comparisons of dpp-4 inhibitors: focus on januvia...
TRANSCRIPT
Comparisons of DPP-4 Inhibitors:
Focus on JANUVIA (Sitagliptin)
DPP-4= Dipeptidyl Peptidase-4
Ⓡ
Sihoon Lee
Gachon Univ School of Med
Agenda
DPP-4 inhibition rate and duration of DPP-4 inhibitors
Non-inferiority design clinical trials of JANUVIA® (Sitagliptin)
PK comparisons of DPP-4 inhibitors
DPP-4 inhibitors in T2DM patients with renal impairment
Selectivity of DPP-4 inhibitors
JANUVIA (Sitagliptin) vs. Sulfonylurea
DPP-4= Dipeptidyl Peptidase-4; PK=Pharmacokinetics; T2DM=Type 2 Diabetes Mellitus
DPP-4 Inhibition Rate and Efficacy of JANUVIA® (sitagliptin) in Animal Studies
In general, inhibition of DPP-IV activity by
80% or greater or a 2-fold augmentation of
postprandial, active GLP-1 levels (or both)
was associated with a maximal or near-
maximal short-term lowering of glucose
levels in some animal studies.
DPP-4=Dipeptidyl Peptidase-4; GLP-1=glucagon-like peptide-1
1. Herman GA et al. Clin Pharmacol Ther. 2005;78:675-688.
Day 1
DPP-4 Inhibition Rate and Duration: Rationale for Once-Daily or Twice-Daily Dosing
DPP-4=dipeptidyl peptidase-4; qd=once daily; OGTT=oral glucose tolerance tests
1. Alba M et al. Curr Med Res Opin. 2009;25(10):2507–2514. Electronic supplementary data published in conjunction with Alba M et al. Curr Med Res Opin. 2009;25:2507–2514. doi: 10.1185/03007990902109514. 2. He
YL et al. J Clin Pharmacol. 2007;47: 633–641. 3. Tahrani AA et al. Adv Ther. 2009;26(3):249–262. 4. Heise T et al. Diabetes Obes Metab. 2009;11:786–794. 5. Herman GA et al. Clin Pharmacol Ther. 2005;78:675-688.
Saxagliptin3
DPP-4 peak inhibition : 80%
100
80
60
40
20
00 4 8 12 16 20 24
Time postdose (hr)
DP
P-4
In
hib
itio
n,
%
The DPP-4 inhibitory effect of saxagliptin was measured in 2 double-blind, randomized 2-week studies:•Study 1 in 40 patients with type 2 diabetes who received once-daily doses of saxagliptin 2.5–50 mg, or placebo•Study 2 in 50 healthy individuals who received once-daily doses of saxagliptin 40–400 mg, or placeboGraph is derived from mean values from study 1 and study 2 on day 1.3
Saxagliptin 2.5 mg (n=6)
Saxagliptin 5 mg (n=5 or 6)
Day1
JANUVIA® (Sitagliptin)1
DPP-4 peak
inhibition : 97%100
80
60
40
20
00 4 8 12 16 24
Time postdose (hr)
DP
P-4
In
hib
itio
na,
%
The time profiles for mean plasma DPP-4 inhibition after administration of a single oral dose of sitagliptin 100 mg to healthy subjects. As shown, the weighted average mean DPP-4 inhibition over 24 hours with sitagliptin 100 mg was 97%.1
The DPP-4 inhibition curve shown here was generated by applying a mathematical correction to previously published sitagliptin results from a single-dose study (5–400 mg) in healthy men. The uncorrected 24-hour weighted average mean DPP-4 inhibition was 87%.1,5
Sitagliptin 100 mg qd (n=6)
a DPP-4 inhibition corrected for sample assay dilution.1
Single-dose study in healthy subjects
Vildagliptin2
DPP-4 peak inhibition : 96%
The DPP-4 inhibitory effect of vildagliptin was measured in a single-center, randomized, open-label, placebo-controlled, 7-period crossover study in 16 patients with type 2 diabetes diagnosed at least 3 months previously. On each study day, following an overnight fast (≥10 hours), patients omitted breakfast and received single oral doses of placebo or vildagliptin (10–400 mg). A 75-g oral glucose load was consumed 30 minutes after study drug. Plasma DPP-4 activity was determined at prespecified time points during the 24 hours following the oral glucose load. Data were not corrected for assay dilution effects.2
Single oral dose study in patients with type 2 diabetes
These data support the rationale for dosing frequency,
but does not have implications for clinical efficacy of the product when dosed as recommended.
