Conflits d’intérêt

M. Buysschaert est membre de comités d’experts et/ou a participé à des conférences et études organisées par Eli Lilly, NovoNordisk, Servier, MSD, BMS, Astra Zeneca, Novartis, Sanofi-Aventis.

10

1

0.55 7 9

IM fatal et non-fatal

Niv

eau

de r

isqu

e

p<0.0001

14% réduction du risque par 1% de diminution en HbA1c

5 7 9

Endpoints microvasculaires

Niv

eau

de r

isqu

e

10

1

0.5

p<0.0001

37% réduction du risque par 1% de diminution en HbA1c

IM = Infarctus du Myocarde .Stratton I, et al. BMJ 2000;321:405―12.

HbA1c (%)

Corrélation épidémiologique entre le contrôle glycémique et le risque de complications

HbA1c (%)

Glycaemic targets for the management of type 2diabetes

• Glycaemic targets for the management of people with type 2 diabetes as recommended by various organisations1–5

1. Nathan DM, et al. Diabetologia. 2009;52:17-30. 2. IDF. Global Guidelines 2005. 3. Rodbard HW, et al. Endocr Pract. 2007;13(Suppl. 1):1-68. 4. NICE clinical guideline 87. Quick reference guide. May 2009. 5. Matthaei S, et al. German Diabetes Association guidelines. October 2008.

Organisation HbA1c (%) FPG (mmol/L) PPG (mmol/L)

ADA-EASD1 <7 — —

IDF-Europe2 <6.5 <6.0 (<110*) <8.0 (<145*)

AACE3 ≤6.5 <6.1 (<110*) <7.8 (<140*)

NICE4 <6.5** — <8.5 (<153*)

DDG5 <6.5 — —

*mg/dL

**<7.5% for people receiving ≥2 oral glucose-lowering drugs or those requiring insulin

FPG, fasting plasma glucose; PPG, postprandial glucose; ADA, American Diabetes Association; IDF, International Diabetes Federation; AACE, American Association of Clinical Endocrinologists; NICE, National Institute of Clinical Excellence; DDG, Deutschen Diabetes-Gesellschaft (German Diabetes Association)

HbA1c : 7.9 ±1.6 %

Patients avec HbA1c < 7% : 30%

Acta Clinica Belgica, 2005

HbA1c: 8.8 ±2.3%

Acta Clinica Belgica,2006

6BY/ELB/11/209/462

Key challenge of type 2 diabetes: outcome

43% of patients do not

achieve glycaemic targets (HbA1c<7%)

Ford et al (NHANES). Diabetes Care 2008;31:102–4

7BY/ELB/11/209/462

Distribution of Risk Factors for Microvascular and MacrovascularDistribution of Risk Factors for Microvascular and Macrovascular Complications among U.SComplications among U.S. . Adults with Diabetes, 1999Adults with Diabetes, 1999––2010.2010.

Ali MK et al. N Engl J Med 2013;368:1613Ali MK et al. N Engl J Med 2013;368:1613--16241624

Barrières pour un bon contrôle

PatientPatient--Effets indEffets indéésirablessirables

--PolymPolyméédicationdication--HypoglycHypoglycéémiemie--Prise de poidsPrise de poids

MaladieMaladie--Chronique Chronique

--AsymptomatiqueAsymptomatique--Epuisement progressif Epuisement progressif

des cellules bêtades cellules bêta

MMéédecindecin--Inertie cliniqueInertie clinique

--Suivi & monitoringSuivi & monitoring--Augmentation de la Augmentation de la

mméédicationdication

7

6

9

8HbA

1c(%

)

10

OAD* monotherapy

Diet andexercise

OAD combination

OAD + basal insulin

OAD monotherapyup-titration

Duration of diabetes

OAD + multiple daily

insulin injections

Conservative management of glycemia:traditional stepwise approach

HbA1c = 6.5%

Campbell IW. Br J Cardiol 2000; 7:625–631.

HbA1c = 7%

*OAD = oral antidiabetic

Diabetes Care,Diabetes Care, Diabetologia. Diabetologia. 1919 April 2012 [Epub ahead of print]April 2012 [Epub ahead of print](Adapted with permission from: Ismail(Adapted with permission from: Ismail--Beigi F, et al. Beigi F, et al. Ann Intern MedAnn Intern Med 2011;154:554)2011;154:554)

DPP-4 comme 2e choix après la metformineDPPDPP--4 comme 24 comme 2ee choix aprchoix aprèès la metformines la metformine

AdaptAdaptéé dd’’apraprèès Inzucchi et al. Diabetes Care 2012;35:1364s Inzucchi et al. Diabetes Care 2012;35:1364--13791379..

