TREATMENT OF T2DM: A SOUND APPROACH BASED UPON ITS PATHOPHYSIOLOGY

Ralph A. DeFronzo, MD Professor of Medicine Chief, Diabetes Division UTHSC, San Antonio, TX

THE TRIUMVIRATE
Impaired Insulin Secretion

Hyperglycemia Increased HGP

Decreased Glucose Uptake

NATURAL HISTORY OF BETA CELL FAILURE IN T2DM Beta cell failure occurs much earlier in the natural history of type 2 diabetes and is more severe than previously appreciated

SAN ANTONIO METABOLISM AND VAGES STUDIES

SUBJECTS NGT IGT T2DM

NUMBER 318 259 201

METHODS: OGTT and Insulin Clamp

Gastaldelli, Ferrannini, Abdul-Ghani, DeFronzo, Diabetologia 47:31-39, 2004; JCEM 90:493-500, 2005, Diabetes 55:1430-35, 2006

Glucose AUC (mmol/L120 min)

12 0 4 8

PLASMA GLUCOSE AND INSULIN AUC

IGT T2DM CON IGT T2DM <160 <180 <200 Q1 Q2 Q3 Q4 0 4 8

CON <160 <180 <200 Q1 Q2 Q3 Q4

Insulin AUC (pmol/L120 min)

12

INSULIN SECRETION / INSULIN RESISTANCE (DISPOSITION) INDEX DURING OGTT

40

INS/ GLU IR

30 20 10

Lean

Obese
0

2-Hour PG (mg/dl)

NGT

IGT

T2DM

Log Normalization of the Relationship Between 2-Hour Plasma Glucose and Insulin Secretion / Insulin Resistance Index
6
Ln I/ G IR (ml/min kgFFM)

4 2 0 -2 -4 4.0
r = 0.91 p < 0.00001

NGT IGT T2DM

4.5

5.0

5.5

6.0

6.5

Ln 2h-PG (mg/dl)

Log Normalization of the Relationship Between 2-Hour Plasma Glucose and Insulin Secretion / Insulin Resistance Index
6
Ln I/ G IR (ml/min kgFFM)

4 2 0 -2 -4 4.0
r = 0.91 p < 0.00001

NGT IGT T2DM

4.5

5.0

5.5

6.0

6.5

Ln 2h-PG (mg/dl)

FASTING PLASMA GLUCOSE (FPG) CONCENTRATION AND RELATIVE BETA CELL VOLUME IN OBESE SUBJECTS WITH NGT, IFG, & T2DM
250

FPG (mg/dl)

200 150 100 50

p<0.001 p<0.01

-cell Volume (%)

NGT

IFG
p<0.01

T2DM

4 3 2 1 0

p<0.001

NGT

IFG

T2DM

Butler et al, Diabetes 52:102-110,2003

INCIDENCE OF MICROVASCULAR COMPLICATIONS IN IGT

Diabetic Retinopathy (%): IGT (HbA1c = 5.9%) IGT (HbA1c = 6.1%) IGT7.9% T2DM12.6%

Diabetic Peripheral Neuropathy (%): Incidence in IGT5-10%

DPP Group, Diab Med 24:137-144, 2007 Diabetes Care 24:1148-53, 2001; 31:464-469, 2008

SUMMARY
Individuals with IGT:
Are maximally/near-maximally insulin resistant Have lost ~80% of their beta cell function (DeFronzo) Have lost significant beta cell mass (Butler) Have an incidence of diabetic retinopathy of ~10%

PREVENTION OF BETA CELL FAILURE IN T2DM

Must intervene early (IGT/IFG) Interventions should target pathogenic mechanisms known to promote beta cell failure and cause insulin resistance

THE HARMONIOUS QUARTET

Decreased Insulin Secretion Increased Lipolysis

E I L GOF D M T OY O T 2
I a e n i p r I l m d s n i u S c t n r i e o e n r e i l i I c s L o s a e d p y

