Harvey L. KatzeffMerck Research Laboratories

Rahway, New Jersey, USA

An update on DPP-4 inhibitors in the management of Type 2 diabetes:

potential roles in monotherapy and combination therapy

Hyperglycaemia

Liver

GI tract+

Pancreas

Muscle/fat

–

CarbohydrateAbsorption

GlucoseProduction

InsulinSecretion

GlucoseUptake

InsulinSecretion

α-Glucosidaseinhibitors

(–)

GlitazonesGlitazones(+)(+)

Metformin (–)

SulfonylureasMeglitinides (+)

Combining Combining antihyperglycaemicantihyperglycaemic agents: agents: major sites of actionmajor sites of action

InjectedInsulin

(–) (+)

GLPGLP--1 analogues1 analoguesDPPDPP--4 inhibitors4 inhibitors

↑ Glucagon

GlucagonSecretion X

DDP-4=dipeptidyl-peptidase-4; GLP-1=glucagon-like peptide-1

DPP-4

Active GLP-1

Inactive GLP-1

Active GIP

Inactive GIP

• Increased insulin secretion• Decreased glucagon release

Glucose control improved

DPP-4 inhibitorΧ

Inhibition of DPPInhibition of DPP--4 increases active incretin 4 increases active incretin levels, enhancing downstream incretin actionslevels, enhancing downstream incretin actions

GIP=glucoseGIP=glucose--dependent insulinotropic peptidedependent insulinotropic peptide

Sitagliptin and vildagliptin overviewSitagliptin and vildagliptin overview

• DPP-4 inhibitors for the treatment of patients with Type 2 diabetes: sitagliptin has recently been FDA approved, and vildagliptin is currently under FDA review

• Provide potent and highly selective inhibition of the DPP-4 enzyme

• No CYP or drug-drug interaction

• 30%–85% excretion via the urine

N

ONH2

NN

CF3

F

F

F

N

Selectivity of oral DPPSelectivity of oral DPP--4 enzyme inhibitors4 enzyme inhibitors

Herman et al. ADA. 2004; Stein. ADA. 2006. Late-breaking clinical presentation

>100,000

>100,000

>100,000

>100,000

>100,000

48,000

18

Sitagliptin IC50 (nM)

–APP

–PEP

–FAP

>100,000DPP-2, DPP-7

–DPP-9

9000DPP-8

120DPP-4

Vildagliptin IC50 (nM)Enzyme

Herman et al. Diabetes. 2005; Stein. ADA. 2006. Late-breaking clinical presentation

Active GLP-1

A single dose of A single dose of sitagliptinsitagliptin increased increased active GLPactive GLP--1 and GIP over 24 hours1 and GIP over 24 hoursCrossover Study in Patients With Type 2 Diabetes Placebo

Sitagliptin 25 mg

Sitagliptin 200 mg

Active GIP

0102030405060708090

0 2 4 6 24 26 28Hours postdose

GIP

(pg/

ml)

OGTT 24 hrs (n=19)

OGTT 2 hrs (n=55)

2-fold increase in active GIP

P<0.001 vs placebo

OGTT 24 hrs (n=19)

0

5

10

15

20

25

30

35

40

0 2 4 6 24 26 28

Hours postdose

GLP

-1 (p

g/m

l)

OGTT 2 hrs (n=55)

2-fold increase in active GLP-1

P<0.001 vs placebo

Sitagliptin increased insulin, decreased glucagon, and Sitagliptin increased insulin, decreased glucagon, and reduced reduced glycaemicglycaemic excursion after a glucose loadexcursion after a glucose load

Placebo

Sitagliptin 25 mg

Sitagliptin 200 mg

Crossover Study in Patients With Type 2 Diabetes

0

10

20

30

40

0 1 2 3 4

mcI

U/m

l Glucoseload

Drug dose

Insulin

P<0.05 for both dose comparisons to placebo for AUC

22%

~12%

50

55

60

65

70

75

0 1 2 3 4Time (hours)

pg/m

l

Glucagon

P<0.05 for both dose comparisons to placebo for AUC

Glucoseload

Drug dose

120

160

200

240

280

320

0 1 2 3 4 5 6

Time (hours)

Glucose

P<0.001 for both dose comparisons to placebo for AUC

~26%

mm

ol/l

Stein. ADA. 2006. Late-breaking clinical presentation

Mari et al. J Clin Endocrinol Metab. 2005

Vildagliptin increased GLPVildagliptin increased GLP--1 and GIP and decreased1 and GIP and decreasedblood glucagon hormone concentrationsblood glucagon hormone concentrations