Linagliptin4
DPP-4 peak inhibition : 92%b
100
80
60
40
20
00 4 8 12 16 20 24
Time postdose (hr)
DP
P-4
In
hib
itio
n,
%
Placebo (n=12)
Linagliptin 5mg qd (n=8)
This randomized, placebo-controlled, double-blind,two-centre, multiple rising dose study was carried out in four sequential groups, each comprising 12 male type 2 diabetic patients, nine receiving linagliptin (in rising doses per cohort of 1, 2.5, 5 or 10 mg) and three receiving placebo once daily for 12 days in order to investigate the safety, tolerability, pharmacokinetic and pharmacodynamic properties of multiple oral doses of linagliptin in patients with type 2 diabetes mellitus. 4
b At steady state4
In patients with type 2 diabetes
Vildagliptin 50 mg (n=16)
Placebo
Vildagliptin 100 mg (n=15)
100
75
50
25
0
-250 2 4 12 16 20 24
Day 1
DP
P-4
In
hib
itio
n,
%
6 8 10
Time postdose, h
Non-Inferiority design Clinical trials of JANUVIA® (Sitagliptin)
T2DM=type II Diabetes Mellitus; OHA=oral antihyperglycemic agents; MET=metformin; SD=standard deviation; LSM=least squares mean; CI=confidence interval; SE=standard error
1. Aschner P et al. Diabetes Obes Metab. 2010;12:252-261. 2. Nauck MA et al; for the sitagliptin study 024 group. Diabetes Obes Metab. 2007;9(2):194–205. 3. Arechavaleta R et al.
Diabetes Obes Metab. 2011;13:160-168. 4. Scheen AJ et al. Diabetes Metab Res Rev. 2010;26:540-549.
† Data from all randomized patients.‡ Adjusted change from baseline
Study
Use of OHAs at screen-
ing (mg/day)
NActive
comparator (mg/day)
Study
Dura-
tion
(Week)
Difference in HbA1c
(%) LSM change (95% CI) between
sitagliptin and comparator
Aschner
P, et al.
20101
Drug naive
455
24
0.14
(0.06, 0.21)Sitagliptin 100
439 Metformin500~ 2000
Nauck
MA, et al.
20072
Met ≥ 1500
382
52
-0.01
(-0.09, 0.08)Sitagliptin 100
411 Glipizide 5~20
Arechav
aleta R,
et al.
20113
Met ≥ 1500
443
30
0.07
(-0.03, 0.16)Sitagliptin 100
436 Glimepiride 1~6
Scheen
AJ, et al.
20104
Met ≥
1500
343
18
Sitagliptin 100
0.09‡
(-0.01, 0.20)334 Saxagliptin
Duration of T2DM (years)
Mean±SD
2.6±3.9
2.1±3.5
6.5±6.1†
6.2±5.4†
6.8±4.6†
6.7±4.8†
6.3±4.7†
6.3±5.0†
Baseline
HbA1c (%)
Mean±SD
7.2 ± 0.7
7.2 ± 0.7
7.48±0.76
7.52±0.85
7.48 ± 0.68
7.49 ± 0.74
7.69
(SE 0.047)
7.68
(SE 0.052)
Follow-up HbA1c (%)
Mean±SD
6.8 ± 0.7
6.7 ± 0.6
6.84±0.66
6.86±0.69
7.04 ± 0.83
6.98 ± 0.89
7.07
(SE 0.051)
7.16
(SE 0.052)
HbA1c (%)
LSM change from baseline
(95% CI)
-0.43
(-0.48, -0.38)
-0.57
(-0.62, -0.51)
-0.67
(-0.75, -0.59)
-0.67
(-0.75, -0.59)
-0.47
(-0.55, -0.39)
-0.54
(-0.62, -0.45)
-0.62‡
(-0.69, -0.54)
-0.52‡
(-0.60, -0.45)5
Aschner P, et al : A multinational,
double-blind, randomized, active-
controlled, noninferiority study
evaluating the efficacy and safety of
sitagliptin (100 mg once daily) compared
with metformin (uptitrated from 500
mg/day to 2000 mg/day for all patients
over a maximum of 5 weeks) in 1050
patients with type 2 diabetes (not taking
an antihyperglycemic agent for at least
16 weeks prior to study entry) with
inadequate glycemic control (HbA1c
≥6.5% to ≤9%). The primary analysis
assessed non-inferiority for HbA1c
change from baseline at 24 weeks using
the PP population.1
Nauck MA, et al. : A multinational,
randomized, double-blind, parallel-group
study evaluating the effect of adding
sitagliptin (100 mg once daily)
vs glipizide (≥5–≤20 mg/day) to
metformin in 1172 patients with T2DM
inadequately controlled with ≥1500
mg/day metformin (HbA1c ≥6.5% to
≤10%). The primary analysis assessed
noninferiority for HbA1c change from
baseline at week 52 using a PP approach
(patients who completed all 52 weeks of
treatment and did not have any reason
for exclusion).2
Arechavaleta R, et al. : A multinational,
double-blind, randomized, parallel-group,
noninferiority study evaluating the effect
of adding sitagliptin (100 mg once daily)
vs glimepiride (≥1–≤6 mg/day) to
metformin in 1035 patients with T2DM
inadequately controlled with ≥1500
mg/day metformin for ≥12 weeks (HbA1c
≥6.5%–≤9%). The primary analysis was
HbA1c change from baseline at 30 weeks
using a PP approach.3
Scheen AJ, et al. : See next page for
study design.