H y r l ma p g y i e c e

e d r e c s n a G H P

c a Gc o e e d u e D r e l s s U p e k a t

E D

F 9 / 3 5 7 N

HYPERGLYCEMIA
Increased HGP
Decreased Glucose Uptake

THE DYSHARMONIOUS QUARTET

Decreased Insulin Secretion Increased Lipolysis

E I L G O F D M T O Y O T 2 a e n i p r I l m d s n i u S c t n r i e o e n r e i l i I c s L o s a e d p y

p g y i e c e H y r l m a

I
E D F 9 / 3 5 7 N

e d r e c s n a G H P

c a G c o e e e u e D r d l s s U t e k a p

HYPERGLYCEMIA
Increased HGP
Decreased Glucose Uptake

LIPOTOXICITY PLAYS A CENTRAL ROLE IN THE PATHOGENESIS OF T2DM

Impaired Insulin Secretion

Increased FFA
Increased HGP
Decreased Glucose Uptake
Kashyap et al, Diabetes 52:2461-68, 2003 Thiebaud et al, Metabolism 21:1128-36, 1982

QUINTESSENTIAL QUINTET
Decreased Incretin Effect Decreased Insulin Secretion Increased Lipolysis

HYPERGLYCEMIA
E O L Y F D I O O T M T G 2
r o i t e n I d n i l u s n I a e r c m e I S c p r i a d e s o p i L i s y l

H y r m a e l p g e i c y

H c n I

P s a e G r

c a u e e e l s D r G o t a p e U k s d c

F E D

9 / 3 5 7 N

Increased HGP

Decreased Glucose Uptake

INSULIN RESPONSES TO PHYSIOLOGICAL AND PHARMACOLOGICAL LEVELS OF GLP-1

Physiological GLP-1 levels1
(15 mM hyperglycemic clamp)

Pharmacological GLP-1 levels2

(15 mM hyperglycemic clamp)

6000 Insulin (pmol/L)

4000

Plasma GLP-1: 46 pM Healthy controls

Insulin (pmol/L)

GLP-1 infusion0.5 pmol/kg/min

6000

GLP-1 infusion1.0 pmol/kg/min

4000
Plasma GLP-1: 126 pmol/L Type 2 diabetes

2000

Plasma GLP-1: 41 pM Type 2 diabetes

2000

60 Time (min)

120

60 Time (min)

120

1. Adapted from Hjberg P et al. Diabetologia 2009;52:199207 2. Adapted from Vilsbll T et al. Diabetologia 2002;45:11111119

SETACEOUS SEXTET
Decreased Incretin Effect Decreased Insulin Secretion Increased Lipolysis

Islet cell

HYPERGLYCEMIA
E r o i t e n I d I L Y F O O O T T G n i l u s n I M D 2 m e I S c p r i a a e r c d e s o p i L i s y l H e p y c y l g r m a e i H c n I G r d P s a e c e D t p U s a e r u e l s G o d c e k a
F E D 9 / 3 5 7 N

Increased Glucagon Secretion

Increased HGP

Decreased Glucose Uptake

CONTRIBUTION OF BASAL GLUCAGON LEVELS TO THE MAINTENANCE OF BASAL HEPATIC GLUCOSE PRODUCTION IN TYPE 2 DIABETIC SUBJECTS
160 Basal HGP (mg/m2min) 120
P<0.001 P<0.001

250 200 150 100

Plasma Glucagon (pg/ml)

80 40 0

58% CON DIAB DIAB -SRIF BASAL CON DIAB

44% DIABSRIF

50 0

Baron et al, Diabetes 36:274-283, 1987

BASAL

SEPTICIDAL SEPTET
Decreased Incretin Effect Decreased Insulin Secretion Increased Lipolysis

Islet cell

HYPERGLYCEMIA
E r o i t e n I d I L Y F O O O T T G n i l u s n I M D 2 m e I S c p r i a a e r c d e s o p i L i s y l H e p y c y l g r m a e i H c n I G r d P s a e c e D t p U s a e r u e l s G o d c e k a
F E D 9 / 3 5 7 N