Two drug Two drug combinationscombinations

Efficacy (Efficacy (↓↓ HbAHbA1c1c))HypoglycemiaHypoglycemiaWeightWeightMajor side effect(s)Major side effect(s)CostsCosts

MetforminMetformin

+ Sulfonylurea+ Sulfonylurea

HighHighModerate riskModerate riskGainGainHypoglycemiaHypoglycemiaLowLow

MetforminMetformin

+ Thiazolidinedione+ Thiazolidinedione

HighHighLow riskLow riskGainGainEdema, HF, fxEdema, HF, fx’’ssHighHigh

MetforminMetformin

+ DDP+ DDP--4 inhibitor4 inhibitor

IntermediateIntermediateLow riskLow riskNeutralNeutralRareRareHighHigh

MetforminMetformin

+ + GLPGLP--1 receptor 1 receptor agonistagonist

HighHighLow riskLow riskLossLossGIGIHighHigh

MetforminMetformin

++ Insulin Insulin (usually basal)(usually basal)

HighestHighestHigh riskHigh riskGainGainHypoglycemiaHypoglycemiaVariableVariable

If needed to reach individualized HbAIf needed to reach individualized HbA1c1c target after ~3 months, proceed to 3target after ~3 months, proceed to 3--drug combination drug combination (order not meant to denote any specific preference):(order not meant to denote any specific preference):

HEALTHY EATING, WEIGHT CONTROL, INCREASED PHYSICAL ACTIVITYHEALTHY EATING, WEIGHT CONTROL, INCREASED PHYSICAL ACTIVITYInitial drug Initial drug monotherapymonotherapy

Efficacy (Efficacy (↓↓ HbAHbA1c1c))HypoglycemiaHypoglycemiaWeightWeightSide effectsSide effectsCostsCosts

HighHighLow riskLow riskNeutral / lossNeutral / lossGI / lactic acidosisGI / lactic acidosisLowLow

If needed to reach individualized HbAIf needed to reach individualized HbA1c1c target after ~3 months, proceed to 2target after ~3 months, proceed to 2--drug combination drug combination (order not meant to denote any specific preference):(order not meant to denote any specific preference):

MetforminMetformin

More complex More complex insulin strategiesinsulin strategies

InsulinInsulin(multipe daily doses)(multipe daily doses)

Three drug Three drug combinationscombinations MetforminMetformin

+ Sulfonylurea+ Sulfonylurea

MetforminMetformin

+ Thiazolidinedione+ Thiazolidinedione

MetforminMetformin

+ DDP+ DDP--4 inhibitor4 inhibitor

MetforminMetformin

+ + GLPGLP--1 receptor 1 receptor agonistagonist

MetforminMetformin

+ + Insulin Insulin (usually basal)(usually basal)

TZDTZD

DDPDDP--44--ii

GLPGLP--11--RARA

InsulinInsulin

++ ++ ++ ++ ++

oror oror oror oror oror

oror oror oror oror oror

oror oror

SUSU

DDPDDP--44--ii

GLPGLP--11--RARA

InsulinInsulin

SUSU

TZDTZD

InsulinInsulin

SUSU

TZDTZD

InsulinInsulin

TZDTZD

DDPDDP--44--ii

GLPGLP--11--RARA

If combination therapy that includes basal insulin has failed toIf combination therapy that includes basal insulin has failed to achieve HbAachieve HbA1c1c target after 3target after 3--6 months,6 months,proceed to a more complex insulin strategy, usually in combinatiproceed to a more complex insulin strategy, usually in combination with 1on with 1--2 non2 non--insulin agents:insulin agents:

Recommandations ADA/ EASD 2012

Adapted Recommendations: Adapted Recommendations: When Goal is to Avoid Weight GainWhen Goal is to Avoid Weight Gain

Diabetes Care,Diabetes Care, Diabetologia. Diabetologia. 1919 April April 2012 [Epub ahead of print]2012 [Epub ahead of print]

TR/E

LB/0

5/20

12/2

36TR

/ELB

/05/

2012

/236

Time (min)

The Incretin Effect Demonstrates the Response to Oral vs IV Glucose1

Mean ± SE; n = 6; *p≤0.05; 01-02 = glucose infusion time.1. Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492–498.

