gaede P, et al. N Engl J Med. 2008;358:580-591.

HbA1c <6.5%

Cholesterol <175 mg/dL

Triglycerides <150 mg/dL

Systolic BP<130 mm Hg

Diastolic BP<80 mm Hg

P=0.31

P=0.35 P=0.005

P=0.27

P=0.14

Intensive therapy Conventional therapy

P=0.06

P<0.001

P=0.005P=0.001

P=0.21

Etiology of Type 2 DiabetesEtiology of Type 2 Diabetes

Insulin Resistance and -Cell DysfunctionInsulin Resistance and -Cell Dysfunction

Etiology of Type 2 DiabetesEtiology of Type 2 Diabetes

Primary PredisposingFactors• Genes• Adverse intrauterine

environment

Tertiary AcceleratingFactors • Glucose and lipid toxicity

Secondary PrecipitatingFactors• Obesity• Low physical activity• Age• Smoking• Sleep disturbance• Other

Metabolic syndrome Hyperglycemia

Failing -cellFunctional -cell

Heine RJ, Spijkerman AM. 2006.

Insulin resistance Insulin resistance

Type 2 Diabetes: A HeterogeneousType 2 Diabetes: A HeterogeneousDisorderDisorder

Type 2 Diabetes: Insulin Resistance Type 2 Diabetes: Insulin Resistance Plus Impaired Plus Impaired -Cell Function-Cell Function

NormalNormal-cell -cell

functionfunction

Compensatoryhyperinsulinemia

Normoglycemia(Metabolic syndrome)

AbnormalAbnormal-cell -cell

functionfunction

Relative insulin deficiency

Hyperglycemia

Type 2 diabetes

Both insulin resistance and -cell dysfunction are present at the time of diagnosis of type 2 diabetes

InsulinInsulinresistanceresistance

DM=diabetes mellitus; IGT=impaired glucose tolerance; INS=insulin; NGT=normal glucose tolerance; OB=obesity. DeFronzo RA. Diabetes. 1988;37:667-687; Jallut D, et al. Metabolism. 1990;39:1068-1075.

Natural History of Type 2 DiabetesNatural History of Type 2 Diabetes

Insulin-MediatedGlucoseUptake(mg/m2 • min)

MeanPlasma Insulin

During OGTT(µU/mL)

MeanPlasma Glucose

During OGTT(mg/dL)

Lo INS

LeanNGT

Hi INS

OB-IGT

Etiology of Etiology of -Cell Dysfunction -Cell Dysfunction in Type 2 Diabetesin Type 2 Diabetes

Insulin Insulin ResistanceResistance

AgeAge

-Cell-CellDysfunctionDysfunction

GeneticsGenetics(TCF 7L2)(TCF 7L2)

LipotoxicityLipotoxicity↑ ↑ Free Fatty AcidsFree Fatty Acids

GlucoseGlucoseToxicityToxicity

Amyloid (Islet Amyloid (Islet Amyloid Amyloid Polypeptide)Polypeptide)DepositionDeposition

↓ ↓ IncretinIncretinEffectEffect

ββ-Cell failure occurs much-Cell failure occurs muchearlier in the natural history earlier in the natural history

of type 2 diabetes and is more of type 2 diabetes and is more severe than previously severe than previously

appreciatedappreciated

Natural History of Natural History of -Cell Dysfunction -Cell Dysfunction in Type 2 Diabetesin Type 2 Diabetes

San Antonio Metabolism andSan Antonio Metabolism andVAGES StudiesVAGES Studies

Normal glucose toleranceNormal glucose tolerance 318318Impaired glucose toleranceImpaired glucose tolerance 259259Type 2 diabetes 201

Subjects were classified asSubjects were classified as

NonobeseNonobese ifif BMI <30 kg/mBMI <30 kg/m22

ObeseObese ifif BMI ≥30 kg/mBMI ≥30 kg/m22

VAGES=Veterans Administration Genetic Epidemiology Study.