Increased Glucose Reabsorption

Increased Glucagon Secretion

Increased HGP

Decreased Glucose Uptake

INCREASED SGLT2 GLUCOSE TRANSPORTER mRNA AND PROTEIN LEVELS IN HUMAN RENAL PROXIMAL TUBULAR CELLS

SGLT 2 mRNA
5 4

SGLT 2 PROTEIN
6

AMG UPTAKE

*
Normalized Glucose Transporter Levels

* P<0.05-0.01

2000

1500 4 1000 CPM

Fold Increase

3 2 1 0

500 0

CON

T2DM

CON

T2DM

CON

T2DM

Rahmoune et al, Diabetes 54:3427-34, 2005

OMINOUS OCTET
Decreased Incretin Effect Decreased Insulin Secretion Islet cell Increased Lipolysis

HYPERGLYCEMIA
E O L Y F 2 T O O T D I G M
n r I c a e m a I l I p d u r e n i n i s c t e e S r o i n s p l d L s e o y i i

H y r m a e l p g e i c y

H c n I

G r P s a e

c a l s e e G o D r d c t e p k U a s u e

F E D

9 / 3 5 7 N

Increased Glucose Reabsorption

Increased Glucagon Secretion

Increased HGP Neurotransmitter Dysfunction

Decreased Glucose Uptake

TREATMENT OF T2DM
(1) Will require multiple drugs in combination to correct multiple pathophysiologic defects Should be based upon known pathogenic abnormalities, and NOT simply on the reduction in HBA1c Must be started early in the natural history of T2DM, if progressive beta cell failure is to be prevented

(2)

(3)

TREATMENT OF TYPE 2 DIABETES: A SOUND APPROACH BASED UPON ITS PATHOPHYSIOLOGY

Increased Lipolysis TZDs

Impaired Insulin Secretion

Metformin TZDs

TZDs GLP-1 analogues DPP-IV Inhibitors Sulfonylureas

Hyperglycemia

TZDs Metformin

Increased HGP

UKPDS: Effect of SU & Metformin Rx on HbA1c

9
Conventional

Median HBA1c (%)

Glibenclamide

6 0 0 3 6 9 12 15

UKPDS 352:837-853 and 853-865, 1998

Time (years)

UKPDS: Effect of SU & Metformin Rx on HbA1c

9
Conventional

Median HBA1c (%)

Glibenclamide

Metformin

6 0 0 3 6 9 12 15

UKPDS 352:837-853 and 853-865, 1998

Time (years)

UKPDS: Effect of SU & Metformin Rx on HbA1c

9
Glibenclamide Conventional

Median HbA1c (%)

Metformin

EXCESS GLYCEMIC BURDEN

6 0 0 3 6 9 12 15

UKPDS 352:837-853 and 853-865, 1998

Time (years)

DURABILITY OF GLYCEMIC CONTROL WITH SULFONYLUREAS

1
Change in HbA1c (%)
Glimepiride Glyburide SU
Alvarsson (n=39) Alvarsson (n=48) RECORD (n=272) Hanefeld (n=250) Charbonnel (n=313) UKPDS (n=1,573) Chicago (n=230) ADOPT (n=1,441) PERISCOPE (n=181) Tan (n=297)

Glyburide

Glyburide GLY SU Gliclazide

Glyburide

-1

Gliclazide

-2

TIME (years)

10

DURABILITY OF GLYCEMIC CONTROL WITH THIAZOLIDINEDIONES

1 Change in HbA1c (%)
Hanefeld (n=250) Charbonnel (n=317) PERISCOPE (n=178) RECORD (n=301) Chicago (n=232) ADOPT (n=1,456) Rosenstock (n=115) Tan (n=249)

PIO PIO ROSI PIO PIO

Rosiglitazone

-1

PIO

-2

TIME (years)

EFFECT OF THIAZOLIDINEDIONES ON INSULIN-MEDIATED GLUCOSE DISPOSAL

Miyazaki & DeFronzo, Diabetologia 44: 2210, 2001 Diabetes Care 24: 710, 2001

mg/kg FFMmin

10 8 6 4

NOGD

GOX
0

Before

PIO

ROSI

EFFECT OF TZD TREATMENT ON BETA CELL FUNCTION 61 type 2 diabetic subjects SUBJECTS: Age = 54 y BMI = 29.3 kg/m2 HbA1c = 8.6% FPG = 10.0 mM Double blind, randomized, placeboPROTOCOL: controlled, 4 months of treatment OGTT with insulin and C-peptide measurements (ISR) Euglycemic insulin (40 mU/m2.min) clamp
DeFronzo, Ferrannini, Gastaldeli (unpublished)