Study Design
Per-Protocol(PP) population result
*Prespecified non-
inferiority
margin=0.40%.
*Prespecified non-
inferiority
margin=0.3%.
*Prespecified non-
inferiority
margin=0.4%.
*Prespecified non-
inferiority
margin=0.30%.
Saxagliptin vs JANUVIA® (Sitagliptin) Head-to-HeadNoninferiority Study: Design1
qd=once daily. 1. Scheen AJ et al. Diabetes Metab Res Rev. 2010;26(7):540–549.
Primary efficacy objective: to assess if the change in HbA1c from baseline to 18 weeks achieved with
saxagliptin 5 mg/day added to metformin is noninferior to sitagliptin 100 mg/day added to metformin in
patients with type 2 diabetes who have inadequate glycemic control on ≥1,500 mg metformin monotherapy.
• Patients with type
2 diabetes (N=801)
• Aged ≥18 years
• Receiving metformin
monotherapy
• HbA1c 6.5%–10%
Stable dose of metformin ≥1,500 mg/day
Sitagliptin 100 mg qd (n=398)
Saxagliptin 5 mg qd (n=403)
Double-blind treatment periodScreening period
Screening
visit
Week 0
Randomization
Week 18
Ch
an
ge
Fro
m B
ase
lin
e i
n
Ad
just
ed
Me
an
Hb
A1
c(S
E),
%
0.00
-0.15
-0.30
-0.45
-0.60
-0.75
Mean baseline HbA1c, % 7.69 7.68
Saxagliptin Was Noninferior to JANUVIA®(Sitagliptin)in Reducing HbA1c at 18 Weeks1
In the FAS population,
numerically greater
HbA1c reductions from
baseline were observed for
sitagliptin 100 mg compared
with saxagliptin 5 mg.
Difference between groups:
0.17% (95% CI: 0.06, 0.28)
Primary End Point (Per-Protocol Population; on background of metformin therapy)
Sitagliptin 100 mg + metformin
Saxagliptin 5 mg + metformin
0.09 (95% CI: –0.01, 0.20)a
(Prespecified noninferiority
margin=0.30%)
CI=confidence interval; FAS=full-analysis-set; SE=standard error.aDifference in adjusted change from baseline vs sitagliptin + metformin.
1. Scheen AJ et al. Diabetes Metab Res Rev. 2010;26(7):540–549.
–0.62(95% CI: –0.69, –0.54)
–0.52(95% CI: –0.60, –0.45)
n=343 n=334
JANUVIA® (Sitagliptin) Resulted in Significantly Greater Reductions in FPG Than Saxagliptin at 18 Weeks1
FP
G L
S M
ea
n (±
SE
) C
ha
ng
e F
rom
Ba
seli
ne
, m
mo
l/L
0
-0.3
-0.6
-0.9
-1.2
Mean baseline FPG,
mmol/L8.89 8.86
0.30 (95% CI: 0.08, 0.53)a
CI=confidence interval; FAS=full-analysis-set; FPG=fasting plasma glucose; LS=least squares; SE=standard error.aBetween-groups difference vs sitagliptin + metformin.
