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Role of DPP4 inhibition in the management of
Type 2 Diabetes
Current Evidences with Sitagliptin
Fasting State• Blood glucose tends to fall• Insulin Secretion lowered• Increased Glucagon secretion
from Alpha cells• Increased Hepatic Glucose
output• Results Euglycemia
Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254
Postprandial State
• Rising Blood Glucose• Insulin secretion Increases,
Glucagon decreases• Increased Peripheral uptake of
Glucose• Decreased Hepatic Glucose output• Results Euglycemia
Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254
Decreased Insulin, Elevated Glucagon, and Hyperglycemia in Type 2 Diabetes
Adapted with permission in 2006 fromMüller WA et al. N Engl J Med. 1970;283:109–115. Copyright © 1970 Massachusetts Medical Society. All rights reserved.
Glucose, mg %
Insulin, μ/mL
Glucagon, μ/mL
360
330
300
270
240
110
80
Meal
120
90
60
30
0
–60 0 60 120 180 240
140
130
120
110
100
90
Healthy subjects(n=11)
Type 2 diabetes(n=12)
Minutes
Is Insulin Secretion from the beta cells a function of ambient glucose level?
A look at the Intestinal Factors in Insulin Secretion; The Incretins
The Incretin Effect in Subjects Without and With Type 2 Diabetes
IR=Immune Reactive.Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.
Time, min
IR In
sulin
, mU
/L nm
ol/L
0.6
0.5
0.4
0.3
0.2
0.1
0
80
60
40
20
0
18060 1200
Control Subjects (n=8)
Patients With Type 2 Diabetes (n=14)
Time, min
IR In
sulin
, mU
/L nm
ol/L
0.6
0.5
0.4
0.3
0.2
0.1
0
80
60
40
20
0
18060 120 0
Oral glucose load Intravenous (IV) glucose infusion
Incretin Effect
The incretin effect is diminished
in type 2 diabetes.
GLP-1 Modes of Action in Humans
GLP-1 is secretedfrom the L-cellsin the intestine
This in turn…
• Stimulates glucose-dependent insulin secretion
• Suppresses glucagon secretion
• Slows gastric emptying
Long term effectsdemonstrated in animals…
• Increases beta-cell mass and maintains beta-cell efficiency
• Reduces food intake
Upon ingestion of food…
Drucker DJ. Curr Pharm Des 2001; 7:1399-1412Drucker DJ. Mol Endocrinol 2003; 17:161-171
Role of Dipeptidyl Peptidase-4
1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913. 2. Ahrén B. Curr Diab Rep. 2003;2:365–372.3. Drucker DJ. Diabetes Care. 2003;26:2929–2940. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.
Insulin synthesis and secretion from beta cells
(GLP-1 and GIP)
Glucagon fromalpha cells
(GLP-1)
Release of gut hormones— Incretins1,2
Pancreas2,3
Glucose DependentGlucose DependentGlucose DependentGlucose Dependent
ActiveGLP-1 & GIP
DPP-4 enzyme
InactiveGIP
InactiveGLP-1
Glucose DependentGlucose DependentGlucose DependentGlucose Dependent
↓ ↓ Blood Blood glucoseglucose
GI tractGI tract
↓↓Glucose Glucose production production
by liverby liver
Food ingestionFood ingestion
↑↑Glucose Glucose uptake by uptake by peripheral peripheral
tissuetissue2,42,4
Beta cellsBeta cellsAlpha cellsAlpha cells
*
GLP-1 Levels Are Decreased in Type 2 Diabetes
** *
*
**
Control (n=33)Type 2 diabetes (n=54)
0
5
10
15
20
0 60 120 180 240
GL
P-1
(p
mo
l/L
)
*p<0.05, type 2 diabetes vs control
Adapted from Toft-Nielsen M-B et al. J Clin Endocrinol Metab. 2001;86:3717–3723.