EFFECT OF TZD TREATMENT ON BETA CELL FUNCTION

TREATMENT GROUPS:
GROUP I: Drug nave + Placebo (n =14) GROUP II: Drug nave + PIO (n = 9) GROUP III: Drug nave + ROSI (n = 15) GROUP IV: Sulfonylurea + Placebo (n = 11) GROUP V: Sulfonylurea + PIO (n = 11)

EFFECT OF TZD AND PLACEBO TREATMENT ON ISR IN RELATIONSHIP TO INSULIN RESISTANCE

1 IR 2500 2000 1500 1000 500 0
Before Rx After Rx

* * *

ISR (AUC) Glucose (AUC)

THIAZOLIDINEDIONES AND PRESERVATION OF BETA CELL FUNCTION

Direct effect on the beta cell (PPAR) Amelioration of insulin resistance Reduction in plasma FFA (lipotoxicity) Mobilization of toxic lipid metabolites (FACoA, DAG, ceramides) out of the beta cell (lipotoxicity) Reversal of glucotoxicity

TZDs PREVENT THE PROGRESSION OF IGT TO T2DM

TRIPOD (52% ) PIPOD (62% ) DREAM (62% )

ACT NOW STUDY

ACTos NOW for the Prevention of Type 2 Diabetes Mellitus TOTAL NUMBER OF SUBJECTS SCREENED (n=1850)

ISOLATED IGT (n = 195) Placebo (n=299)

IGT* (n=602)

IGT + IFG (n = 407) Pioglitazone (n=303)

*Diagnosed with single OGTT (2-hour PG = 140-199 mg/dl)

TIME TO OCCURRENCE OF DIABETES (KAPLAN MEIER)

7.6% per year HR=0.28 95% CI = (0.16-0.49) P<0.00001

2.1% per year

EFFECT OF PIOGLITAZONE ON GLUCOSE TOLERANCE

IGT Placebo (n=299) Pioglitazone (n=303) P value T2DM IGT NGT

50 (7.6%)

84 (28%)

15 (2.1%) 127 (42%) <0.00001 <0.001

CHANGE IN BETA CELL FUNCTION (I/G X MATSUDA INDEX AND AIR x SI) IN RELATION TO CHANGE IN GLUCOSE TOLERANCE STATUS I0-120/G0-120 X Matsuda Index NGT

8 6 4

1400 1200 1000

AIR x SI
NGT

IGT

IGT DM

800 600 400

IGT

IGT

2 0

DM PRE POST

PRE

POST

RATE OF CHANGE: CAROTID INTIMAL MEDIA THICKNESS

12
P<0.05

m/year

Pioglitazone

Placebo

NUMBER NEEDED TO TREAT

18 IGT subjects need to be treated for one year to prevent the development of one case of T2DM

PROACTIVE
In high risk type 2 diabetics: To examine whether pioglitazone reduces total mortality and macrovascular morbidity 19 European Countries 5238 Type 2 Diabetics

PROACTIVE: NUMBER OF FIRST EVENTS CONTRIBUTING TO THE PRIMARY COMPOSITE ENDPOINT

Pioglitazone n=2605 Placebo 2633

Any endpoint Death Non-fatal MI (excluding silent) Silent MI Stroke Leg amputation ACS CABG/PCI Leg revascularization

514 110 85 20 76 9 42 101 71

572 122 95 23 96 15 63 101 57

PIOGLITAZONE REDUCES CARDIOVASCULAR EVENTS

PROACTIVE (n=5238): TIME TO DEATH, MI, OR STROKE
LANCET 366:1279-89,2005

CARDIOVASCULAR OUTCOMES FROM PIOGLITAZONE META-ANALYSIS OF CLINICAL TRIALS

FDA and Center for Drug Evaluation & Research; July 30,2007

Kaplan-Meier Event Rate

0.15

# Events

0.10 0.05 0

Plc 358 PIO 301

3 Year Estimate

Placebo HR = 0.06 0.84 0.04 Pioglitazone 0.02 P=0.027 0

14.4% 12.3%

Comparator (n = 5,203)