1. Scheen AJ et al. Diabetes Metab Res Rev. 2010;26(7):540–549.
-0.90
-0.60
Secondary End Point (FAS Population; on background of metformin therapy)
n=392 n=397 Sitagliptin 100 mg + metformin
Saxagliptin 5 mg + metformin
Pharmacokinetic Properties of DPP-4 Inhibitors
DPP-4=dipeptidyl peptidase-4 ; N/A=Not available.
1. JANUVIA EU prescribing information, MSD. 2. Vildagliptin EU prescribing information. 3. Saxagliptin EU prescribing information. 4. EPAR for Saxagliptin.
Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001039/WC500044319.pdf. 5. Heise T et al. Diabetes Obes
Metab. 2009;11:786–794. 6. Reitlich S et al. Clin Pharmacokinet. 2010;49:829–840. 7. Fuchs H et al. J Pharm Pharmacol. 2009;61:55–62. 8. Blech S et al.
Drug Metab Dispos.2010;38:667–678. 9. Linagliptin EU prescribing information.
JANUVIA®
(Sitagliptin)1 Vildagliptin2 Saxagliptin3 Linagliptin5-9
Absorption tmax(median)
Bioavailability
1–4 h87%
1.7 h85%
2 h (4 h for active metabolite)
>75%4
2 h30%
Half-life (t1/2) atclinically
relevant dose12.4 h 2-3 h
2.5 h (parent)
3.1 h (metabolite)
113–131 h(1–10 mg)
Metabolism 16% metabolized69% metabolized
mainly renal (inactive metabolite)
Hepatic
(active metabolite) CYP3A4/5
10% metabolized
Distribution 38% protein bound
9.3% protein bound
Neglibible protein binding
Prominent concentration-dependent protein binding:
99% at 1nmol/l75%–89% at ≥30nmol/l
Elimination Renal 87%(79% unchanged)
Renal 85%(23% unchanged)
Renal 75%(24% as parent;
36% as active metabolite)
Feces 80%Urine 5%
Data not representative of head-to-head trials. Not all pharmacokinetic data are from studies
using locally approved dosage.
10
Recommendations for Diabetes and CKD1
2007 KDOQI guideline
Management Topic Target / Action
Screening and diagnosis of
Diabetic kidney disease
Urinary albumin-creatinine ratio in a spot urine sample
Serum creatinine - eGFR
Management of
Hyperglycemia and General
Diabetes Care in CKD
Target HbA1c for people with diabetes should be <7.0%, irrespective of the
presence or absence of CKD.
In case of intensive treatment,
- monitor patients' glucose levels closely
- reduce doses of medicines (insulin and oral agents) as needed to avoid hypoglycemia
Should be treated with an ACE inhibitor or an ARB, usually in combination with a
diuretic.
Target blood pressure should be <130/80 mmHg
Hypertension*
Dyslipidemia*
Target LDL-C should be <100 mg/dL (<70 mg/dL is a therapeutic option)
LDL-C ≥100 mg/dL should be treated with a statin
Treatment with a statin should not be initiated in patients with type 2 diabetes
on maintenance hemodialysis therapy who do not have a specific cardiovascular
indication for treatment.
Comorbid
diseases
Nutrition* Target dietary protein intake should be the RDA of 0.8 g/kg body weight per day
CKD=Chronic Kidney Disease; eGFR= estimated Glomerular Filtration Rate; ACE=Angiotensin Converting Enzyme; ARB=Angiotensin Receptor Blocker;
LDL-C=low-density lipoprotein cholesterol; RDA=Recommended Daily Allowance; KDOQI=Kidney Disease Outcomes Quality Initiative