Abdul-Ghani MA, et al. Diabetes. 2006;55:1430-1435; Ferrannini E, et al. J Endocrinol Metab. 2005;90:493-500; Gastaldelli A, et al. Diabetologia. 2004;47:31-39.

Methods: OGTT and insulin clamp

SubjectsSubjects NumberNumber

NGT NGT

IGT IGT IGTIGT

T2DM T2DM

T2DMT2DM

Plasma Glucose and Insulin AUCPlasma Glucose and Insulin AUC

Gastaldelli A, et al. Diabetologia. 2004;47:31-39.

∆ I / ∆ G÷IR

2-Hour Plasma Glucose (mg/dL)

Insulin Secretion / Insulin Resistance Insulin Secretion / Insulin Resistance (Disposition) Index During OGTT(Disposition) Index During OGTT

G=glucose; I=insulin; IR=insulin resistance.

<120<14

IGTIGT

6.54.0 4.5 5.0 5.5 6.0

Ln ∆I / ∆G÷ IR

(mL/min • kgFFM)

Ln 2-Hour Plasma Glucose (mg/dL)

r=0.91P<0.00001

Log Normalization of the Relationship Between Log Normalization of the Relationship Between 2-Hour Plasma Glucose and Insulin Secretion / 2-Hour Plasma Glucose and Insulin Secretion / Insulin Resistance IndexInsulin Resistance Index

Ln=log normalization.

GENFIEV: Insulin Secretion as a GENFIEV: Insulin Secretion as a Function of Insulin SensitivityFunction of Insulin Sensitivity

HOMA-R=homeostasis model assessment index ratio.

Diabetes. 2006;55(suppl 2):A322.

<100 120 140 160 180 200 240 280 >280

Δ AUC C-peptide /

Δ AUCGlucose ÷ HOMA-R

Δ AUC C-peptide /

Δ AUCGlucose ÷ HOMA-R

2-Hour Plasma Glucose(mg/dL)

Trend test P<0.001

3 6 9 12

NFG/NGT IFG/NGT NFG/IGT IFG/IGT

NFG/DGT IFG/DGT DFG/IGT DFG/DGT

Plasma Glucose (mmol/L)

-1 . m

*P<0.01 vs NFG/NGT; §P<0.05 vs NFG/IGT and IFG/NGT; #P<0.05 vs IFG/IGT and NFG/DGT.

Diabetes. 2006;55(suppl 2):A2472.

GeNFIEV: Stimulus-response Curve (Proportional Control) of Insulin Secretion

GENFIEV: Stimulus-Response CurveGENFIEV: Stimulus-Response Curve(Proportional Control) of Insulin Secretion(Proportional Control) of Insulin Secretion

Insulin Secretion and Insulin Resistance Insulin Secretion and Insulin Resistance in Different Ethnic Populations With IGTin Different Ethnic Populations With IGT

AIR=acute insulin response to glucose.

Abdul-Ghani MA, et al. Diabetes Care. 2006;29:1130-1139.

Latino/HispanicPima Indian White

Insulinresistance ↑↑↑ ↑↑ ↑

Decrease in AIR Necessary to Convert From NGT to IGT

Insulin Resistance and Insulin Resistance and -Cell-CellDysfunction: SummaryDysfunction: Summary

• Individuals with impaired glucose tolerance

– Are maximally or near-maximally insulin resistant

– Have lost ~80% of their -cell function

– Have an incidence of diabetic retinopathy of ~10%

Pathogenesis of DiabetesPathogenesis of Diabetes

Evolving ConceptsEvolving Concepts

Pathogenesis of Type 2 DiabetesPathogenesis of Type 2 Diabetes

HGP=hepatic glucose production.

Islet -cell

ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion

IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP

Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake

HGP=hepatic glucose production.