GLP-1

GIP

Glucagon

Day -1Day 28

250

200

150

100

50

0

125

100

75

50

A

B

C

35

30

25

2015

10

5

0

Inta

ct G

LP-1

(p

mol

/l)In

tact

GIP

(pm

ol/l)

Glu

cago

n (n

g/l)

6:00 9:00 12:00 15:00 18:00 21:00Time

• DPP-4 vs placebo• DPP-4 vs metformin• DPP-4 vs TZD

Monotherapy trials

TZD=thiazolidinedione

SitagliptinSitagliptin improved both fasting and postimproved both fasting and post--meal meal glucose in monotherapy vs placeboglucose in monotherapy vs placebo

*Least-squares (LS) mean difference from placebo after 24 weeks Aschner et al. ADA. 2006. Abstract 1995-PO; Stein. ADA. 2006. Late-breaking clinical presentation

Fasting Glucose

Pla

sma

gluc

ose

(mg/

dl)

Time (weeks)

0 5 10 15 20 25144

153

162

171

180

189

Placebo (n=247)Sitagliptin 100 mg (n=234)

Δ FPG* = -17.1 mg/dl (P<0.001)

Post-meal Glucose

Time (minutes)

Pla

sma

gluc

ose

(mg/

dl)

Δ in 2-hr PPG* = -46.7 mg/dl (P<0.001)

0 60 120 0 60 120

144

180

216

252

288

Placebo (n=204) Sitagliptin (n=201)

Baseline24 weeks

Baseline24 weeks

24-Week Study

-0.57

-0.8

-1.52-1.8-1.6-1.4-1.2-1.0-0.8-0.6-0.4-0.20.0

18-Week Study

-0.44-0.61

-1.2-1.8-1.6-1.4-1.2-1.0-0.8-0.6-0.4-0.20.0

DPPDPP--4 inhibitors provide progressively greater reductions4 inhibitors provide progressively greater reductionsin HbAin HbA1c1c with progressively higher baseline HbAwith progressively higher baseline HbA1c1c

Reductions are placebo-subtractedRaz et al. ADA. 2006. Abstract 1996-PO; Aschner et al. ADA. 2006. Abstract 1995-PO;Stein. ADA. 2006. Late-breaking clinical presentation

Baseline HbA1c (%)

Mean (%)

Red

uctio

n in

HbA

1c (%

)

Inclusion Criteria: 7%–10%

Red

uctio

n in

HbA

1c(%

)

<8% 8%–9% ≥9%

7.37 8.40 9.48

<8% 8%–9% ≥9%

7.39 8.36 9.58

N=96

N=70

N=27

N=130

N=62

N=37

VildagliptinVildagliptin monotherapy:monotherapy:similar response to 50 and 100 mg daily similar response to 50 and 100 mg daily

-0.78 -0.79

-0.88

-0.3

-1.0

-0.9

-0.8

-0.7

-0.6

-0.5

-0.4

-0.3

-0.2

-0.1

0.0

Vildagliptin 50 mg QD (n=104)Vildagliptin 50 mg BID (n=90)Vildagliptin 100 mg QD (n=92)Placebo (n=94)

Mean HbA1c reduction from baseline at 24 weeks (7.5%–11%)

*P=0.006; †P=0.001 vs placeboSource: Study 2301, NovartisPrimary ITT (intent-to-treat) population

* *†

Cha

nge

in H

bA1c

(%)

VildagliptinVildagliptin monotherapymonotherapyvs metforminvs metformin

Dejager et al. ADA. 2006. Abstract 120-OR

Time (weeks)

Mea

n H

bA1c

(%)

9.5

9.0

8.5

8.0

7.5

7.0

6.5-4 0 4 8 12 16 20 24 28 32 36 40 44 48 52

Vildagliptin Metformin

Vildagliptin did not achieve non-inferiority

7.0

7.5

8.0

8.5

9.0

-4 0 4 8 12 16 20 24

Time (weeks)

Mea

n H

bA1c

(%)

VildagliptinVildagliptin monotherapymonotherapyvs rosiglitazonevs rosiglitazone

Vildagliptin

Rosiglitazone

Rosenstock et al. ADA. 2006. Abstract 557-P

SitagliptinSitagliptin improved the improved the ββ--cell response cell response to glucose: monotherapy studies to glucose: monotherapy studies

200

400

600

800

1000

1200

1400

160 180 200 220 240 260Glucose concentration

(mg/dl)

Insu

lin s

ecre

tion

(pm

ol/m

in)

Pooled Monotherapy Studies – Subset of Patients With Frequently Sampled MTTModel-based assessment of β-cell function