HR= 0.75 CI = 0.55-1.02 Pioglitazone (n = 5,944)

12 24 TIME (months)

36

40

80 120 TIME (weeks)

160

INCRETINS
In response to equivalent hyperglycemic stimuli, ORAL glucose elicits a greater insulin response than IV glucose

Glucagon-like Peptide 1 (GLP-1) and Glucose-Dependent Insulinotrophic Polypeptide (GIP) account for ~90% of the incretin effect

INCRETIN HORMONE PHYSIOLOGY

Gastric emptying

K-cells

L-cells

Satiety Fullness

GIP

Glucagon

GLP-1

Insulin

Glucose-Stimulated Secretion of Insulin

Glucose

SUR Potassium channel

GLUT2

Pancreatic Cell

Glucose

K+
ATP

GK

Pyruvate

ATP
TCA Cycle*

+ +

GLP-1 GIP

Calcium channel

AC

[Ca2+]

cAMP
Amplifying

Triggering

AC = adenylyl cyclase; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; GK = glucokinase; GLUT2 = glucose transporters; SUR = sulfonylurea receptor; *TCA = Tricarboxylic acid (Krebs cycle).

Insulin
Hinke SA, et al. J Physiol. 2004;558:369-380. Henquin JC. Diabetes. 2000;49:1751-1760. Henquin JC. Diabetes. 2004;53(suppl 3):S48-S58.

MOLECULAR ACTIONS OF GLP-1 ON BETA CELL

INSULIN SECRETION cAMP PKA Epac2 IC Ca++ PI-3K
Insulin Secretion

INSULIN GENE TRANSCRIPTION Pdx-1 replenishes beta cell insulin stores prevents beta cell exhaustion BETA CELL GLUCOSE SENSITIVITY increased GLUT2 and Glucokinase restores glucose responsitivity to resistant beta cells

GLP-1 ANALOGUES Exenatide Liraglutide

EXENATIDE AND LIRAGLUTIDE

Effectively reduce HbA1c Preserve beta cell function Promote weight loss Correct known pathophysiologic defects in T2DM Do not cause hypoglycemia Have an excellent safety profile

TIME COURSE OF EFFECT OF EXENATIDE ON HbA1c

0.5 0
Placebo

20

40

Time (weeks)
60

80

156

Baseline HbA1C=8.3%
Exenatide10 g bid DeFronzo et al, Diabetes Care 28:1092-1100, 2005 Data on file, Amylin Pharm

HbA1c (%)

-1.0

-2.0

Exenatide10 g bid

Placebo-Controlled Trials

Open-Label Extension

EFFECT OF EXENATIDE THERAPY ON POSTPRANDIAL GLUCOSE AND INSULIN CONCENTRATIONS

Evaluable Meal Tolerance Cohort
Plasma Glucose (mg/dL) - Week 0
Exenatide or Placebo

Plasma Glucose (mg/dL) - Week 30

Plasma Insulin (U/mL) - Week 30

250

250 200 150 100 -30 30 90 150 -30

10 g Exenatide

Placebo

45 30 15 0

200 50 00

Meal

30

90

150

-30 30

90 150

Time (min)

DECREMENT IN A1c IN PIVOTAL LIRAGLUTIDE (1.8 mg/d) TRIALS

LEAD 3 Mono RX LEAD 2 MET LEAD 1 SU LEAD 4 MET + TZD LEAD 5 MET + SU

51%

42%

42%

54%

53%

A1c (%)

-0.4 -0.8 -1.2 -1.6

-1.1 -1.0 -1.1 -1.3 -1.5

Percent Reaching A1c < 7.0%

A SINGLE DOSE OF LIRAGLUTIDE (7.5 / kg) RESTORES BETA CELL INSULIN RESPONSE TO HYPERGLYCEMIA IN T2DM PATIENTS
Chang et al, Diabetes 52:1786-91, 2003