Meal Started
Meal Finishe
d
(10–15)
Time after start of meal, minutes
BUT, the levels are never ZERO
DPP4 activity increases in Hyperglycemia
0
5
10
15
20
25
30
T2DM T2DM-ND IGT NGT
T2DM
T2DM-ND
IGT
NGT
Mannucci et al, Diabetologia April 2005
Incretin Based Therapies
GLP1 receptor agonists(DPP4 resistant)
Incretin Enhancers(DPP4 Inhibitors)
Substrate-like inhibitors(Vildagliptin, Saxagliptin)
1st Generation Gliptins(Shorter Half Life,
Less DPP4 Specificity)
Non Substrate-like inhibitors
(Sitagliptin, Alogliptin)2nd Generation Gliptins
(Longer Half Life,Very High DPP4 Specificity)
Exendin Based Therapies
(Exenatide)
Human GLP1 Analogue
(Liraglutide)
doi:10.1016/j.bcp.2008.07.029 Lambeir, Scharpe, Meester10.1002/ddr.20138, von Geldern, Trevillyan
Sitagliptin - Overview
• First and ONLY 2nd Generation DPP4 inhibitor available for patient benefits and approved by the FDA on October 17 2006. Also approved by EMeA, March 2007
• Unique >100 fold selectivity for DPP4 (over DPP8 & 9)
• Fully reversible and competitive inhibitor• Most Widely Used Gliptin (currently >19 million patients
worldwide)
N
ONH2
NN
CF3
F
F
F
N
Glucose dependent Insulin from beta cells(GLP-1 and GIP)
Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:2653–2659; Zander M et al Lancet 2002;359:824–830; Ahrén B Curr Diab Rep 2003;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.
Hyperglycemia
Sitagliptin Improve Glucose Control by Normalizing Incretin Levels in Type 2 Diabetes
Glucagon from alpha cells
(GLP-1)Glucose
dependent
Release of incretins from the
gut
Pancreas
α-cellsβ-cells
Insulinincreases peripheral glucose uptake
Ingestion of food
GI tract
↑insulin and ↓glucagon reduce hepatic glucose output
Inactive incretins
Improved Physiologic
Glucose Control
DPP-4 Enzyme
SITAGLIPTINDPP-4
Inhibitor
X
DPP-4 = dipeptidyl peptidase 4
Pharmacokinetics of 100mg Sitagliptin Supports Once-Daily
Dosing• >80% DPP4 inhibition for 24hrs, >90% for16hrs
>80% inhibition required for full Incretin enhancement
• No effect of food on pharmacokinetics
• Tmax app 2 hours, t1/2 app 12.4 hours at 100 mg dose
• Low protein binding, app 38%
• Minimal Metabolism in the Liver, primarily renal excretion as parent drug
– ~80% of a dose recovered as intact drug in urine
• No clinically important drug-drug interactions
– No meaningful P450 system inhibition or activation
What is the effect of a Single Tablet of Sitagliptin?
OGTT 24 hrs (n=19)
Herman et al. Diabetes. PN005, 2005.
Active GLP-1
A Single Dose of Sitagliptin
Increased Active GLP-1 and GIP
Over 24 Hours
0
5
10
15
20
25
30
35
40
0 2 4 6 24 26 28
Hours Postdose
GL
P-1
(p
g/m
L)
OGTT 2 hrs (n=55)
Crossover study in patients with T2DM Placebo
Sitagliptin 25 mg
Sitagliptin 200 mg
2-fold increase in active GLP-1
p< 0.001 vs placebo
Active GIP
0
10
20
30
40
50
60
70
80
90
0 2 4 6 24 26 28
Hours Postdose
GIP
(p
g/m
L)
OGTT 24 hrs (n=19)
OGTT 2 hrs (n=55)
2-fold increase in active GIP
p< 0.001 vs placebo
A Single Dose of Sitagliptin Increased Insulin, Decreased Glucagon, and Reduced Glycemic
Excursion After a Glucose Load
Placebo
Sitagliptin 25 mg
Sitagliptin 200 mg
0
10
20
30
40
0 1 2 3 4
mcI
U/m
L
50
55
60
65
70
75
0 1 2 3 4
Time (hours)
pg
/mL
Glucose load
Drug Dose 22%
~12%
Insulin
Glucagon
Crossover Study in Patients with T2DM
p<0.05 for both dose comparisons to placebo for AUC
p<0.05 for both dose comparisons to placebo for AUC
Glucose load
Drug Dose
120
160
200
240
280
320
0 1 2 3 4 5 6
Time (hours)
Glucose
~26%
p<0.001 for both dose comparisons to placebo for AUC
Is Sitagliptin effective as Monotherapy?