Veno

us P

lasm

a G

luco

se (m

mol

/L)

C-p

eptid

e (n

mol

/L)

11

5.5

001 60 120 180 01 60 120 180

0.0

0.5

1.0

1.5

2.0

Time (min)02 02

Incretin Effect

Oral Glucose IV Glucose

*

*

*

**

**

La Barre La Barre «« Sur les possibilitSur les possibilitéés ds d’’un traitement du diabun traitement du diabèète par lte par l’’incrincréétinetine »», , Bulletin de Bulletin de ll’’AcadAcadéémie Royale de Mmie Royale de Méédecine de Belgiquedecine de Belgique, 1932, 12, 620, 1932, 12, 620--634634

INCRETINS

Glucagon-like peptide 1[GLP-1]

Gastric inhibitory polypeptide [GIP]

L cellsGlucose dependant

Inactivation by DPP-4Reduced secretion in diabetes

K cellsGlucose dependant

Inactivation by DPP-4Normal secretion and

reduced effect in diabetes

GLP-1 Effects in Humans: Understanding the Glucoregulatory Role of Incretins1–4

Promotes satiety and reduces appetite

Beta cells:Enhances glucose-dependent insulin

secretion

1. Adapted from Flint A, et al. J Clin Invest. 1998;101:515–520. 2. Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413–422. 3. Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546–1553. 4. Adapted from Drucker DJ. Diabetes. 1998;47:159–169.

Liver:↓ Glucagon reduces

hepatic glucose output

Alpha cells:↓ Postprandial

glucagon secretion

Stomach:Helps regulate

gastric emptying

GLP-1 secreted upon the ingestion of food

09-A

ug-2

008-

JAN

-200

7-B

E-12

63-S

S

GLP-1 Preserved Morphology of Human Islet Cells In Vitro

Day 1

GLP-1–treated cellsControl

Day 3

Day 5

Adapted from Farilla L et al Endocrinology 2003;144:5149–5158.

Islets treated with GLP-1 in culture were able to maintain their integrity for a longer period of time.

GLP-1 actions in the heart

CELL METABOLISM 3, 153–165, MARCH 2006. The biology of incretin hormones ReviewDaniel J. Drucker

09-A

ug-2

008-

JAN

-200

7-B

E-12

63-S

S

* * **

**

*p<0.05, type 2 diabetes vs. NGT Meal started at time 0 and finished at 10–15 minutes.Adapted from Toft-Nielsen M-B et al J Clin Endocrinol Metab 2001;86:3717–3723.

GLP-1 Levels Decreased in Type 2 Diabetes

NGT (n=33)Type 2 diabetes (n=54)

0

5

10

15

20

0 60 120 180 240

Time (minutes)

GLP

-1 (p

mol

/L)

*

Meal Test Study

21BY/ELB/11/2009/462

Incretin Effect

Intravenous glucose

T2DControl Subjects

Glu

cose

†[m

mol

/L]

Glu

cose

†[m

mol

/L]

Insu

lin†

[pm

ol/L

]

Insu

lin†

[pm

ol/L

]

* * *

* * * * * *

5

0

10

15

20

5

0

10

15

20

0

100

200

300

400

500

Time (min)60 120 1800

0

100

200

300

400

500

60 120 1800

Time (min)60 120 1800

Time (min)60 120 1800

Time (min)

Oral glucose

Incretin Effect The incretin effect is diminished in patients

with type 2 diabetes (T2D)

*p<.05; †PlasmaAdapted from Nauck MA, et al. Diabetologia. 1986;29:46-52.

Rapid Inactivation (1–2 minutes) of GLP-1

DPP-4: Dipeptidyl peptidase-4.Adapted from Drucker DJ Expert Opin Invest Drugs 2003;12(1):87–100; Ahrén B Curr Diab Rep 2003;3:365–372.

IntestinalGLP-1release

GLP-1 (9-36)inactive

Mixed meal

GLP-1 (7-36)Active

(half-life <2 mins)

DPP-4inhibitor

DPP-4

Inhibiteurs DPPInhibiteurs DPP--44

Nom de Nom de substancesubstance

Nom de Nom de spspéécialitcialitéé

LaboratoireLaboratoire Dosage recommandDosage recommandéé

SitagliptineSitagliptine JanuviaJanuvia MSDMSD 100 mg/jour p.o.100 mg/jour p.o.

VildagliptineVildagliptine GalvusGalvus NovartisNovartis 2 x 50 mg/jour p.o.2 x 50 mg/jour p.o.

SaxagliptineSaxagliptine OnglyzaOnglyza BMS / Astra BMS / Astra ZenecaZeneca

5 mg/jour p.o. 5 mg/jour p.o.