Islet -cell

Time (minutes)

1st Phase 2nd Phase

i.v. Glucose

Diabetes

Normal glucose tolerance

0 5 10

Time (minutes)

1st Phase 2nd Phase

i.v. Glucose

Diabetes

Normal glucose tolerance

-5-10 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 10095

Adapted from Weyer C, et al. J Clin Invest. 1999;104:784-789; Ward WK, et al. Diabetes Care. 1984;7:491-502.

Islet -cell

DeFronzo RA, et al. Metabolism. 1989;38:387-395.

Islet -cell

FPG (mg/dL)

100 200 300

r = 0.85P<0.001

Control

FPG (mg/dL)

100 200 300

r=0.85P<0.001

Control

Islet -cell

DeFronzo RA, et al. J Clin Invest. 1979;63:939-946; DeFronzo RA, et al. J Clin Invest. 1985;76:149-155.

•min

P<0.01

P<0.05

t per m

Time (minutes)

180140

P<0.01

cose U

/kg leg

er min

Time (minutes)1801401006040

The Disharmonious QuartetThe Disharmonious Quartet

Islet -cell

Decreased GlucoseDecreased GlucoseUptakeUptake

↑ FFA↑ FFAIncreasedIncreasedLipolysisLipolysis

FFA=free fatty acids.FFA=free fatty acids.

FACoA FACoA

Gluconeogenesis Glucose Utilization

Lipolysis

Plasma FFA

Role of Free Fatty Acids Role of Free Fatty Acids HyperglycemiaHyperglycemia

MuscleMuscle LiverLiver

FACoA=FFA-derived long-chain acyl-CoA esters. Boden G. Proc Assoc Am Physicians. 1999;111:241-248.

IncreasedIncreasedLipolysisLipolysisIncreasedIncreasedLipolysisLipolysis

Free Fatty Acids Impair Free Fatty Acids Impair -Cell Function-Cell Function

*Percent difference between lipid infusion and saline infusionin subjects with family history of T2DM.

Kashyap S, et al. Diabetes. 2003;52:2461-2474.

Δ C-peptide Concentration

First PhaseFirst Phase Second PhaseSecond Phase

Hyperglycemic Clamp Procedure in NGT Individuals With Positive Family History of T2DM

P<0.001 P<0.04P<0.04

The Quintessential QuintetThe Quintessential Quintet

Islet -cell

DecreasedDecreasedIncretin EffectIncretin EffectDecreasedDecreasedIncretin EffectIncretin Effect

*P<0.05.GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

Jones IR, et al. Diabetologia. 1989;32:668-677; Toft-Nielsen MB, et al. J Clin Endocrinol Metab. 2001;86:3717-3723.

00 60 120 180 240

Time (min)

) * * * * ** *

Meal P<0.01

GIP Levels AreIncreased in T2DM

Time (min)

Postprandial GLP-1 Levels Are Decreased in Patients with

IGT and T2DM

GLP-1 and GIP Responses in GLP-1 and GIP Responses in Type 2 DiabetesType 2 Diabetes

NGT IGT T2DMNGT IGT T2DM

2100 60

-30 120 180

GLP-1, GIP, and Insulin AUC Across the Spectrum of Glucose Tolerance

Vaag AA, et al. Eur J Endocrinol. 1996;135:425-432.

P<0.00005

P<0.005

4 P<0.05

Controls NGT IGT T2DM

Controls NGT IGT T2DMControls NGT IGT T2DM

The Setaceous SextetThe Setaceous Sextet

Islet -cell

IncreasedIncreasedGlucagon SecretionGlucagon SecretionIncreasedIncreasedGlucagon SecretionGlucagon Secretion

DecreasedDecreasedIncretin EffectIncretin Effect

Islet -cell

Pancreatic Pancreatic -Cells and -Cells and -Cells in-Cells inNormal IndividualsNormal Individuals

Cabrera O, et al. PNAS. 2006;103:2334-2339; Cleaver O, et al. In: Joslin’s Diabetes Mellitus. Lippincott Williams & Wilkins; 2005:21-39.