Mea
n C
ha
ng
e in
A1C
, %
‡
A1C
CI=confidence interval. *Compared with placebo. †Least-squares means adjusted for prior antihyperglycemic therapy status and baseline value. ‡Difference from placebo. §Combined number of patients on JANUVIA or placebo. ||P<0.001 overall and for treatment-by-subgroup interactions. 1. Raz I et al. Diabetologia. 2006;49:2564–2571.2. Aschner P et al. Diabetes Care. 2006;29:2632–2637.
Mean Baseline: 8.0% P<0.001*
–0.6†
–1.0
–0.8
–0.6
–0.4
–0.2
0.0
–0.8†
Placebo-adjusted results
24-week monotherapy study2
(95% CI: –1.0, –0.6)
18-week monotherapy study1
(95% CI: –0.8, –0.4)
n=193
n=229
Inclusion Criteria: 7%–10%
Overall <8 ≥8–<9 ≥≥99Baseline A1C, %
–1.4
–0.6–0.7
–1.8
–1.6
–1.4
–1.2
–1.0
–0.8
–0.6
–0.4
–0.2
0.0
n=411§
n=239§
n=119§
Mea
n C
ha
ng
e in
A1C
, %
Prespecified Pooled Analysis at 18 Weeks||
–0.7
n=769§
Sitagliptin: Significant A1C Reductions as Monotherapy
Is it a PP Drug or a Fasting Drug?
Sitagliptin Monotherapy Impacts both FPG and PPG
Fasting Glucose
Pla
sma G
luco
se m
g/d
L
Time (weeks)
0 5 10 15 20 25144
153
162
171
180
189
Placebo (n=247)Sitagliptin 100 mg (n=234)
FPG* = –17.1 mg/dL (p<0.001)
Post-meal Glucose
Time (minutes)
Pla
sma
Glu
cose
mg
/dL
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
* LS mean difference from placebo after 24 weeks Adapted from Aschner et al. Diabetes Care. 2006;29:2632–2637.
How Fast does Sitagliptin Start Working?
Rapid Improvement in Blood Glucose in the First Days of Monotherapy
• Baseline A1c 7.8% (ABG ~ 202)
• After 3 days, Average Blood Glucose -20.4)• After 7 days, Average Blood Glucose -23.5)
• After 24 weeks, the mean changes from baseline for A1C, FPG (FFPG) and PPG were −0.7%, −27 mg/dL, and −61 mg/dL, respectively
• Greater reductions in ABG on Day 7 were observed in patients with higher baseline A1C and FPG
Is Sitagliptin effective when sensitizers fail?