LinagliptineLinagliptine TrajentaTrajenta Boeringher/LBoeringher/Lillillyy 5 mg/jour p.o.5 mg/jour p.o.

Efficacité

*Diminution moyenne de HbA1c versus placebo. **pas d*Diminution moyenne de HbA1c versus placebo. **pas d’é’étude comparative existante entre les difftude comparative existante entre les difféérentes molrentes moléécules.cules.1. R1. Réésumsuméé des caractdes caractééristiques du produit Trajentaristiques du produit Trajenta®®, 2. R, 2. Réésumsuméé des caractdes caractééristiques du produit Onglyzaristiques du produit Onglyza®®, ,

3. R3. Réésumsuméé des du produit Januviades du produit Januvia®®, 4. R, 4. Réésumsuméé des Caractdes Caractééristiques du produit Galvusristiques du produit Galvus®®..

Compilation graphique de lCompilation graphique de l’’effet theffet théérapeutique de diffrapeutique de difféérents inhibiteurs de la DPPrents inhibiteurs de la DPP--4 en monoth4 en monothéérapie comme rapie comme mentionnmentionnéé dans le Rdans le Réésumsuméé des Caractdes Caractééristiques du Produit (RCP). Pour le changement moyen en HbAristiques du Produit (RCP). Pour le changement moyen en HbA1c1c corrigcorrigéé par par placebo, aprplacebo, aprèès 18 / 24 semaines de traitement par rapport s 18 / 24 semaines de traitement par rapport àà la valeur de basela valeur de base****

Linagliptine1 Saxagliptine2 Sitagliptine3 Vildagliptine4

Dosage 5 mg QD 5 mg QD 5 mg QD 5 mg QD 100 mg QD 100 mg QD 50 mg BID 50 mg BID

n = 147 272 69 103 193 229 90 79

Valeur p* < 0,0001 < 0,0001 < 0,0059 < 0,0001 < 0,0001 < 0,0001 < 0,05 < 0,05

Valeur initiale HbA1c

8,1% 8,0% 7,9% 8,0% 8,0% 8,0% 8,6% 8,4%

--0,6%0,6%

--0,7%0,7%

--0,4%0,4%

--0,6%0,6% --0,6%0,6%

--0,8%0,8%

--0,5%0,5%

--0,7%0,7%

Dim

inut

ion

moy

enne

de

HbA

Dim

inut

ion

moy

enne

de

HbA

1c1c**

Chemistry Metabolism Elimination route

Sitagliptin β-amino acid-based Not appreciably metabolised Renal (~80% unchanged as parent)

Vildagliptin CyanopyrrolidineHepatically hydrolysed to inactive metabolite (P450 enzyme independent)

Renal (22% as parent, 55% as metabolite)

Saxagliptin Cyanopyrrolidine Hepatically metabolised to active metabolite (via P450 3A4/5)

Renal (12-29% as parent, 21-52% as metabolite)

Alogliptin Modified pyrimidinedione Not appreciably metabolised Renal (>70% unchanged

as parent)

Linagliptin Xanthine-based Not appreciably metabolised Biliary (unchanged as parent); <6% via kidney

Characteristics of DPPCharacteristics of DPP--4 Inhibitors4 Inhibitors

TR/ELB/04/2012/169TR/ELB/04/2012/169

Deacon CF, Diabetes, Obesity and Metabolism , 2011, 13: 7Deacon CF, Diabetes, Obesity and Metabolism , 2011, 13: 7––1818

11‐‐4: Trajenta, Januvia, Galvus, Onglyza, Summaries of Product 4: Trajenta, Januvia, Galvus, Onglyza, Summaries of Product Characteristics, consulted on line march 2012, www.afmps.beCharacteristics, consulted on line march 2012, www.afmps.be

DPPDPP--4 Inhibitors Have Different Durations of Action4 Inhibitors Have Different Durations of Action

% Plasma % Plasma DPPDPP--4 inhibition4 inhibition

VildagliptinVildagliptin

SitagliptinSitagliptin, ,

4040

100100

8080

00

6060

2020

PlaceboPlaceboSaxagliptin Saxagliptin (5 mg qd)(5 mg qd)

SaxagliptinSaxagliptin

Day 10Day 10

Adapted from Adapted from Boulton et alBoulton et alPoster 0606Poster 0606--P; ADA 2007 P; ADA 2007

4040

100100

8080

00

6060

2020

PlaceboPlaceboAlogliptin Alogliptin (25 mg qd)(25 mg qd)

