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Pathophysiology of type 2 diabetes and mechanism of action of sitagliptin
Clinical data overview of sitagliptin:Monotherapy (PN021, 023, A201)
Complexities of getting patients to goal: a rationale for earlier combination therapy
Mechanism of action of the co-administration of sitagliptin plus metformin
Clinical data overview of combination therapy with sitagliptin and metformin 8
Major Pathophysiologic Defects in Type 2 Diabetes
Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.
Hepatic glucoseoutput
Insulin resistance
Glucose uptake
Glucagon(α cell)
Insulin(β cell)
LiverLiver
Hyperglycaemia
Islet-Cell Dysfunction
MuscleMuscleAdipose Adipose tissuetissue
PancreasPancreas
4
Mechanism of Action of Sitagliptin
Release ofactive incretins
GLP-1 & GIP Blood glucose in fasting and postprandial
states
Ingestion of food
Glucagon(GLP-1)
Hepatic glucose
production
GI tract
DPP-4 enzyme
InactiveGLP-1
XJANUVIA(DPP-4
inhibitor)
Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels in response to a meal.
Insulin(GLP-1and
GIP)
Glucosedependent
Glucose-dependent
Pancreas
InactiveGIP
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.
Concentrations of the active intact hormones are increased by JANUVIA™ (sitagliptin phosphate), thereby increasing and prolonging the actions of these hormones.
Beta cellsAlpha cells
Glucose uptake by peripheral
tissue
Sitagliptin - Overview
Provides potent and highly selective inhibition of the DPP-4 enzyme
Fully reversible and competitive inhibitor
DPP-4 inhibitor in development for the treatment of patients with type 2 diabetes, approved by the FDA on October 17 2006, and approved in EU on March 26 2007
Approved in Korea on September 21 2007
N
ONH2
NN
CF3
F
F
F
N
Pharmacokinetics of Sitagliptin Supports Once-Daily Dosing
With once-daily administration, trough (at 24 hrs) DPP-4 inhibition is ~ 80%> 80% inhibition provides full enhancement of active incretin levels
No effect of food on pharmacokinetics Well absorbed following oral dosing
Tmax app 2 hours, t1/2 app 12.4 hours at 100 mg doseLow protein binding, app 38% Primarily renal excretion as parent drug
Approximately 80% of a dose recovered as intact drug in urine
No clinically important drug-drug interactionsNo meaningful P450 system inhibition or activation
Single-Dose OGTT Study
One Dose of Sitagliptin Inhibited Plasma DPP-4 Activity
Hours post-dose
~80%
~50%
Trough DPP-4inhibition
Inhi
bitio
n of
pla
sma
DPP
-4ac
tivity
from
bas
elin
e (%
)
0 1 2 4 8 12 16 20 24–10
0
40
50
60
80
100
90
70
30
20
10
6 10 14 18 22 26
OGTT
Sitagliptin 25 mg (n=56)Sitagliptin 200 mg (n=56)Placebo (n=56)
OGTT=oral glucose tolerance test; AUC=area under the curveHerman et al. J Clin Endocrinol Metab, November 2006, 91(11):4612–4619. PN005
OGTT 24 hrs (n=19)
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
GLP
-1 (p
g/m
L)
Hours Postdose
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
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
Herman et al. J Clin Endocrinol Metab, November 2006, 91(11):4612–4619. PN005
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 4Time (hours)
pg/m
L
Glucose load
Drug Dose 22%
~12%
Insulin
Glucagon