1. KDOQI. Am J Kidney Dis. 2007;49(2,Supp12):S12-154.
* for people with diabetes and CKD stage 1-4
Severe(n=7)
<30
Plasma exposure of DPP-4 Inhibitors in non-diabetic patients with various degrees of renal insufficiency
Fo
ld i
ncr
ea
se i
n e
xp
osu
re (
AU
C0
-∞)
Re
lati
ve
to
no
rma
l re
na
l fu
nct
ion
[GM
R (
90
% C
l)] 7
6
5
4
3
2
1
JANUVIA® (Sitagliptin)1
Normal†
(n=151†)
>80
Mild(n=6)
50 to 80
Moderate(n=6)
30 to 50
Severe(n=6)
<30
ESRD(n=6)
on HD
Renal impairment status
Creatinine clearance
(ml/min)
Fo
ld i
ncr
ea
se i
n e
xp
osu
re (
AU
C)
Re
lati
ve
to
no
rma
l re
na
l fu
nct
ion
[Me
an
] 7
6
5
4
3
2
1
Vildagliptin2
Normal Mild
50 to 80
Moderate
30 to 50
Severe
<30
ESRD
Renal impairment status
Fo
ld i
ncr
ea
se i
n e
xp
osu
re (
AU
C∞
)
Re
lati
ve
to
no
rma
l re
na
l fu
nct
ion
[GM
R] 7
6
5
4
3
2
1
Saxagliptin3 (5-hydroxy saxagliptin-metabolite)
Normal(n=8)
>80
Mild(n=8)
>50 to ≤80
Moderate(n=8)
≥30 and ≤50
ESRD(n=8)
on HD
Renal impairment status
Creatinine clearance
(ml/min)
Fo
ld i
ncr
ea
se i
n e
xp
osu
re (
AU
C0
-24)
Re
lati
ve
to
no
rma
l re
na
l fu
nct
ion
[G
MR
(9
0%
CI)
]
7
6
5
4
3
2
1
Linagliptin4
Normal(n=6)
>80
Mild(n=6)
>50 and ≤80
Moderate(n=6)
>30 and ≤ 50
Severe(n=6)
≤30
ESRD(n=6)
≤ 30 on HD
Renal impairment status
Creatinine clearance
(ml/min)
DPP-4=Dipeptidyl Peptidase-4; ESRD=end-stage renal disease; HD=hemodialysis; AUC=area under the curve; GMR=geometric mean ratio; CI=clearance; T2DM=type 2 Diabetes Mellitus
† The study involved 6 subjects with normal renal func>on and the data from these subjects were then combined with data from 145 more subjects with normal renal function from 11 other studies.1
1. Bergman AJ et al. Diabetes Care. 2007; 30(7):1862-1864. 2. Vildagliptin EU prescribing information. 3. Boulton DW et al. Clin Pharmacokinet. 2011;50(4):253-265. 4. Graefe-Mody U et al. Diabetes, Obes Metab. 2011;13:939-946.
A parallel-group, open-label, pharmacokinetic study under 5mg linagliptin single-dose
and steady-state conditions in subjects with mild, moderate, and severe renal
impairment(with and without T2DM), ESRD and subjects with normal renal function
(with and without T2DM). The data presented are from single-dose condition in
subjects without T2DM.4
An open-label trial was conducted to evaluate the
pharmacokinetics of the lower therapeutic dose
of vildagliptin (50 mg once daily) in patients with
varying degrees of chronic renal impairment
defined by creatinine clearance compared to
normal healthy control subjects.2
A single-dose, open-label study evaluated the
pharmacokinetics of sitagliptin 50 mg in patients with
varying degrees of renal insufficiency compared with that
of healthy (control) subjects. The study included 30
patients with renal insufficiency classified on the basis of
creatinine clearance as mild (50-80 mL/min), moderate
(30-50 mL/min), and severe (<30 mL/min), as well as
patients with end-stage renal disease (ESRD) on
hemodialysis. (Normal [>80ml/min]).1
An open-label, parallel-group, single-dose study was
conducted. Subjects received a single oral dose of
saxagliptin 10 mg(two 5 mg tablets) to compare the
pharmacokinetics and tolerability of saxagliptin and its
pharmacologically active metabolite, 5-hydroxy
saxagliptin, in nondiabetic subjects with mild, moderate
or severe renal or hepatic impairment, or end-stage
renal disease (ESRD) in healthy adult subjects.3
In a single-dose, open-label pharmacokinetic study In a multiple-dose, open-label trial evaluating
pharmacokinetics
In an open-label, single-dose study In a single-dose, open label study
Creatinine clearance
(ml/min)
1.6
2.3
3.8
4.5
1.4 1.72.0
Limited data
from patients
with ESRD
indicate that
vildagliptin
exposure is
similar to that in
patients with
severe renal
impairment.