Day 14Day 14

--2020

Adapted from Adapted from Covington et al, Covington et al, Clin Ther 2008Clin Ther 2008

4040

100100

8080

00

6060

2020

PlaceboPlaceboLinagliptin Linagliptin (5 mg qd)(5 mg qd)

Day 12Day 12

Adapted from Heise et al, Adapted from Heise et al, Diab Obes Metab 2009Diab Obes Metab 2009

% Plasma % Plasma DPPDPP--4 inhibition4 inhibition

00 44 88 1212 1616 2020 2424Time (hr)Time (hr)

AlogliptinAlogliptin

LinagliptinLinagliptin

Sitagliptin Sitagliptin (100 mg qd)(100 mg qd)PlaceboPlacebo

00 44 88 1212 1616 2020 2424Time (hr)Time (hr)

00

2020

40406060

8080

100100

Nb: No direct comparisons of degree of inhibition Nb: No direct comparisons of degree of inhibition attained by different inhibitors attained by different inhibitors

Adapted from HeAdapted from He et alet alJ Clin Pharmacol 2007 J Clin Pharmacol 2007

100100

8080

6060

4040

202000

Day 1Day 1

Vilda Vilda (50 mg)(50 mg)PlaceboPlacebo

Vilda Vilda (100 mg)(100 mg)

Deacon CF, Diabetes, Obesity and Metabolism , 2011, 13: 7Deacon CF, Diabetes, Obesity and Metabolism , 2011, 13: 7––1818

Adapted from Bergman et alAdapted from Bergman et alClin Ther 2006Clin Ther 2006..

Selectivity QPP/DPP II PEP FAPα DPP-8 DPP-9

Sitagliptin High >5 550 >5 550 >5 550 >2 660 >5 550

Vildagliptin Moderate >100 000 60 000 285 270 32

Saxagliptin Moderate >50 000 ? >4 000 390 77

Alogliptin High >14 000 >14 000 >14 000 >14 000 >14 000

Linagliptin Moderate >100 000 >100 000 89 40 000 >10 000

DPPDPP--4 Inhibitor 4 Inhibitor in vitro in vitro SelectivitySelectivity(Fold Selectivity for DPP(Fold Selectivity for DPP--4 vs Other Enzymes4 vs Other Enzymes))

Sitagliptine + MetformineSitagliptine + Metformine

7,0

7,2

7,4

7,6

7,8

8,0

8,2

0 6 12 18 24

Semaines

HbA1C

Placebo (n=224)

Sitagliptine 100 mg (n=453)

0 6 12 18 24

8.0

8.5

9.0

9.5

10.0

10.5

Semaines

Placebo (n=226)

Sitagliptine 100 mg (n=454)

Glycémie à jeun

Sitagliptine + Metformine vs. Metformine + Placebo

24 semaines

Charbonnel et al. Diabetes Care 2006; 29: 2368-2643

- 0.65 %p<0.001 - 0.9 mmol/L

p<0.001

? 1305-04-2010

VildagliptinAdd-on to metformin

Adapted from: Ferrannini E, et al. Diabetes Obes Metab. 2009;11:157-66.

Similar to glimepiride in reducing HbA1c when added to metformin

Vildagliptin100 mg/day, n = 1118 1081 1062 1081 1037 1023 992

Glimepiride upto 6 mg/day, n = 1072 1042 1011 1039 1001 989 976

0

6.50

7.00

7.25

7.50

-4 12 24 32 40 52

Vildagliptin 100 mg/day+ metformin

Glimepiride up to 6 mg/day+ metformin

Week

6.75

0 16

Mea

n H

bA

1C

(%)

Sitagliptine Sitagliptine vsvs. Sulfamides. SulfamidesH

bA

1c

(% ±

SE

)

Nauck et al. Diabetes Obes Metab 2007; 9: 194–205

Semaines

5.8

6.0

6.2

6.4

6.6

6.8

7.0

7.2

7.4

7.6

7.8

0 6 12 18 24 30 38 46 52

Sulfamide + metformine (n=411)

Sitagliptine + metformine (n=382)

Sitagliptine + Metformine vs.Glipizide + Metformine

52 semaines

- 0.67 %

Poids:Poids:--1.5 kg 1.5 kg SitagliptineSitagliptine+ 1.1 kg + 1.1 kg GlipizideGlipizide

HypoglycHypoglycéémies:mies:5 % 5 % SitagliptineSitagliptine32 % 32 %

Comparative efficacy of DPP4iComparative efficacy of DPP4i’’s vs oral antidiabetic drugs s vs oral antidiabetic drugs Head to head trials in drug naive and metforminHead to head trials in drug naive and metformin--treated patientstreated patients