MTT=meal tolerance testΦs=static component; describes relationship between glucose concentration and insulin secretion Stein. ADA. 2006. Late-breaking clinical presentation

Baseline

End-Treatment

BaselineEnd-Treatment

Sitagliptin 100 mg QD Placebo

SitagliptinSitagliptin improved markers of improved markers of ββ--cell function:cell function:2424--week monotherapy studyweek monotherapy study

Proinsulin/insulin ratio

Aschner et al. ADA. 2006. Abstract 1995-PO; Stein. ADA. 2006. Late-breaking clinical presentation

0.3

0.35

0.4

0.45

0.5

0.55

P<0.001*

*P value for change from baseline compared with placebo

Hatched=BaselineSolid=Week 24

∆ from baseline vs pbo=0.078(95% CI: -0.114, -0.023)

Placebo Sitagliptin 100 mg

Rat

io (p

mol

/l/pm

ol/l)

30

35

40

45

50

55

60

65

70

75

80

P<0.001*

∆ from baseline vs pbo=13.2 (95% CI: 3.9, 21.9)

Placebo Sitagliptin 100 mg

HOMA-β

VildagliptinVildagliptin increases increases disposition indexdisposition index

*P<0.05 vs baseline; †P<0.05 vs placeboD’Alessio et al. ADA. 2006. Abstract 454-P

Dis

p osi

t ion

i nd e

x (A

IRg

X Si

)

0

20

40

60

80

100

120

140

*†

*

Placebo Vildagliptin

BaselineWeek 12Post washout

160

180

• Add-on therapy– Add-on to metformin– Add-on to pioglitazone– Add-on to insulin

• Initial combination– DPP-4 + metformin– DPP-4 + pioglitazone

Combination therapyCombination therapy

Sitagliptin once daily lowered HbASitagliptin once daily lowered HbA1c1cwhen added to metformin or pioglitazonewhen added to metformin or pioglitazone

*Placebo-subtracted difference in LS meansRosenstock et al. ADA. 2006. Abstract 556-P; Karasik et al. ADA. 2006. Abstract 501-P;Stein. ADA. 2006. Late-breaking clinical presentation

Δ in HbA1c vs Pbo* = -0.65% (P<0.001) Δ in HbA1c vs Pbo* = -0.70% (P<0.001)

Add-on to Metformin Study

7.0

7.2

7.4

7.6

7.8

8.0

8.2

0 6 12 18 24Time (weeks)

HbA

1c (%

)

Placebo (n=224)Sitagliptin 100 mg (n=453)

Placebo (n=174)Sitagliptin 100 mg (n=163)

Add-on to Pioglitazone Study

7.0

7.2

7.4

7.6

7.8

8.0

8.2

0 6 12 18 24Time (weeks)

HbA

1c (%

)

Vildagliptin added to metformin Vildagliptin added to metformin improved glycaemic controlimproved glycaemic control

Garber et al. ADA. 2006. Abstract 121-OR

Vildagliptin 50 mg QD & metformin

Vildagliptin 50 mg BID & metformin

Placebo & metformin

Time (weeks) Time (weeks)

HbA

1c(%

)

8.5

8.0

7.5

7.0-8 -4 0 4 8 12 16 20 24

FPG

(mM

)

8.0-8 -4 0 4 8 12 16 20 24

9.0

10.0

11.0

Difference in 24-hour weighted LS mean glucose: -32.8 mg/dl(-1.82 mmol/l), P<0.001

Stein. ADA. 2006. Late-breaking clinical presentation; adapted from Brazg et al. ADA. 2005.Abstract 11-OR

SitagliptinSitagliptin added to metformin improvedadded to metformin improved2424--hour glucose profile in Type 2 diabeteshour glucose profile in Type 2 diabetes

Glu

cose

(mg/

dl)

8:00 Day 1

13:00 19:00 0:00Day 2

7:30

100

120

140

160

180

240

200

220Dose 1

7:30Dose 218:30

Breakfast Lunch Dinner

Placebo + metformin (n=13)Sitagliptin 50 mg BID + metformin (n=15)

Time

Placebo + pioglitazone (n=174)Sitagliptin 100 mg QD + pioglitazone (n=163)

Sitagliptin added to ongoing metforminSitagliptin added to ongoing metforminor pioglitazone: change in body weight over timeor pioglitazone: change in body weight over time

LS m

ean

chan

ge fr

om b

asel

ine

body

wei

ght (

kg)

Placebo + metformin (n=169)Sitagliptin 100 mg QD + metformin(n=399)

0.0

-0.4

-0.6

-0.8

-0.2

0 12 24

Time (weeks)