1.3
1.61.4 1.5
1.7
2.9
4.5
4.1
Effect of Creatinine Clearance on Plasma Concentration AUC of a Single Dose of JANUVIA® (Sitagliptin)
AUC=area under the curve; GMR=geometric mean ratio; CrCl:Creatinine clearance
1. Bergman AJ et al. Diabetes Care. 2007;30:1862-1864.
2. Data on file, MSD Korea.
3. JANUVIA® prescribing information, MSD Korea.
Creatinine Clearance (mL/min)
28
24
20
16
12
8
4
0
Do
se-A
dju
ste
d (
to 5
0 m
g)
AU
C (
uM
.hr)
10 30 50 70 90 110 130 150 170 190 210 230
AUC Increases With Decreasing Creatinine Clearance Necessitating
a Dose Reduction to Maintain Therapeutic Concentration
AUC GMR increase <2-fold
when CrCl ≥50 mL/min
Dose adjustments
CrCl <30 mL/min – ¼ dose
CrCl 30 – 50 mL/min – ½ dose
CrCl ≥50 mL/min – full dose
In a single-dose, open-label pharmacokinetic study,
To achieve plasma concentrations of sitagliptin similar to those in patients with normal renal function, lower dosages are
recommended in patients with moderate and severe renal insufficiency, as well as in ESRD patients requiring hemodialysis.3
Dosage of DPP-4 Inhibitors in Renal Impairment
DPP-4=dipeptidyl peptidase-4; BID=twice a day; QD=once a day; TZD=thiazolidinedione; SU=sulphonylurea
a Monotherapy, Initial combination therapy with Metformin, and Add-on combination therapy to Metformin, or TZD when the single agent alone does
not provide adequate glycemic control.
b Monotherapy, Initial combination therapy with Metformin, and Add-on combination therapy to SU when the single agent alone does not provide
adequate glycemic control.
c Monotherapy, Initial combination therapy with Metformin , Add-on combination therapy to Metformin, TZD, or SU when the single agent alone does
not provide adequate glycemic control, and Add-on combination therapy to Insulin(alone or with metformin) when the Insulin therapy does not
provide adequate glycemic control.
d Monotherapy, and Add-on combination therapy to Metformin, TZD, or SU when the single agent alone does not provide adequate glycemic control.
e ESRD requiring hemodialysis or peritoneal dialysis.
f ESRD requiring hemodialysis.
1. JANUVIA 제품설명서, MSD Korea. 2. Vildagliptin 제품설명서. 3. Saxagliptin 제품설명서. 4. Linagliptin 제품설명서.
*2012년 12월 3일, 각제품의제품설명서정보기준
JANUVIA®(Sitagliptin)1
Patients with normal renal
function100mg QD
Vildagliptin2 Saxagliptin3 Linagliptin4
Renal impairment:
Dosage
adjustment is
not necessary
50mg BIDa
50mg QDb
Dosage adjustment is not necessary
5mg QDc
2.5mg QDd
Dosage adjustment is not necessary
5mg QD
Dosage adjustment is not necessary
Mild
Moderate
Severe
ESRD
50mg QD 50mg QD 2.5mg QD
25mg QD 50mg QD 2.5mg QD
25mg QDe 50mg QD 2.5mg QDf
DPP-4 Is a Member of a Family of Closely Related Proteases1
APP=aminopeptidase P; DPP=dipeptidyl peptidase; FAP=fibroblast activation protein; PEP=prolyl endopeptidase;
QPP=quiescent cell proline dipeptidase.
1. Drucker DJ. Diabetes Care. 2007;30(6):1335–1343.
DPP9
DPP8
FAP
DPP-4
DPP6
PEP
QPP/DPPII
APP
prolidase
DPP-4 Gene
Family
Other Proline- Specific
Peptidases
Comparative Toxicity Studies
Inhibition of DPP-8 and/or DPP-9 results in multi-organ toxicities in rats and dogs
2 week rat study at 10, 30, 100mg/kg/day; acute dog at 10mg/kg
2 wk. Rat Toxicity
alopecia
thrombocytopenia
anemia
enlarged spleen
mortality
Non-Selective QPP Selective DPP-8/9 Selective DPP-4 Selective
Bloody diarrhea
Acute Dog Toxicity Non-Selective QPP Selective DPP-8/9 Selective DPP-4 Selective
1. Lankas GR et al. Diabetes. 2005;54(10):2988-2994.
In vitro Selectivity of DPP-4 Inhibitors
DPP=Dipeptidyl Peptidase; FAPα=Fibroblast Activation Protein α; QPP=quiescent cell proline dipeptidase; IC50=inhibitory concentration 50%
1. Deacon CF. Diabetes Obes Metab. 2011;13:7–18.
JANUVIA®(Sitagliptin) Vildagliptin Saxagliptin Linagliptin
DDP-8
DDP-9
FAPα
QPP/DPP-2
Fold selectivity for DPP-4 vs. other enzymes in IC50
> 2660 270 390 40000
> 5550 32 77 >10000
> 5550 285 > 4000 89
> 5550 > 100000 > 50000 > 100000
Data not representative of head-to-head trials.