•• MetforminMetformin : greater reduction in HbA1c and weight: greater reduction in HbA1c and weight•• SUSU : no significant difference in HbA1c but : no significant difference in HbA1c but greater weight gain and higher incidence of greater weight gain and higher incidence of hypohypo’’s, more s, more ““escapeescape”” with secondary increase in HbA1cwith secondary increase in HbA1c••TZD TZD : slightly greater reduction in HbA1c but : slightly greater reduction in HbA1c but greater weight gaingreater weight gain•• DPP4iDPP4i’’s s : No expected differences in efficacy in the class (shown for sa: No expected differences in efficacy in the class (shown for saxa vs sitagliptin)xa vs sitagliptin)

Mean changes in HbA1cMean changes in HbA1c

Mean changes in body weightMean changes in body weight

Scheen AJ, Diabetes & Metabolism, available on line, march 2012Scheen AJ, Diabetes & Metabolism, available on line, march 2012 TR/ELB/04/2012/169TR/ELB/04/2012/169

Résultats : effet sur l’HbA1c

- 0.6 %

p<0.001

0 %

Même diminution HbA1c en fonction des traitements prémix ou insuline basaleMême diminution HbA1c selon prise ou non de metformineMême diminution HbA1c après ajustement pour poids, BMI et race

Vilsboll et al, 2010

Linagliptine – Tolerability profile

•• Overall incidence of Adverse Events or Serious AE, with linaglipOverall incidence of Adverse Events or Serious AE, with linagliptin,  was tin,  was similar  to placebo        similar  to placebo         ((AEAE’’ss : 53,8% vs 55,0% , serious AE: 53,8% vs 55,0% , serious AE’’s: 2.8% vs 2.7%)s: 2.8% vs 2.7%)

•• InfectionsInfections:  19.5% Linagliptin vs  21.4% placebo:  19.5% Linagliptin vs  21.4% placebo

•• Upper respiratory tract :  3.3% vs 4.9%Upper respiratory tract :  3.3% vs 4.9%

•• Nasopharyngitis : 5.9% vs 5.1%Nasopharyngitis : 5.9% vs 5.1%

•• Urinary tract : 2.2% vs 2.7%Urinary tract : 2.2% vs 2.7%

•• Diarrhoea : 2.1% vs 2.1%Diarrhoea : 2.1% vs 2.1%

•• HeadacheHeadache : 2.9% vs 3.1%: 2.9% vs 3.1%

•• Blood and lymphatic disorders : 1.0% vs 1.2%Blood and lymphatic disorders : 1.0% vs 1.2%

•• Hypersensitivity : 0.1% vs 0.1%Hypersensitivity : 0.1% vs 0.1%

•• Hepatic enzyme increase: 0.1% vs 0.1%Hepatic enzyme increase: 0.1% vs 0.1%

•• Serum creatinine increase : 0.0% vs 0.1%Serum creatinine increase : 0.0% vs 0.1%

•• Chronic   pancreatitis Chronic   pancreatitis :  1 patient  Linagliptin :  1 patient  Linagliptin 

•• Neoplasms Neoplasms  benign, malignant and unspecified : 0.2% vs 0.5%benign, malignant and unspecified : 0.2% vs 0.5%

•• Less discontinuation  of study drug  with linagliptin because ofLess discontinuation  of study drug  with linagliptin because of AEAE’’s  s  : 2.2% vs 2.9% placebo: 2.2% vs 2.9% placebo

Pooled analysis of 8 monotherapy and combination trials vs plaPooled analysis of 8 monotherapy and combination trials vs placebocebo2523 patients on linagliptin vs 1049 patients on placebo2523 patients on linagliptin vs 1049 patients on placebo

Schernthaner G et al , Diab Obes Metab 2012, available on line, Schernthaner G et al , Diab Obes Metab 2012, available on line, april 2012april 2012

including including hypoglycemiahypoglycemia and and weightweight

BMS/AZ Highly Confidential - For training purposes only- Not be copied, circulated or used in any context before approval from BMS and before the Marketing Authorization for Saxagliptin has been granted

? 1305-04-2010

Cardiovascular events: Saxagliptin controlled Phase 2b/3 pooled population

Patients at risk

Control 1,251 935 860 774 545 288 144 123 102 57All saxagliptin 3,356 2,615 2,419 2,209 1,638 994 498 436 373 197

All saxagliptin

Control

Time to onset of first primary Major Adverse Cardiovascular Event (MACE)

0 24 37 50 63 76 89 102 115 1280

1

2

3

4

5

Weeks

Firs

t ad

vers

e ev

ent

(%)

Saxagliptin, FDA’s Endocrinologic and Metabolic Drugs Advisory Committee Briefing Document for April 2009 Meeting: NDA 22-350. Available at http://www.fda.gov/OHRMS/DOCKETS/ac/09/briefing/2009-4422b1-02-Bristol.pdf. Accessed: 7 May, 09.

