Transcript 053 Slides - Josephine Carlos

Initial Fixed-Dose Combination Therapy With
JANUMET™† (sitagliptin/metformin FDC) vs
Metformin Monotherapy
079 Study – Phase A
†Trademark
of Merck & Co., Inc., Whitehouse Station, NJ, USA.
Initial Fixed-Dose Combination Therapy With
JANUMET™ vs Metformin Monotherapy: Study
Objective
Objective
 To assess the efficacy, safety, and tolerability of initial therapy
with sitagliptin/metformin FDC (JANUMET) compared with
metformin alone in patients with type 2 diabetes and moderate
to severe hyperglycemia on diet and exercise.1,2
FDC=fixed-dose combination.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
Initial Fixed-Dose Combination Therapy With
JANUMET™ vs Metformin Monotherapy:
Study End Points
Primary end points1,2
 Effect of sitagliptin/metformin FDC on mean HbA1c compared with
that of metformin at 18 weeks
 Safety and tolerability of sitagliptin/metformin FDC
Selected secondary end points1,2
 Change from baseline in HbA1c (by mean and median baseline HbA1c
values), FPG, proinsulin-to-insulin ratio, and HOMA-β
 Proportion of patients at HbA1c goal (<7%) at 18 weeks
FDC=fixed-dose combination; FPG=fasting plasma glucose; HOMA-β=homeostasis model assessment of beta-cell function.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
Initial Fixed-Dose Combination Therapy With JANUMET™ vs
Metformin Monotherapy: Overall Disposition of Patients
Screened (N=2042)
Excluded (n=792)
Randomized (n=1250)
Sitagliptin/
metformin FDC (n=626)
Discontinued (n=142)
Adverse experience
(n=23)
Creatinine/CrCl criteria
(n=0)
Hyperglycemia criteria
(n=7)
Lack of efficacy
(n=2)
Lost to follow-up
(n=57)
Physician decision
(n=3)
Pregnancy
(n=3)
Protocol Violation
(n=5)
Study Terminated
(n=1)
Withdrawal by Subject (n=41)
Completed study (n=484)
Metformin (n=624)
Discontinued (n=142)
Adverse experience
(n=19)
Creatinine/CrCl criteria
(n=1)
Hyperglycemia criteria
(n=2)
Lack of efficacy
(n=12)
Lost to follow-up
(n=48)
Physician decision
(n=4)
Pregnancy
(n=2)
Protocol Violation
(n=14)
Study Terminated
(n=1)
Withdrawal by Subject (n=39)
Completed study (n=482)
CrCl=creatinine clearance; FDC=fixed-dose combination.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9,2009.
2. Data on file, MSD.
Initial Fixed-Dose Combination Therapy With JANUMET™ vs
Metformin Monotherapy: Baseline Patient Characteristics
Sitagliptin/
metformin FDC
(n=626)
Metformin
(n=624)
49.4
50.0
56.5
57.3
White
81.3
78.7
Asian
2.7
3.9
Black
13.1
14.2
Other
2.9
3.2
Mean HbA1c, %
9.91
9.83
Mean FPG, mmol/L
12.4
12.3
Mean weight, kg
94.7
97.2
Mean BMI, kg/m2
32.9
33.7
Duration of diabetes, y
3.5
3.2
Mean Age, y
Sex, %
Male
Race, %
BMI=body mass index; FDC=fixed-dose combination; FPG=fasting plasma glucose.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
Initial Fixed-Dose Combination Therapy With
JANUMET™ vs Metformin Monotherapy: Study Design
T2DM, aged
18–78 yrs,
Off OHA
≥4 months,
HbA1c ≥7.5%
Sitagliptin 50 mg bid + metformin 1000 bida (n=626)
R
Metformin 1000 mg bida (n=624)
Screening
period
Phase A
Phase B
1 week
18 weeks
26 weeks
Screening
aMetformin
Day 1
Randomization
Week 18
Week 44
was initiated at 500 mg bid and titrated up to 1000 mg bid over 4 weeks. Patients who were unable to tolerate the
maximum dose of sitagliptin/metformin FDC or metformin were allowed to be down-titrated to a minimum dose of
sitagliptin/metformin FDC 50/500 mg bid or metformin 500 mg bid.