p<0.05 for both dose comparisons to placebo for AUC
Crossover Study in Patients with T2DM
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 6Time (hours)
Glucose
~26%
p<0.001 for both dose comparisons to placebo for AUC
Herman et al. J Clin Endocrinol Metab, November 2006, 91(11):4612–4619. PN005
Contents
Pathophysiology of type 2 diabetes and mechanism of action of sitagliptin
Clinical data overview of sitagliptin:Monotherapy (PN021, PN023, A201, and PN040)
Complexities of getting patients to goal: a rationale for earlier combination therapy
Mechanism of action of the co-administration of sitagliptin plus metformin
Clinical data overview of combination therapy with sitagliptin and metformin 8
11
Sitagliptin Consistently and Significantly Lowers A1C with Once-Daily Dosing in Monotherapy
7.2
7.6
8.0
8.4
Placebo (n=244)
Sitagliptin 100 mg (n=229)
Time (weeks)
24-week Study
0 5 10 15 20 25
-0.79%(p<0.001)
*between group difference in LS means
Japanese Study
-1.05%(p<0.001)
Placebo (n=75)
Sitagliptin 100 mg (n=75)
Time (weeks)
0 4 8 12
A1C
(%)
7.6
8.0
8.4
7.2
6.8
Δchange vsplacebo*
18-week Study
Placebo (n=74)
Sitagliptin 100 mg (n=168)
Time (weeks)
0 6 12 18
A1C
(%)
7.2
7.6
8.0
8.4
-0.6%(p<0.001)
A1C
(%)
=
Raz I et al. Diabetologia 2006;49:2564-2571 ; PN023; Aschner P et al. Diabetes Care 2006;29:2638-2643 ; PN021; Nonaka K et al; A201. Abstracts presented at: ADA 2006
Sitagliptin Provides Significant and Progressively Greater Reductions in A1C with Progressively Higher Baseline A1C
Reductions are placebo-subtracted
Baseline A1c (%)
Mean (%)
Red
uctio
n in
A1c
(%)
Inclusion Criteria: 7%–10%
Red
uctio
n in
A1c
(%)
<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
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
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
N=130
N=62
N=37
Raz I et al. Diabetologia 2006;49:2564-2571 ; PN023; Aschner P et al. Diabetes Care 2006;29:2638-2643 ; PN021; Nonaka K et al; A201. Abstracts presented at: ADA 2006
Sitagliptin Once Daily Significantly Improves Both Fasting and Post-meal Glucose In Monotherapy
* LS mean difference from placebo after 24 weeks Aschner P et al, PN021. Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC
Fasting Glucose
Pla
sma
Glu
cose
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)
Time (minutes)
Post-meal Glucose
Pla
sma
Glu
cose
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
Sitagliptin Improved Markers of Beta-Cell Function In 24-Week Monotherapy Study
Proinsulin/insulin ratio
p< 0.001*
*P value for change from baseline compared to 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 /
pmol
/L)
HOMA-β
p< 0.001*
∆ from baseline vs pbo = 13.2 (95% CI 3.9, 21.9)
Placebo Sitagliptin 100 mg0.3
0.35
0.4
0.45
0.5
0.55
30
35
40
45
50
55
60
65
70
75
80
Raz I et al. Diabetologia 2006;49:2564-2571 ; PN023; Aschner P et al. Diabetes Care 2006;29:2638-2643 ; PN021; Nonaka K et al; A201. Abstracts presented at: ADA 2006
Sitagliptin Monotherapyin Asian Patients (PN040)
A Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of Sitagliptin
Monotherapy in Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control
Study Design
AHA = antihyperglycemic agent; FPG = fasting plasma glucose; R = randomization; T2DM = type 2 diabetes mellitus.
