Upload
pk-doctors
View
1.346
Download
3
Embed Size (px)
Citation preview
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