bid=twice daily; FDC=fixed-dose combination; OHA=oral antihyperglycemic agent; qd=once daily; R=randomization; T2DM=type 2
diabetes mellitus.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
Initial Fixed-Dose Combination Therapy With
JANUMET™ vs Metformin Monotherapy: HbA1c Results
Over 18 Weeks
FAS Population
HbA1c LS Mean (±SE)
Change From Baseline, %
10
9
8
LS means
difference
–0.6; P<0.001
7
0
6
Week
12
Sitagliptin/metformin FDC (n=560)
Mean baseline HbA1c=9.9%
18
Metformin (n=566)
Mean baseline HbA1c=9.8%
FAS=full analysis set; FDC=fixed-dose combination; LS=least-squares; SE=standard error.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
Initial Fixed-Dose Combination Therapy With
JANUMET™ vs Metformin Monotherapy: HbA1c
Results at 18 Weeks
FAS Population
Mean baseline HbA1c, %
9.9
9.8
HbA1C LS Mean (±SE)
Change from Baseline, %
0
–1
–2
–1.8
Sitagliptin/metformin FDC (n=560)
–2.4
–3
–0.6a; P<0.001
aBetween-groups
Metformin (n=566)
difference.
FAS=full analysis set; FDC=fixed-dose combination; LS=least-squares; SE=standard error.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
Initial Fixed-Dose Combination Therapy With JANUMET™ vs
Metformin Monotherapy: Subgroup Analysis of HbA1c Results
at 18 Weeks by Median Baseline HbA1c
FAS Population
Median Baseline
HbA1c ≤9.7%
Mean Baseline HbA1c, %
HbA1c LS Mean Change
from Baseline, %
0
8.4
n=288
Median Baseline
HbA1c >9.7%
8.4
11.4
11.4
n=291
n=271
n=273
–1
–1.1
–2
–1.5
Metformin (n=564)
–0.4a; P=0.003
–2.4
–3
–3.3
–4
aBetween-groups
Sitagliptin/
metformin FDC (n=559)
difference.
FAS=full analysis set; FDC=fixed-dose combination; LS=least-squares.
Data on file, MSD.
–0.9a; P<0.001
Initial Fixed-Dose Combination Therapy With
JANUMET™ vs Metformin Monotherapy: Proportion
of Patients at HbA1c Goal of <7% at 18 Weeks
FAS Population
P<0.001a
Patients at Goal, %
60
50
49
40
34
30
20
10
0
Mean Baseline HbA1c, %
9.9
Sitagliptin/metformin FDC (n=559)
aBetween-groups
9.8
Metformin (n=564)
difference.
FAS=full analysis set; FDC=fixed-dose combination.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
Initial Fixed-Dose Combination Therapy With
JANUMET™ vs Metformin Monotherapy: FPG Results
at 18 Weeks
FAS Population
FPG LS Mean (±SE) Change
from Baseline, mmol/L
Mean baseline FPG, mmol/L
12.4 mmol/L
12.2 mmol/L
0
–1.1
–2.2
Sitagliptin/
metformin FDC (n=560)
–3.3
–4.4
–3.0
Metformin (n=566)
–3.9
–0.9a; P<0.001
FAS=full analysis set; FDC=fixed-dose combination; FPG=fasting plasma glucose; LS=least-squares; SE=standard error.
aBetween-groups difference.
Data on file, MSD.
Initial Fixed-Dose Combination Therapy With JANUMET™ vs
Metformin Monotherapy: Change from Baseline in HbA1c by
Baseline HbA1c at Week 18
FAS (Week 18)
Baseline HbA1c,%
Mean HbA1c,%
HbA1c LS Mean Change
from Baseline, %
0
<8
7.6
n= 87 101
≥8 and <9
8.4
124 109
≥9 and <10
9.5 9.4
99
95
≥10 and <11
10.4
99
111
≥11
12.2
150 148
–0.5
–0.8
–1.0
–1.1
–1.1
–1.5
–2.0
P=0.158
–1.6
P=0.009
–2.5
–1.7
–2.0
–2.1
P=0.111
–3.0
–3.5
–4.0
–2.7
–2.9
Sitagliptin/metformin FDC
Metformin
P<0.001
–3.6
P<0.001
FAS=full analysis set; FDC=fixed-dose combination.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
Initial Fixed-Dose Combination Therapy With JANUMET™ vs
Metformin Monotherapy: Markers of Beta-Cell Function at
Week 18
0.556
0.518
n=469
n=458
HOMA-β
60
54.6
22.8a (P=0.004)
50
-0.05
-0.1
-0.15
–0.186
-0.2
-0.25
FAS Population
–0.238
–0.052a (P=0.002)
LS Mean
Change From Baseline
LS Mean
Change From Baseline
Mean
baseline value:
0
Proinsulin-toinsulin ratio
40
31.8
30
20
10
0
Mean
baseline value:
n=465
n=456
50.5
62.4
Sitagliptin/metformin FDC
Metformin
difference.