Risk ratio for major CV eventsRisk ratio for major CV events11‐‐55

11. . Johansen OJohansen O‐‐E., et al. E., et al. Cardiovascular Diabetology 2012, 11:3;  Cardiovascular Diabetology 2012, 11:3;  2. 2. WilliamsWilliams‐‐Herman D, et al. Herman D, et al. BMC Endocr DisordBMC Endocr Disord. 2010;10:7. 2010;10:7..3. 3. Schweizer A, et al. Schweizer A, et al. Diabetes Obes MetabDiabetes Obes Metab. 2010;12(6):485. 2010;12(6):485––494494; ;  4. 4. Frederich R, et al. Frederich R, et al. Postgrad MedPostgrad Med. 2010;122(3):16. 2010;122(3):16––2727;;5. 5. White et al. 2010, ADA Scientific Sessions. Abstract 391White et al. 2010, ADA Scientific Sessions. Abstract 391‐‐PPPP

Total patients Total patients in analysisin analysis

5,2395,239

10,24610,246

10,98810,988

4,6074,607

3,4893,489

PrimaryPrimaryendpointendpoint

CV death, MI, stroke,CV death, MI, stroke,hospitalisation due to hospitalisation due to angina pectorisangina pectoris

Med DRA termsMed DRA termsfor MACEfor MACE

Acute coronary syndrome, Acute coronary syndrome, transient ischaemic attack, transient ischaemic attack, stroke, CV deathstroke, CV death

MI, stroke, CV deathMI, stroke, CV death

NonNon‐‐fatal MI, nonfatal MI, non‐‐fatalfatalstroke, CV deathstroke, CV death

CommentsComments

PrePre‐‐specified/specified/independent independent adjudicationadjudication

No formal No formal adjudication;adjudication;PostPost‐‐hoc analysishoc analysis

PrePre‐‐specified/specified/Independent Independent adjudicationadjudication

PrePre‐‐specified/specified/Independent Independent adjudicationadjudication

PrePre‐‐specified/specified/Independent Independent adjudicationadjudication

DPPDPP‐‐4 inhibitor better4 inhibitor better Comparator betterComparator better

111/21/21/41/41/81/8 22 44 88

LinagliptinLinagliptin11

SitagliptinSitagliptin22

VildagliptinVildagliptin33

SaxagliptinSaxagliptin44

AlogliptinAlogliptin55

0.340.34

0.680.68

0.840.84

0.420.42

0.630.63

0.150.15 0.740.74

0.410.41 1.121.12

0.620.62 1.141.14

0.230.23 0.800.80

0.210.21 1.191.19

No increased risk of CV events was observed in patients No increased risk of CV events was observed in patients treated with DPPtreated with DPP--4 inhibitors 4 inhibitors ( retrospective analyses of existing trials)( retrospective analyses of existing trials)

Rapid Inactivation (1–2 minutes) of GLP-1

DPP-4: Dipeptidyl peptidase-4.Adapted from Drucker DJ Expert Opin Invest Drugs 2003;12(1):87–100; Ahrén B Curr Diab Rep 2003;3:365–372.

IntestinalGLP-1release

GLP-1 (9-36)inactive

Mixed meal

GLP-1 (7-36)Active

(half-life <2 mins)

DPP-4inhibitor

DPP-4

Analogue du GLP-1 humain97% d’homologie

Analogue GLP-1 d’origine animale 53% homologie/ GLP-1 humain

44 AA

Analogues du GLP-1 :Structure et origine

Analogue du GLP-1 humain97% d’homologie

31 AARésistance à la dégradation par les DPP-4

- Auto-aggrégation- Liaison à l’albumine

Demi-vie longue (t½= 13 h)

Lixisenatide ( Lyxumia Lixisenatide ( Lyxumia ))

LEAD programme: reductions in HbA1c when adding liraglutide

Chan

ge

in H

bA

1c

(%)

