An Update On Dpp 4 Inhibitors In The Management Of Type 2 Diabetes
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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
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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
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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
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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
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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
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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
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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
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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
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• DPP-4 vs placebo• DPP-4 vs metformin• DPP-4 vs TZD
Monotherapy trials
TZD=thiazolidinedione
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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
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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
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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
(%)
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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
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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
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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
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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
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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
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• 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
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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 (%
)
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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
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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
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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)
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-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
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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
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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
(%)
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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)
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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
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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)
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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