FAS=full analysis set; FDC=fixed-dose combination.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
aBetween-groups
Initial Fixed-Dose Combination Therapy With JANUMET™
vs Metformin Monotherapy: Adverse Experience Summary
at 18 Weeks
APaT Population
Sitagliptin/
metformin FDC
(N=625)
n (%)
Metformin
(N=621)
n (%)
With one or more AEs
271 (43.4)
301 (48.5)
With no AEs
354 (56.6)
320 (51.5)
With drug-related AEsb
109 (17.4)
116 (18.7)
With serious AEs
13 (2.1)
20 (3.2)
With serious drug-related AEsb
1 (0.2)
1 (0.2)
Who died
1 (0.2)
1 (0.2)
Discontinued due to AEs
25 (4.0)
25 (4.0)
Discontinued due to drug-related AEsb
18 (2.9)
16 (2.6)
Discontinued due to serious AEs
6 (1.0)
5 (0.8)
Discontinued due to serious drug-related AEsb
1 (0.2)
1 (0.2)
Clinical AEsa
aExcluding
data after initiation of an additional antihyperglycemic agent.
by the investigator to be possibly, probably, or definitely drug-related.
AE=adverse experience; APaT=all patients as treated; FDC=fixed-dose combination.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
bConsidered
Initial Fixed-Dose Combination Therapy With
JANUMET™ vs Metformin Monotherapy:
Prespecified Gastrointestinal AEs Over 18 Weeks
APaT Populationa
Sitagliptin/
metformin FDC
n=625
Metformin
n=621
P value
Diarrhea
12.0
16.6
0.021
Nausea
5.6
6.3
0.612
Vomiting
2.9
2.6
0.742
Abdominal Painb
1.1
3.9
0.002
Prespecificed Gastrointestinal AEs, %
aExcluding
bIncludes
data after initiation of an additional antihyperglycemic agent.
abdominal pain lower, abdominal pain upper, abdominal pain, abdominal discomfort, and epigastric pain.
AE=adverse experience; APaT=all-patients-as-treated; FDC=fixed-dose combination.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
Initial Fixed-Dose Combination Therapy With
JANUMET™ vs Metformin Monotherapy:
Hypoglycemia
All Patients as Treated (Weeks 0–18)
Excluding Data After Initiation of an Additional Antihyperglycemic Agent
Treatment
n/N (%)
Episodes of Any Type
Sitagliptin/metformin FDC
13/625 (2.1)
Metformin
11/621 (1.8)
Episodes Requiring Non-Medical Assistance
and Not Exhibiting Marked Severitya
Sitagliptin/metformin FDC
0/625 (0.0)
Metformin
0/621 (0.0)
Episodes Requiring Medical Assistance
or Exhibiting Marked Severitya
Sitagliptin/metformin FDC
0/625 (0.0)
Metformin
0/621 (0.0)
aMarked
severity includes markedly depressed level of consciousness, loss of consciousness, or seizure.
FDC=fixed-dose combination.
Data on file, MSD.
JANUMET™ (sitagliptin/metformin, MSD) Indications:
Based on the Worldwide Product Circular
Indications
– JANUMET is indicated in patients with type 2 diabetes mellitus to
improve glycemic control
• As initial therapy when diet and exercise do not provide adequate glycemic
control
• As an adjunct to diet and exercise in patients who have inadequate
glycemic control on metformin or sitagliptin alone or in patients already
being treated with the combination of sitagliptin and metformin
• In combination with a sulfonylurea (ie, triple combination therapy) as an
adjunct to diet and exercise in patients who have inadequate glycemic
control with any 2 of the 3 agents: metformin, sitagliptin, or a sulfonylurea
• In combination with a PPARγ agonist (ie, triple combination therapy) as an
adjunct to diet and exercise in patients who have inadequate glycemic
control with any 2 of the 3 agents: metformin, sitagliptin, or a PPARγ
agonist (ie, thiazolidinediones)
• In combination with insulin as an adjunct to diet and exercise
JANUMET™ (sitagliptin/metformin, MSD) Contraindications:
Based on the Worldwide Product Circular
Contraindications
– JANUMET is contraindicated in patients with:
• Renal disease or renal dysfunction, e.g., as suggested by serum creatinine
levels ≥1.5 mg/dL [males], ≥1.4 mg/dL [females], or abnormal creatinine
clearance, which may also result from conditions such as cardiovascular
collapse (shock), acute myocardial infarction, and septicemia.
• Known hypersensitivity to sitagliptin phosphate, metformin hydrochloride or
any other component of JANUMET
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis, with
or without coma.