Insulin Secretion Rate (pmol/min kg)

12

NGT Controls

8
T2DM (Lira)

4
T2DM (Placebo)

80

120

Glucose (mg/dl)

160

200

240

EXENATIDE AND LIRAGLUTIDE

Effectively reduce HbA1c Preserve beta cell function Promote weight loss Correct known pathophysiologic defects in T2DM Do not cause hypoglycemia Have an excellent safety profile

EFFECT OF EXENATIDE ON BODY WEIGHT

0 2 10 20 Time (wk) 30 40 50 60 70 80
215 lbs 220 lbs

90

Weight (lbs)

0 -2 -4 -6 -8 -10 -12
Placebo-Controlled Trials

Baseline Weight Placebo BID (N = 128) BYETTA 10 mcg BID (N = 137)

Open-Label Extension

EFFECT OF LIRAGLUTIDE ON BODY WEIGHT IN OBESE SUBJECTS WITH FPG <126 mg/dl
Subjects:
564 obese subjects (BMI = 30-40 kg/m2) Prediabetes (IGT/IFG) = 31% Metabolic Syndrome = 26% Placebo run-in (2 weeks) 20 weeks active therapy 500 calorie, low fat diet plus
placebo liraglutide (1.2, 1.8, 2.4, 3.0 mg/d) orlistat
Astrup A et al, Lancet 374:1606-16, 2009

Study Design:

EFFECT OF LIRAGLUTIDE THERAPY IN OBESE NONDIABETIC INDIVIDUALS >5% weight loss = 61% (placebo = 30%)* >10% weight loss = 19% (placebo = 9%)* weight loss was dose related

Prediabetes 84-96%* Metabolic syndrome 60%* Sys/diastolic BP 5.7/3.7 mmHg* HbA1c 0.14-0.24%*
Astrup A et al, Lancet 374:1606-16, 2009

*all p<0.01 vs placebo and orlistat

EXENATIDE AND LIRAGLUTIDE

Effectively reduce HbA1c Preserve beta cell function Promote weight loss Correct known pathophysiologic defects in T2DM Do not cause hypoglycemia Have an excellent safety profile

OMINOUS OCTET
Decreased Incretin Effect Decreased Insulin Secretion Islet cell Increased Lipolysis

HYPERGLYCEMIA
E O L Y F D I O O T M T G 2 n r I c a e m a I l I p d u r e n i n i s c t e e S r o i n s p l d L s e o y i i H y r m a e l p g e i c y H a c e n G I r d P s c a u s e e l o D r G c t d p a U e s k e
F E D 9 / 3 5 7 N

Increased Glucose Reabsorption

Increased Glucagon Secretion

Increased HGP Neurotransmitter Dysfunction

Decreased Glucose Uptake

EXENATIDE AND LIRAGLUTIDE

Effectively reduce HbA1c Preserve beta cell function Promote weight loss Correct known pathophysiologic defects in T2DM Do not cause hypoglycemia Have an excellent safety profile

CARDIOVASCULAR BENEFITS OF LIRAGLUTIDE/EXENATIDE Improves plasma lipid levels Reduces blood pressure Decreases hsCRP Decreases BNP Reduces infarct size (preclinical) Improves endothelial dysfunction

LIRAGLUTIDE REDUCES INFARCT SIZE AT 28 DAYS POSTMYOCARDIAL INFARCTION IN MICE

Noyan-Ashraf et al, Diabetes 58:975-83, 2009

40 30 Infarct (%) 20 10 0

P<0.05

Placebo

Liraglutide

DPP-4 INHIBITORS
EFFICACY AND MECHANISM OF ACTION

EFFECT OF SITAGLIPTIN ON HbA1c: CHANGE FROM BASELINE (HbA1c ~ 8.0%)

Diabetes Care 29:2638, 2006; Clin Ther 28:1556, 2006; Diabetolgia 49:2564, 2006

HbA1c(%)