-Cells-Cells -Cells-Cells

Endocrine massEndocrine mass ~50% ~35%

RoleRole Produce insulin and amylin Produce glucagon

Mechanism of Mechanism of actionaction

Secrete insulin in response to blood glucose elevations

Secrete glucagon in response to blood glucose decreases

Metabolic effectMetabolic effect

Permit glucose uptake by peripheral tissues

Suppress glucagon and HGP

Stimulate HGP to meet energy needs between

Control Type 2 Diabetes

P<0.05

Clark A, et al. Diabetes Res. 1988;9:151-159.

Area of Area of -Cells Is Increased in-Cells Is Increased inType 2 DiabetesType 2 Diabetes

-CellIslet Area

(n=10)(n=10) (n=15)(n=15)

SRIF=somatostatin infusion.

Baron A, et al. Diabetes. 1987;36:274-283.

/m2 •

P<0.001 P<0.001

T2DM+ SRIF

44% 58%

NGT T2DM NGT T2DM

Basal Glucagon Levels and Basal HepaticBasal Glucagon Levels and Basal HepaticGlucose Production in Type 2 DiabetesGlucose Production in Type 2 Diabetes

0 24 48 hr

Del Prato S, et al. J Clin Invest. 1987;79:547-556.

Hyperglucagonemia and Insulin-Hyperglucagonemia and Insulin-Mediated Glucose MetabolismMediated Glucose Metabolism

Inverse Relationship Between Insulin:Glucagon Inverse Relationship Between Insulin:Glucagon Ratio and Plasma Glucose in IGTRatio and Plasma Glucose in IGT

Yellow symbols=NGT; green symbols=IGT; circles=nonobese; squares=obese.

Mitrakou A, et al. N Engl J Med. 1992;326:22-29.

Peak Postprandial PlasmaGlucose Level (mmol/L)

Plasma Insulin:Glucagon Ratio

r=0.72P<0.0001

10 14 1550 10 20

r=-0.62P<0.001

Abnormal Meal-Related Insulin and Abnormal Meal-Related Insulin and Glucagon Dynamics in Type 2 DiabetesGlucagon Dynamics in Type 2 Diabetes

Glucose (mg %)

Insulin (µU/mL)

Glucagon (pg/mL)

Time (min)

Type 2 diabetes (n=12)

Normal subjects (n-=11)

-60 0 60 120 180 240

33030027024011080

140130120110100

1209060300

Delayed/depressedinsulin response

Nonsuppressed glucagon

Müller WA, et al. N Engl J Med. 1970;283:109-115.

The Septicidal SeptetThe Septicidal Septet

Increased GlucoseIncreased GlucoseReabsorptionReabsorptionIncreased GlucoseIncreased GlucoseReabsorptionReabsorption

Islet -cell

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

Renal Handling of GlucoseRenal Handling of Glucose

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

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

P<0.05

The Ominous OctetThe Ominous Octet

Islet -cell

NeurotransmitterNeurotransmitterDysfunctionDysfunction

Islet -cell

Increased GlucoseIncreased GlucoseReabsorptionReabsorptionIncreased GlucoseIncreased GlucoseReabsorptionReabsorption

Lower Posterior Hypothalamus

Obese Lean

P<0.01

Obese Lean

P<0.0112

Matsuda M, et al. Diabetes. 1999;48:1801-1806.

Altered Hypothalamic Function inAltered Hypothalamic Function inResponse to Glucose Ingestion inResponse to Glucose Ingestion inObese HumansObese Humans

1. Should be based upon known pathogenic abnormalities, and NOT simply on the reduction in HbA1c

2. Will require multiple drugs in combination to correct multiple pathophysiologic defects

3. Must be started early in the natural history of T2DM, if progressive -cell dysfunction is to be prevented

Treatment of Type 2 DiabetesTreatment of Type 2 Diabetes

DPP-4 InhibitorsSulfonylureas/Meglitinides

Treatment of Type 2 Diabetes: A SoundTreatment of Type 2 Diabetes: A SoundApproach Based Upon Its PathophysiologyApproach Based Upon Its Pathophysiology

MetforminTZDs

TZDsMetformin

GLP-1 analogues

Islet -cell

DPP-4=dipeptidyl peptidase-4.DPP-4=dipeptidyl peptidase-4.