– JANUMET should be temporarily discontinued in patients
undergoing radiologic studies involving intravascular
administration of iodinated contrast materials, because the use of
such products may result in acute alteration of renal function
JANUMET™ (sitagliptin/metformin, MSD) Recommended
Dosing: Based on Worldwide Product Circular
 In general: twice daily with meals, with gradual dose escalation, to reduce the
gastrointestinal (GI) side effects associated with metformin
 Available dosage forms:
– Sitagliptin 50 mg/metformin 500 mg; sitagliptin 50 mg/metformin 850 mga;
sitagliptin 50 mg/metformin 1000 mg
 Dosing recommendations:
– As initial therapy for patients inadequately controlled with diet and exercise alone:
• Sitagliptin 50 mg/metformin 500 mg twice daily. May be titrated up to sitagliptin 50 mg/metformin
1000 mg
– For patients inadequately controlled on metformin monotherapy:
• 50 mg twice daily (100 mg total daily dose) plus the current dose of metformin
– For patients inadequately controlled on sitagliptin monotherapy:
• Sitagliptin 50 mg/metformin 500 mg twice daily. May titrate up to sitagliptin 50 mg/metformin
1000 mg
– For patients switching from coadministration of sitagliptin and metformin:
• Initiate at current dose of sitagliptin and metformin
aThis
dose should be considered for inclusion on a country-by-country basis.
JANUMET™ (sitagliptin/metformin, MSD) Recommended
Dosing (cont) : Based on Worldwide Product Circular
 Dosing recommendations (cont):
– For patients inadequately controlled on dual combination therapy with any 2 of the
following 3 antihyperglycemic agents: sitagliptin, metformin, or a sulfonylurea:
• 50 mg twice daily (100 mg total daily dose). Consider gradual dose escalation to reduce GI
side effects associated with metformin. Patients may require lower sulfonylurea doses to
reduce the risk of sulfonylurea-induced hypoglycemia
– For patients inadequately controlled on dual combination therapy with any 2 of the
following 3 antihyperglycemic agents: sitagliptin, metformin, and PPARγ agonist (ie
thiazolidinediones):
• 50 mg twice daily (100 mg total daily dose). Consider gradual dose escalation to reduce GI
side effects associated with metformin.
– For patients inadequately controlled on dual combination therapy with any 2 of the
following 3 antihyperglycemic agents: sitagliptin, metformin or insulin:
• 50 mg twice daily (100 mg total daily dose). Consider gradual dose escalation to reduce GI
side effects associated with metformin. Patients currently on or initiating insulin therapy may
require lower doses of insulin to reduce the risk of hypoglycemia.
 Before initiation of therapy with JANUMET, and at least annually thereafter, renal function
should be assessed and verified as normal. In patients in whom development of renal
dysfunction is anticipated, renal function should be assessed more frequently and JANUMET
discontinued if evidence of renal impairment is present.
JANUMET™ (sitagliptin/metformin, MSD) Warnings and
Precautions: Based on Worldwide Product Circular
 In clinical studies, the most common adverse reactions reported,
regardless of investigator assessment of causality, in ≥5% of patients
and more commonly than in patients treated with placebo were as
follows: diarrhea, upper respiratory tract infection, and headache (for
initial sitagliptin and metformin combination therapy); nasopharyngitis
(for sitagliptin monotherapy); and diarrhea, nausea/vomiting,
flatulence, abdominal discomfort, indigestion, asthenia, and
headache (for metformin therapy).
Initial Fixed-Dose Combination Therapy With
JANUMET™ vs Metformin Monotherapy:
Conclusions
Compared with metformin alone, in patients with
type 2 diabetes and moderate to severe hyperglycemia
on diet and exercise initial combination therapy with
sitagliptin/metformin FDC (JANUMET) provided1,2
• Superior glycemic improvements resulting in more patients
achieving HbA1c goal
• A similar incidence of hypoglycemia, and lower incidences of
abdominal pain and diarrhea compared with metformin alone.
FDC=fixed-dose combination.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
2. Data on file, MSD.
Bibliography
Data on file, MSD.
Reasner C, Olnasky L, Seck TL, et al. Initial therapy with the fixed-dose combination
(FDC) of sitagliptin and metformin (JANUMET™) in patients with type 2 diabetes
mellitus provides superior glycemic control and hemoglobin A1C goal attainment with
lower rates of abdominal pain and diarrhea versus metformin alone. Poster presented
at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–
9, 2009.
Before prescribing JANUMET™ (sitagliptin/metformin, MSD), please
read the Prescribing Information available at this presentation.
Merck does not recommend the use of any product in any different
manner than as described in the Prescribing Information.
Copyright © 2009 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.
06-2010-JAN-09-PH-8029-SS
(JAN-2009-W-1308137-SS)
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