-0.5

-0.60 -0.67 -0.85

-1.0

Drug Naive

Metformin

Pioglitazone

ADDITION OF SITAGLIPTIN TO

EFFECT OF VILDAGLIPTIN ON PLASMA GLUCOSE AND HORMONE LEVELS IN DIET-TREATED PATIENTS WITH T2DM
Ahren B et al., J Clin Endocrinol Metab 89:2078-84, 2004 275

Glucose

GLP-1

pmol/L

mg/dL

225

Placebo (n=19)

20

Vildagliptin

175

Vildagliptin (n=18)

10 Placebo 0 120

125 300

Insulin

Glucagon

pmol/L

pg/mL

200

Placebo Vildagliptin

100 Placebo 80 Vildagliptin

100

0
0 60 120

60
0 60 120
66

Time (min)

Time (min)

PLASMA GLP-1 CONCENTRATION OVER 24 HOURS FOLLOWING LIRAGLUTIDE AND VILDAGLIPTIN

Degn et al, Diabetes 53:1187-94, 2004: Mari et al , JCEM 90:4888-94, 2005

120
LIRA DOSE

GLP-1 (pmol/L)

90 60
VILDA DOSE

VILDA DOSE

30 0 8 12 16 Time (hours) 20 24

ADA/EASD ALGORITHM Lifestyle + Metformin

TIER 1
HbA1c > 7.0%
Add Basal Insulin Add Pioglitazone

TIER 2

Add Sulfonylurea

Add Exenatide

Add PIO, Exen, Basal Insulin

Intensify Insulin

Add SU or Basal Insulin

Add SU, PIO, Insulin

An American Diabetes Association consensus statement represents the authors collective analysis, evaluation, and opinion at the time of publication and does not represent official association opinion.
Diabetes Care 32:193-203, 2009

PATHOPHYSIOLOGIC-BASED (DEFRONZO) ALGORITHM

Lifestyle + TRIPLE COMBINATION: TZD + Metformin + Exenatide/Liraglutide HbA1c < 6.0%

RATIONALE FOR SGLT2 INHIBITOR THERAPY

NORMALIZATION OF THE PLASMA GLUCOSE CONCENTRATION INDEPENDENT OF THE MECHANISM IS A CORNERSTONE OF DIABETES MANAGEMENT

HYPERGLYCEMIA
Biochemical marker by which the diagnosis of diabetes is made Is responsible for microvascular complications (DCCT, UKPDS) and, to a lesser extent, macrovascular complications (EDIC) Is a self perpetuating cause of diabetes: glucotoxicity insulin resistance and impaired insulin secretion

SGLT2 INHIBITORS RATIONALE

Inhibit glucose reabsorption in the renal proximal tubule The resultant glucosuria leads to a decline in plasma glucose and reveral of glucotoxicity The beauty of the therapy resides in its simplicity and nonspecificity Even the most refractory to treat diabetic patients will respond

EFFECT OF DAPAGLIFLOZIN VERSUS GLIPIZIDE ON A1c AND BODY WEIGHT IN METFORMIN-TREATED PATIENTS
Del Prato et al, Diabetolgia 53:5107, 2010

0 Change in A1c (%) GLIP -0.2 DAPA

+1.4 GLIP

2 Change in BW (kg)

0 DAPA

-0.4 -0.52 -0.52 -3.2

-2

-0.6

-4

EFFECT OF DAPAGLIFLOZIN ADDITION TO INSULIN-TREATED T2DM PATIENTS (n=71)

Wilding et al, Diabetes Care 32:1656-62, 2009

A1C (%) 9.0 8.5 8.0 7.5 7.0 0 4 6 8

1 0
Placebo
DAPA-10mg

Body Weight (kg)

-1 -2 -3 -4 -5 1 2
DAPA-10mg

Placebo
DAPA-20mg

DAPA-20mg

10 12

10

12

Weeks

SGLT 2 INHIBITION: MEETING UNMET NEEDS IN DIABETES CARE

Corrects a Novel Pathophysiologic Defect Reduces HbA1c

Promotes Weight Loss

Improves Glycemic Control and CVRFs

Complements Action of Other Antidiabetic Agents

Reduces Blood Pressure

No Hypoglycemia