-1.0

Karasik et al. ADA. 2006. Abstract 501-P; Rosenstock et al. ADA. 2006. Abstract 556-P

0.0

0.5

1.0

1.5

2.0

-0.5

-1.00 6 12 18 24

Time (weeks)

-8 0 12 24 52Time (weeks)Fonseca et al. ADA. 2006. Poster 467-P

Fonseca et al. EASD. 2006. PS 62. 0802

HbAHbA1c1c during insulin addduring insulin add--on:on:core and extension studycore and extension study

Mea

n H

bA1c

(%)

7.0

7.5

8.0

8.5

9.0 Vildagliptin 50 mg + insulinPbo + insulin

Vildagliptin 50 mg BID + insulin

∆ HbA1c -0.4 ± 0.1, P=0.001

SitagliptinSitagliptin once daily showed similar once daily showed similar glycaemicglycaemicefficacy to glipizide when addedefficacy to glipizide when added

to metformin (52 weeks)to metformin (52 weeks)

Sitagliptin 100 mg QD (n=382)

Glipizide (n=411)

Mea

n ch

ange

in H

bA1c Mean change from baseline (for both groups)*: 0.67%

6.0

6.2

6.4

6.6

6.8

7.0

7.2

7.4

7.6

7.8

8.0

8.2

8.4

0 12 24 38 52

Time (weeks)*Per-protocol analysis; -0.51% and -0.56% for sitagliptin and glipizide in LOCF analysisStein. ADA. 2006. Late-breaking clinical presentation

Change in Body Weight

86

88

90

92

94

0 12 24 38 52Time (weeks)

Bod

y w

eigh

t (kg

)

Stein. ADA. 2006. Late-breaking clinical presentation

SitagliptinSitagliptin once daily showed better safety once daily showed better safety and tolerability profile comparedand tolerability profile compared

with glipizide (52 weeks)with glipizide (52 weeks)

Glipizide (n=584)Sitagliptin 100 mg (n=588)Sitagliptin 100 mg QD (n=382)

Glipizide (n=411)

Δ between groups = -2.5 kg (P<0.001)

Hypoglycaemia

P<0.00132%

4.9%

0

10

20

30

40

50

Week 52In

cide

nce

(%)

Initial combination of Initial combination of vildagliptinvildagliptinand pioglitazone (24 weeks) and pioglitazone (24 weeks)

-1.1

-1.4

-1.9

-2.5

-2.0

-1.5

-1.0

-0.5

0.0

Cha

nge

from

bas

elin

e in

HbA

1c (%

)

Mean HbA1c reduction from baseline=8.7%

Intention-to-treat population *P=0.001 vs pioglitazone 30 mg; low-dose combination arm is not includedNathwani. ADA. 2006. Late-breaking clinical presentation

*Vildagliptin 100 mg daily (n=150)

Pioglitazone 30 mg daily (n=157)Vildagliptin 100 mg daily + pioglitazone30 mg daily (n=146)

Metabolic effects of DPPMetabolic effects of DPP--4 inhibitors4 inhibitors

• Small decrease in VLDL with corresponding increase in HDL

– No change in LDL

• Small decrements in blood pressure

• Small decrease in high-sensitivity C-reactive protein

• Animal models may reveal improvement in β-cell mass

– Studies in humans have not yet been performed to validate these findings

Safety and tolerability overview Safety and tolerability overview of DPPof DPP--4 inhibitors4 inhibitors

• Well tolerated in phase 1-3 trials; in completed and ongoing studies, >4000 patients on sitagliptin (to doses of 200 mg QD in phase 3 studies)

• Pre-specified pooled phase 3 analysis, including monotherapy and combination studies: over 1500 patients on sitagliptin and over 750 patients on placebo

– Summary measures of adverse experiences (AEs) were similar to placebo

• Including overall clinical AEs, serious AEs, discontinuations due to AEs, drug-related AEs, laboratory AE summary measures

– Small differences in incidence of specific AEs

• Between-group difference (sitagliptin 100 mg and placebo group) in incidence >1% for only 1 specific AE (nasopharyngitis 1.2% difference)

SummarySummary• DPP-4 inhibitors administered for the treatment of Type 2 diabetes

– Significant reductions in HbA1c across a range of starting HbA1c levels in monotherapy and combination use

– Sustained HbA1c reduction to 1 year

– Improvements in multiple measures of β-cell function

• Compared with a sulfonylurea or TZD, DPP-4 inhibitors provide

– Similar efficacy

– Superior improvements in β-cell function, less hypoglycaemia, and weight loss (vs weight gain)

• DPP-4 inhibitors are well tolerated with summary measures of AEs similar to placebo