Add-on to patients
failing on pioglitazone2
Mean Baseline A1C: 8.0%, 8.1%
Me
an
Ch
an
ge
in
A1
C F
rom
Ba
se
lin
e,
%SITAGLIPTIN: Significant A1C Reductions From
Baseline When Added to Metformin or Pioglitazone
n=224
Metformin+ Sita
–1.0
–0.8
–0.6
0
–1.0
0
Me
an
Ch
an
ge
in
A1
C F
rom
Ba
se
lin
e,
%–0.7%
Mean Baseline A1C: 8.0%
P<0.001*
P<0.001*
Add-on to patients
uncontrolled on metformin 1
–0.0%
Metformin+ Placebo
Pioglitazone+ Sita
Pioglitazone+ Placebo
*Compared with placebo.1. Charbonnel B et al. Diabetes Care. 2006;29:2638–2643.2. Rosenstock J et al. Clin Ther. 2006;28:1556–1568.
n=453 n=174 n=163
0.7% placebo-subtracted result
0.7% placebo-subtracted result
–0.9%
–0.4
–0.2
–0.8
–0.6
–0.4
–0.2
–0.2%
Is Sitagliptin’s efficacy comparable to that of a Sulfonylurea?
aSpecifically glipizide; bSitagliptin 100 mg/day with metformin (≥1500 mg/day);
Per-protocol population; LS=least squares.
Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205.
HbA1c Over Time With Sitagliptin or Glipizide
as Add-on Combination With Metformin: Comparable Efficacy
LS mean change from baseline (for both groups): –0.67%
Achieved primary hypothesis of
noninferiority to sulfonylurea
Sulfonylureaa + metformin (n=411)
Sitagliptinb + metformin (n=382)
Hb
A1
c (
% ±
SE
)
Weeks
6.2
6.4
6.6
6.8
7.0
7.2
7.4
7.6
7.8
0 6 12 18 24 30 38 46 52
8.0
8.2
Continuous Up-titration in Glipizide arm
Effects of Sitagliptin and Glipizide on Body Weight and Hypoglycemia
LS Mean Change in Body Weight (kg) Over Time
(APaT population)
Overall Number of Episodes of Hypoglycemia:
Week 0 Through Week 104
805
57
0
200
400
600
800
1000
Week 104 To
tal N
um
ber
of E
pis
od
es, (
n)
Glipizide Sitagliptin 100 mg/d
*(95% CI) LS Means Change in Body Weight (kg) in Between Treatment Groups
Sitagliptin 100 mg/d(n = 253)
Glipizide(n = 261)
LS
Mea
n C
han
ge
Fro
m B
asel
ine
(kg
)
0 12 24 38 52 78 104
–2
–1
0
1
2
Week
∆=−2.3 (−3.0, −1.6)*
CSR
Incidences similar to Placebo+Metformin
Will Sitagliptin work in very late Diabetes?
Pooled Results from all Phase III studies of Sitagliptin 100mg
monotherapyGlycemic endpoints analyzed by duration of type 2 diabetes
Influence of Measures of Beta Cell Function on Efficacy of Sitagliptin in Patients with Type 2 Diabetes – pooled analysis of data from 4 phase III placebo controlled studies of Sitagliptin 100 mg monotherapy, involving 1691 patients. Poster by Harvey L. Katzeff et al. at ADA 2008.
Pla
ceb
o a
dju
sted
LS
mea
n c
han
ge
fr
om
bas
elin
e H
bA
1c
,%,
(95%
CI)
Pla
ceb
o a
dju
sted
LS
mea
n c
han
ge
fro
m
bas
elin
e F
PG
mg
/dl,
(95
% C
I)
Pla
ceb
o a
dju
sted
LS
mea
n c
han
ge
fro
m
bas
elin
e 2-
h P
PG
mg
/d)
(95%
CI)
*Significant reduction of A1c across all duration
Sitagliptin Improved A1C When Added to Glim + MF
*T2DM of long duration
Δ -0.9%; p<0.001*
*Difference in LS Mean change from baseline
Hermansen et al, Diabetes Obesity Metabolism 2007
Weeks
0 6 12 18 24
A1
C (%
)
7.2
7.6
8.0
8.4
8.8
Sitagliptin +Glim + MF (n=116)Placebo + Glim + MF (n=113)
Will Sitagliptin work when Beta cell function is very poor?