The consequences, if any, of differences in protease selectivity are not established.
DPP-4 inhibitors in this slide are considered DPP-4 selective inhibitors.
LS M
ea
n (±
SE
) H
bA
1c,
%8.0
7.8
7.6
7.4
7.2
7.0
6.8
6.6
6.4
6.2
6.0
Week
JANUVIA® (Sitagliptin) vs. Glimepiride Added to
Metformin : Sitagliptin achieved non-inferiority to
glimepiride
0 6 12 18 24 30
† Data from all randomized pa>ents.
LS=least squares; SE=standard error; T2DM=Type 2 Diabetes Mellitus
a Mean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
Average T2DM Duration: 6.7-6.8 years†
-0.54
-0.47
△(95% CI)
0.07% (–0.03, 0.16)
JANUVIA (Sitagliptin) 100 mg + metformin (n=443)
Glimepiridea + metformin (n=436)
Per-Protocol Population
A multinational, double-blind, randomized, parallel-group, noninferiority study evaluating the effect of adding sitagliptin (100 mg once daily) vs
glimepiride (≥1 -≤6 mg/day) to metformin in 1035 patients with T2DM inadequately controlled with ≥1500 mg/day metformin for ≥12 weeks (HbA1c
≥6.5% -≤9%). The primary analysis was HbA1c change from baseline at 30 weeks using a PP approach.
JANUVIA® (Sitagliptin) vs. Glimepiride :
Body Weight Change and Hypoglycemia over
week 30
APaT=all patients as treated; LS=least squares; SE=standard error
a Mean dose of glimepiride (following the 18-week titration period) was 2.1 mg per day.
1. Arechavaleta R et al. Diabetes Obes Metab. 2011;13(2):160–168.
Weight Change
1.5
1.0
0.5
-0.5
-1.5
0
-1.0
Sitagliptin 100 mg
Added to Metformin
(n=465)
Glimepiridea
Added to Metformin
(n=461)
LS M
ea
n C
ha
ng
e (±
SE
) in
Bo
dy
We
igh
t F
rom
Ba
seli
ne
, k
g
△= -2.0 kgP<0.001
Cumulative Incidence
of Hypoglycemia25
20
10
0
15
5
Sitagliptin 100mg
Added to Metformin
(n=516)
Glimepiridea
Added to Metformin
(n=518)P
ati
en
ts w
ith
≥1
Hy
po
gly
cem
ic E
pis
od
e,
%
Δ (95% CI)
–15.0%
(–19.3, –10.9)
P<0.001
Patients on Sitagliptin experienced a small weight loss while those on glimepiride
gained weight, resulting in a significant between group difference of 2.0kg (p<0.001).
Incidence of hypoglycemia was lower with sitagliptin therapy.
APaT Population
+1.2kg
-0.8kg
7%
22%
Cardiovascular Safety of JANUVIA® (Sitagliptin)vs a Sulphonylurea in Patients with T2DM: a Pooled Analysis
Objective: To compare the incidence of CV-related events with sitagliptin
100mg/day versus sulphonylurea in patients with T2DM
Cardiovascular Safety of Sitagliptin versus a
Sulphonylurea in Patients with T2DM:
a Pooled AnalysisBarry J. Goldstein, Samuel S. Engel, Gregory T. Golm, Michael J. Davies, Keith D. Kaufman
1
Design: Post hoc CV safety analysis (N = 2,451) of 3 randomized, double-
blinded clinical trials
• Add-on to metformin trial for 104 weeks: sitagliptin vs. glipizide
• Add-on to metformin trial for 30 weeks: sitagliptin vs. glimepiride
• Monotherapy trial for 104 weeks: sitagliptin vs. glipizide
2
A post hoc CV safety analysis was performed using custom major adverse CV events (MACE) that incorporated ischaemic events and CV deaths,
without adjudication of these events. Exposure-adjusted incidence rates stratified by study were calculated. The cumulative incidence of custom
MACE was evaluated over the duration of each study.