SU combination

LEAD-1

Met combination

LEAD-2

Met + TZD combination

LEAD-4

−1.3*

−1.5*−1.5*

Monotherapy

LEAD-3

51% 43%

−1.4*−1.3

−1.1

−1.6*

−1.2*

−1.5*

Change in HbA1c from baseline for: overall population (LEAD-4,-5); add-on to diet and exercise failure (LEAD-3); add-on to previous oral antidiabetic (OAD) monotherapy (LEAD-2,-1); or add-on to met and/or SU (LEAD-6).; *Significant vs. comparator

−0.9

−1.3

−0.8

−1.1

−0.5

8.3 8.18.68.58.38.68.58.2 8.28.6 8.6 8.48.4 8.4

−1.1*

−0.8

Met and/or SU

LEAD-6

8.2 8.1

Liraglutide 1.8 mgLiraglutide 1.2 mg Glimepiride Rosiglitazone Glargine Placebo Exenatide

0.0

−0.2

−0.4

−0.6

−1.0

−1.2

−1.4

−1.6

Met + SU combination

LEAD-5 Baseline A1c %

Marre et al. Diabetic Medicine 2009;10.1111/j.1464-5491.2009.02666.x (LEAD-1); Nauck et al. Diabetes Care 2009;32;84–90 (LEAD-2); Garber et al. Lancet 2009;373:473–81 (LEAD-3); Zinman et al. Diabetologia 2008;51(Suppl. 1):S359 (A898) (LEAD-4); Russell-Jones et al. Diabetes 2008;57(Suppl. 1):A159 (LEAD-5); Blonde et al. Can J Diabetes 2008;32 (Suppl.):A107 (LEAD-6)

−0.8

40BY/ELB/11/2009/462

HbA1c Evolution

-1.2%

7,7

Results are presented as mean and (standard deviation) Buysschaert et al ,2010

41BY/ELB/11/2009/462

Weight evolution

All changes from baseline : p< 0.001

Results are presented as mean and (standard deviation)

Results

T0 T6 p

HOMA-B (%) 33 ± 24 43 ± 23 0.0210

HOMA-S (%) 58 ± 35 61 ± 40 0.6150

Product BxS (%) 15 ± 7.0 22 ± 15.0 0.0055

in the fasting state, after discontinuation for 24h of all antihyperglycemic drugs,including exenatide.

Preumont et al, 2010Preumont et al, 2010

BY/ELB/12/2008/486 43

Change in Weight and HbA1c Over 3-Years of Exenatide

N=217 Mean±SE

Baseline 99.3 ± 1.2 kg

0 26 52 78 104 130 156-6

-4

-2

0 Week 156-5.3 kg (95% CI: -6.0 to -4.5 kg)

Treatment (week)

Wei

ght C

hang

e fr

om B

asel

ine

(kg)

Klonoff DC, et al. Curr Med Res Opin 2008;24:275-286.

HbA

0 26 52 78 104 130 1564

5

6

7

8

9

10Baseline 8.2 ± 0.1%

Week 156-1.0% (95% CI:-1.1 to -0.8%)

Treatment (week)1c

(%)

44BY/ELB/11/2009/462

ABDOMINAL PAIN UPPER: 2 (0.70%)

ADVERSE EVENT: 6 (2.1%)

BLOOD AMYLASE INCREASED: 1 (0.35%)

CHOLECYSTITIS: 1 (0.35%)

DUODENAL ULCER: 1 (0.35%)

DYSPNOEA: 1 (0.35%)

FOOD AVERSION: 1 (0.35%)

GASTROINTESTINAL DISORDER: 64 (22.5 %)

• 31% had Nausea-gastrointestinal disorder

• 3.5% had Hypoglycemia

SAFETY

HYPERSENSITIVITY: 1 (0.35%)

HYPOGLYCEMIA: 10 (3.5%)

INJECTION SITE REACTION: 1 (0.35%)

LIPASE INCREASED : 1 (0.35%)

NAUSEA: 21 (7.4%)

OEDEMA : 1 (0.35%)

SKIN REACTION: 1 (0.35%)

URTICARIA: 1 (0.35%)

VOMITING: 2 (0.70%)

• 93 patients (33%) reported any adverse effect (safety set n=284)

Data on file

Preumont, Baeck, Dumoutier et Buysschaert, SFD,2013Preumont, Baeck, Dumoutier et Buysschaert, SFD,2013

Gæde P. et al. New Eng J Med 2008, 358 (6): 580-591.

STENO-2 FOLLOW-UP: résultats après 13.3 années

48BY/ELB/11/209/462