Influence of Measures of Beta Cell Function on Efficacy of Sitagliptin in Patients with Type 2 Diabetes – pooled analysis of data from 4 phase III placebo controlled studies of Sitagliptin 100 mg monotherapy, involving 1691 patients. Poster by Harvey L. Katzeff et al. at ADA 2008.
Glycemic endpoints analyzed by baseline HOMA β
Pooled Results from all Phase III studies of Sitagliptin 100mg monotherapy
*Significant efficacy shown even when baseline Beta cell function is poor
Any Indian Data with Sitagliptin?
Placebo Subtracted Change from Baseline in HbA1c Per Country
Country
Placebo Subtracted % A1c change
*Baseline 8.74%
95% Confidence limits
India -1.36 (-1.73, -0.99)
China -0.69 (-0.92, -0.46)
Korea -1.38 (-1.92, -0.83)
DRCP Mohan Yang Son, 2009 Jan;83(1):106-16. Epub 2008 Dec 20
Sitagliptin helps to improve beta-cell function and increases insulin synthesis and release.
Sitagliptin helps to reduce HGO through suppression of glucagon from alpha cells.
Metformin decreases HGO by targeting the liver to decrease gluconeogenesis and glycogenolysis.
Metformin has insulin- sensitizing properties.
Beta-Cell Dysfunction
Hepatic Glucose Overproduction
(HGO)
Hepatic Glucose Overproduction
(HGO)
Sitagliptin Reduces HyperglycemiaMetformin Reduces HyperglycemiaThe Combination of Sitagliptin and MetforminAddresses the 3 Core Defects of T2DM in a
Complementary Manner
Insulin Resistance
*Please see corresponding speaker note for references.
Co-administration of Sitagliptin and Metformin in Healthy Adults Increased Active GLP-1 Greater Than Either Agent Alone
* Values represent geometric mean±SE.
Placebo
Metformin 1000 mg Sitagliptin 100 mg
Co-administration of sitagliptin 100 mg + metformin 1000 mg
Mean AUC ratio*Sita + Met: 4.12
Mean AUC ratios*Sita: 1.95 Met: 1.76
–20
10
20
30
40
50
–1 0 1 2 3 4
Act
ive
GLP
-1
Con
cent
ratio
ns, p
M
MealMorning Dose Day 2 Time (hours pre/post meal)
N=16 healthy subjectsAUC=area under the curve
Migoya EM et al. 67th ADA 2007. Oral Presentation OR-0286.Data available on request from Merck & Co., Inc. Please specify 20752937(1)-JMT.
Metformin + Sitagliptin: Effect on Incretin Axis
Mean A1C = 8.8%
Sitagliptin 50 mg + metformin 1,000 mg bid
Metformin 1,000 mg bid
Sitagliptin 100 mg qd
Sitagliptin 50 mg + metformin 500 mg bid
Metformin 500 mg bid
LS
M A
1C C
han
ge
Fro
m B
asel
ine,
%
–3.5
–3.0
–2.5
–2.0
–1.5
–1.0
–0.5
0.0
0.5
n=178 n=177 n=183 n=178n=175
–0.8a
–1.0a
–1.3a
–1.6a
–2.1a
Open label
n=117
–2.9b
All patients Treated Populationa LSM placebo adjusted change b LSM change from baseline without adjustment for placebo.bid=twice a day; qd=once a day.
24-Week Placebo-Adjusted Results
A1C Results at 24 Weeks
Mean A1C = 11.2%
Sitagliptin With Metformin Coadministration Initial Therapy Study
Goldstein et al. Diabetes Care 2007; 30: 1979-1987
>77% of patients achieved target A1c in Sita Met1000 arm
Efficacy with Other Sensitizers?
Initial Combination of Sitagliptin with Pioglitazone
2.4%2.4%
1.5%1.5%
3%3%
> 10%
FPG -63
FPG -40
Sita+P30P30
Sita+P30
9.5%
Sita-Pio combination currently undergoing Phase III Trials
For How Long Will Sitagliptin Continue to work?