T2DM=type 2 Diabetes Mellitus; CV=cardiovascular
1. Data on file, MSD Korea.
JANUVIA® (Sitagliptin) vs. SU : Pooled analysis of 3 trials
Data are expressed as mean ± SD, frequency (n [%]), or median (*).BMI=body mass index; T2DM=type II Diabetes Mellitus; CVD=cardiovascular disease; CV=cardiovascular; SU= Sulphonylurea; SD=Standard Deviation
1. Data on file, MSD Korea.
CharacteristicJANUVIA®
(Sitagliptin)(n=1226)
Sulphonylurea (n=1225)
Age, years 56.4±9.5 56.3±10.0
Male, n(%) 685 (56) 706 (58)
BMI, kg/m2 30.5±4.9 30.8±4.9
Duration of T2DM, years* 5.0 5.0
History of dyslipidemia, n(%) 657 (54) 650 (53)
History of hypertension, n(%) 744 (61) 725 (59)
History of smoking, n(%) 448 (41) 463 (42)
HbA1c % 7.6±0.8 7.6±0.9
History of CVD, n(%) 153 (12) 148 (12)
Proportion of patients with known
CV risk factors other than T2DM and
history of CVD, n(%)
941 (85) 934 (85)
Baseline Characteristics
CharacteristicJANUVIA
(Sitagliptin)(n=1226)
Sulphonylurea
(n=1225)
Cumulative exposure, Patient-years 1269 1274
MACE, n 0 11
Incidence rate per 100 patient-years 0 0.9
Difference in incidence rate (95% CI)=-0.9 (-1.6, -0.5)
Risk ratio= 0.00 (0.00, 0.31)
MACE
JANUVIA® (Sitagliptin) vs. SU : Pooled analysis of 3 trials
MACE=major adverse cardiovascular events; SU=Sulphonylurea; CI=Confidence Interval; CV=cardiovascular
1. Data on File, MSD Korea.
Major adverse cardiovascular events (MACE) were assessed
- Included ischaemic events and CV deaths
- No formal adjudication of these events
In other JANUVIA® (sitagliptin) Pooled Safety Analysis: No Difference in MACEa
Between Sitagliptin and Non-exposed Groups1
JANUVIA
(Sitagliptin)
n=5,429
Non-exposed
n=4,817
Between-Groups
Difference (95% CI)b
Relative Risk Ratio (95% CI)
Incidence Rate per 100 Patient-Years
Adverse
Experience
0.6 0.9 –0.3 (–0.7, 0.1) 0.68 (0.41, 1.12)MACE
CI=confidence interval; MACE=major adverse cardiovascular events. aThere was no adjudication of any cardiac event.bBetween-groups difference and 95% CI based on stratified analysis. Positive differences indicate that the incidence rate for the sitagliptin group was higher than the incidence
rate for the non-exposed group.
1. Williams-Herman D et al. BMC Endocr Disord. 2010;10:7.
Custom MACE analysis with terms similar to those requested by the US Food and Drug Administration for recent
MACE analyses with other antihyperglycemic agents
Total of 64 patients with at least 1 MACE-related event
This pooled safety analysis included 19 double-blind, randomized, controlled clinical studies up to 2 years in duration, for which results were available as of July 2009. For this
analysis, 10,246 patients from the 19 clinical trials were divided into 2 groups: the sitagliptin 100 mg/day group (n=5,429) and the non-exposed group (n=4,817). The
sitagliptin group consisted of patients who received sitagliptin 100 mg/day alone or in combination with other oral antihyperglycemic agents, including metformin,
pioglitazone, sulfonylurea (with or without metformin), rosiglitazone plus metformin, and insulin (with or without metformin). The non-exposed group consisted of patients
who did not receive sitagliptin treatment during their respective studies. These patients received therapy with placebo, metformin, pioglitazone, sulfonylurea (with or
without metformin), rosiglitazone (with or with metformin), and insulin (with or without metformin).1
Summary
JANUVIA® (Sitagliptin) substantially reduces glucose and has a favorable PK/PD profile.
JANUVIA (Sitagliptin) was generally well tolerated.
JANUVIA (Sitagliptin) has broad indication with supporting data.
• Monotherapy
• Initial Combinaion Therapy with Metformin
• Dual Therapy: Add-on to MET / SU / TZD
• Triple Therapy: Add-on to MET + SU / MET + TZD
• Insulin Therapy: Add-on to Ins / Ins + MET
PK=pharmacokinetics; MET=metformin; SU=sulphonylurea; TZD=thiazolidinedione; Ins=insulin