0 3 6 9 12 15

UKPDS Group. Lancet. 1998;352:854-865.

Median HbA1c

UKPDS: Effect of Glibenclamide and UKPDS: Effect of Glibenclamide and Metformin Therapy on HbAMetformin Therapy on HbA1c1c

IDF Treatment

Goal:<6.5%

IDF Treatment

Goal:<6.5%

Conventional Glibenclamide MetforminConventional Glibenclamide Metformin

Kahn SE, et al. N Engl J Med. 2006;355:2427-2443.

ADOPT: Effect of Glyburide, Metformin, ADOPT: Effect of Glyburide, Metformin, and Rosiglitazone on HbAand Rosiglitazone on HbA1c1c

HbA1c (%)

IDF Treatment

Goal:<6.5%

IDF Treatment

Goal:<6.5%

00 1 2 3 4 5

-0.13% (P=0.002)

-0.42% (P<0.001)

Glyburide Metformin RosiglitazoneGlyburide Metformin Rosiglitazone

WeightManagement

Type 2Diabetes

Diabetes

Hyperglycemia

Unmet Needs in Diabetes CareUnmet Needs in Diabetes Care

CVD Risk(Lipid and

SGLT2 InhibitionSGLT2 Inhibition

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

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

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

Renal Handling of GlucoseRenal Handling of Glucose

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

Km=2 mM

Glucose transport Glucose transport capacitycapacity

Low High

RoleRole

Dietary absorption of glucose and galactose

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++

Glucose

BloodBloodLumenLumen

SGLT2 Mediates GlucoseSGLT2 Mediates GlucoseReabsorption in the KidneyReabsorption in the Kidney

Plasma Glucose Concentration (mmol/L)

Glucose Reabsorptionand Excretion

Actual Threshold

Reabso

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)

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

Diabetes +/-

Phlorizin

Diabetes +

Phlorizin

Diabetes

Control

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

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

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

Control–

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

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

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.

Glucose Reabsorption

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

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

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

Glucose Reabsorptionand Excretion

Actual Threshold

Reabso

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)

*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 Dapagliflozin on Fasting Effects of Dapagliflozin on Fasting Plasma Glucose in ZDF RatsPlasma Glucose in ZDF Rats

†* †

atic Glu

cose P

• min

CON DAPA CON DAPA

P<0.01

CON=controls; DAPA=dapagliflozin.

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

Effect of Dapagliflozin on Insulin-Stimulated Effect of Dapagliflozin on Insulin-Stimulated Glucose Disposal and Hepatic Glucose Glucose Disposal and Hepatic Glucose Production in ZDF RatsProduction in ZDF Rats

Dapagliflozin-Induced GlucosuriaDapagliflozin-Induced 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

2.5DAPA

10DAPA

50PBO MET MET

XRXR15001500

Dapagliflozin: Glucosuric and Dapagliflozin: 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.

Investigational SGLT2 InhibitorsInvestigational SGLT2 Inhibitors

AgentAgent ManufacturerManufacturer

Phase IIIPhase III DapagliflozinDapagliflozin AstraZeneca/Bristol-Myers Squibb

Phase IIPhase II AVE-2268 sanofi-aventis

BI 10773 Boehringer Ingelheim

JNJ-28431754 Johnson & Johnson

Remogliflozin

Sergliflozin

GSK/Kissei

TS-033 Taisho

YM-543 Astellas/Kotobuki Pharmaceuticals

Phase IPhase I CSG-452A Chugai/Roche

SAR-7226 sanofi-aventis

TA-7284 Mitsubishi Tanabe/Johnson & Johnson

• 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

Diabetes

Hyperglycemia

CVD Risk(Lipid and

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 University of Texas Health Science Center Audie L.

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