Long-Term Efficacy with Sitagliptin as Monotherapy or Add-On Therapy to Metformin
ADA 2009 Abstract 540-P
Can Sitagliptin be used with Insulin?
Robust Reduction of A1c when used in patients uncontrolled with Insulin
0.60.6 0.0
Insulin+Sitagliptin Insulin+Placebo
• Average duration of Diabetes ~13 years• Double the reduction achieved with other Gliptins
Baseline 8.7%
Efficacy of Sitagliptin with Glargine
1.69%1.69%
Baseline 8.1%Glar+Sita+Met Glar+Met
1.37%1.37%
Sitagliptin now approved with Insulin by EU
How Safe is Sitagliptin?
Safety and Tolerability Overview
• Completed and ongoing studies more than 8000 patients on sitagliptin (to doses upto 800 mg q.d.)
– 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
– No Significant Drug-Drug Interaction, except increased risk of Hypoglycemia with Sulfonylureas, thus necessitating use of lower dose of SU
Summary Measures of Clinical Adverse Events for Sitagliptin is Similar to Placebo
Pooled Phase III Population Placebo(N=778)
Sitagliptin 100 mg(N=1082)
Sitagliptin 200 mg(N=456)
% of Patients with % % %One or more AEs 55.5 55.0 54.2
Drug-related AEs 10.0 9.5 9.4
Serious AEs 3.2 3.2 3.3
Drug-related SAEs 0.1 0.3 0.0
Deaths 0.0 0.0 0.0
Discontinued due to AE 1.9 2.6 0.9Discontinued due to drug-related AE 0.8 0.6 0.0
Discontinued due to SAE 0.6 1.3 0.7Discontinued due to drug-related SAE 0.1 0.1 0.0
Recommended dose in proposed label: 100 mg q.d.
Cardiovascular Safety 2 years Data
• Only Gliptin with a 2 years Cardio-safety data
• Overall Incidence Rates of Serious Adverse Events, 1.2% vs 1.5% (Sita vs Placebo)
• Ischemia 2% vs 2.3%• Serious Ischemia related events, 1.1% vs 1.5%• Fatal Cardiac events, 0.09% vs 0.23%
Clinically Insignificant Differences in Incidence of AEs: Pooled Phase III Population
Placebo (N = 778)
Sitagliptin 100 mg (N = 1082)
% % Difference vs Placebo
(95% CI)
Upper Respiratory Tract Infection
6.7 6.8 0.1
Headache 3.6 3.6 0
Nasopharyngitis
3.3 4.5 1.2
Diarrhea 2.3 3.0 0.7
Arthralgia 1.8 2.1 0.3
Urinary Tract Infection
1.7 1.7 0
AEs with at least 3% incidence and Numerically Higher in Sitagliptin than Placebo Group
Safety in Hepatic Impairment
• Sitagliptin is studied and only Gliptin approved for use in mild to moderate hepatic impairment, but not in fulminant hepatitis as it is not studied in these cases.
• Reason of safety, primarily excreted unchanged in urine, unlike most other drugs which are metabolized in the liver
• 2 years pooled safety analysis showed no risk of increased liver enzymes post treatment, and was safe and effective in patients with pretreatment elevated liver enzymes 3xULN
Patients With Renal Insufficiency
Renal Insufficiency
Mild ModerateSevere and
ESRD*
Increase in Plasma AUC of Sitagliptin†
~1.1 to 1.6-fold increase‡
~2-fold increase
~4-fold increase
Recommended Dose
100 mg no dose
adjustment required
50 mg 25 mg
• To achieve plasma concentrations similar to patients with normal renal function, lower doses of Sitagliptin
are recommended in moderate and severe renal insufficiency.
ESRD=end-stage renal disease; AUC=area under the curve.*Includes patients on hemodialysis or peritoneal dialysis.†Compared with normal healthy control subjects.‡Not clinically relevant.
Studied in post-Renal Transplant cases; Effective and SafeNo change in tacrolimus/sirolimus (Immunosuppressive drugs) levels
Safety related to Pancreatitis
0.00%
0.10%
0.20%
0.30%
0.40%
0.50%
Exentd Sita Ctrl
Incidences ofPancreatitis
• 540 Days• 13 million patients
•No Increased Risk of Pancreatitis with Sitagliptin in any Randomized trial
•88 cases reported by FDA based upon Voluntary submissions, out of over 10 million patients, No claim of establishing cause effect relationship by FDA
Hypoglycemia; How Safe is Sitagliptin
Sitagliptin Lowers A1C Without Increasing the Incidence of Hypoglycemia or Leading
to Weight Gain
Placebo Sitagliptin 100 mg q.d. Sitaglitpin 200 mg q.d.
Patients with hypoglycemia (%)
0.9% 1.2% 0.9%
• Neutral effect on body weight
– In monotherapy studies, small decreases from baseline (~ 0.1 to 0.7 kg) with sitagliptin; slightly greater reductions with placebo (~ 0.7 to 1.1 kg)
– In combination studies, weight changes with sitagliptin similar to placebo-treated patients
ADA-EASD Consensus Statement; Sitagliptin Does Not cause Hypoglycemia when used as monotherapy
Hypoglycemia
Weight Changes
JANUVIA™ (sitagliptin)
Indications and Usage
• Monotherapy– JANUVIA is indicated as an adjunct to diet and exercise to
improve glycemic control in patients with type 2 diabetes mellitus.
• Combination therapy
– JANUVIA is indicated in patients with type 2 diabetes mellitus to improve glycemic control in combination with metformin or a PPAR agonist (eg, thiazolidinediones) when the single agent alone, with diet and exercise, does not provide adequate glycemic control.
• Important limitations of use
– JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.
Please ADD ON, Do Not REPLACE
PPARγ=peroxisome proliferator-activated receptor gamma.
Use in Specific Populations• Pregnancy (Category B)
– No adequate and well-controlled studies in pregnant women. JANUVIA should be used during pregnancy only if clearly needed.
• Nursing Mothers
– Not known whether sitagliptin is excreted in human milk. Caution should be exercised when administered to a nursing woman.
• Pediatric Use
– Safety and effectiveness in pediatric patients are not established.
• Geriatric Use
– No overall differences in safety and efficacy observed between subjects upto 95 years and younger subjects.
– No dosage adjustment is required based solely on age.
• Because the elderly are more likely to have decreased renal function, it may be useful to assess renal function before initiating dosage and periodically thereafter.
50 mg once daily 25 mg once daily
Moderate Severe and ESRD‡
CrCl 30 to <50 mL/min(~Serum Cr levels [mg/dL]
Men: >1.7–≤3.0; Women: >1.5–≤2.5)
CrCl <30 mL/min(~Serum Cr levels [mg/dL]Men: >3.0; Women: >2.5)
Dosage and Administration• Usual Dosing for JANUVIA™ (sitagliptin phosphate)*
The recommended dose of JANUVIA is 100 mg once daily
as monotherapy or as combination therapy with metformin or a PPAR agonist.
• Patients With Renal Insufficiency*,†
*JANUVIA can be taken with or without food. †Patients with mild renal insufficiency—100 mg once daily.‡ESRD = end-stage renal disease requiring hemodialysis or peritoneal dialysis.
Positioning of Sitagliptin + Metformin (Janumet) FDC
• This FDC is for drug naïve, newly detected T2DM patient uncontrolled on LSM alone
• Positioning is as first line therapy• It is dosed twice daily
(Sitagliptin50mg, Metformin500mg)
(Sitagliptin50mg, Metformin1000mg)
Janumet OD with Extended Release Metformin currently being developed
DPP4 Inhibitors, position in Guidelines
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