Single-Blind Placebo
Sitagliptin100 mg
Pbo
Screening Period
• Patients with T2DM
• ≥18 years of age
• Not on AHA A1C ≥7.5% and ≤11%
• On AHA A1C ≥7% and ≤10%
Double-Blind Treatment Period
Diet/ExerciseRun-in Period
R
Single-Blind
Placebo Run-in
A1C ≥7.5 and ≤11% FPG ≥130 mg/dL and ≤ 280 mg/dL
Visit 1ScreeWk –9
ning Visit 2Run-in
Start Wk –8
Visit 4Wk –2
Start SB
Visit 5Day 1
Randomization
Visit 8Wk 18
Visit 3Wk –5
Visit 6Wk 6
Visit 7Wk 12
Baseline Glycemic and Disease Characteristics Balanced Between Groups
Age (yrs)
BMI (mean, kg/m2 )
A1C (%)
FPG (mg/dl)
Fasting insulin (μIU/mL )
Duration of Diabetes Mellitus ( yrs)
HOMA Beta (%)
Characteristic
50.9 ± 9.3
24.9 ± 3.4
8.75 ± 1.06
181.6 ± 42.5
10.0 ± 8.4
1.9 ±1.6
32.0
Placebo
(n=178)Sitagliptin
(n=352)
50.9 ± 9.3
25.1 ± 3.4
8.74 ± 1.01
189.0 ±
44.0
9.7 ± 8.2
2.1 ± 1.7
33.0
Change from Baseline in HbA1c Full-Analysis-Set Population
0 6 12 18
Week
-0.8
-0.6
-0.4
-0.2
0.0
0.2
LS M
ean
Cha
nge
from
Bas
elin
e
0.4
Sitagliptin 100 mg Placebo
-1.03%
Change from Baseline Per Country
Country GroupPlacebo
Subtracted % A1c change
Placebo Subtracted
mg/dL FPG
Placebo Subtracted
mg/dL PPG
Sita (n=119)India
Plbo (n=59)
ChinaPlbo (n=79)
Plbo (n=31)Korea
-38.8 -49.8
Sita (n=158)
-1.36
-0.68
-1.37
-18.2 -49.9
Sita (n=62)-54.5 -90.6
HbA1c Reduction in Korean Diabetes Patients
GroupPlacebo
Subtractedmg/dL FPG
Placebo Subtractedmg/dL PPG
Sita (n=62)Plbo (n=31)
-54.5 -90.6
Mea
n ch
ange
of A
1Cfr
om b
asel
ine(
%)
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
12wks 18wks
Sitagliptin vs. placebo = -1.37%
-10wks 6wks
Sitagliptin
Placebo
Summary(PN040: Sitagliptin Monotherapy in Asian patients)
Sitagliptin demonstrated strong glycemic efficacy compared to placebo, as measured by HbA1c, FPG and PPG
Sitagliptin was overall well tolerated
No hypoglycemia
For adverse experiences within GI system organ class, a higher incidence was observed with Sitagliptin
Contents
Pathophysiology of type 2 diabetes and mechanism of action of sitagliptin
Clinical data overview of sitagliptin:Monotherapy (PN021, 023, A201)
Complexities of getting patients to goal: a rationale for earlier combination therapy
Mechanism of action of the co-administration of sitagliptin plus metformin
Clinical data overview of combination therapy with sitagliptin and metformin 8
ADA and IDF Guidelines:Treatment Goals for HbA1c, FPG, and PPG
ParameterNormalLevel
ADA Goal
IDF Goal
FPG, mg/dl(mmol/L)
<110(<6.1)
90–130(5.0–7.2)
<100(<5.5)
PPG, mg/dl(mmol/L)
<140(<7.8)
<180(<10.0)
<140(<7.8)
HbA1c 4%–6% <7%* <6.5%
*Reference to a nondiabetic range of 4.0% to 6.0% using a DCCT-based assay.ADA=American Diabetes Association; IDF=International Diabetes Federation.American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41; International Diabetes Federation. 2007:1–32.Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483.
9
Societies Recommend Earlier Intervention to Help Attain Glycaemic Control
2006 Consensus statement from the ADA and EASD“Our consensus is that an HbA1c of ≥7 should serve as a call to action to initiate or change therapy…”
“If lifestyle intervention and maximal tolerated dose of metformin fail to achieve or sustain glycaemic goals, another medication should be added within 2–3 months of the initiation of therapy or at any time when HbA1c goal is not achieved”
2005 Global Guideline by IDF“Begin with metformin unless evidence or risk of renal impairment, titrating the dose over early weeks to minimise discontinuation due to gastro-intestinal intolerance”
“Step up doses, and add other glucose-lowering drugs, at frequent intervals until blood glucose control is at target levels”
EASD=European Association for the Study of Diabetes.Nathan DM et al. Diabetologia. 2006;49:1711–1721; International Diabetes Federation. 2005:1–79.
10
HbA1c Levels Above ADA/EASD Target Goals HaveNot Triggered Timely Therapy Modificationsa
aUS Physicians; 1994–2002bMean number of months that elapsed until a new or additional treatment was started. cMonotherapy switched to another agent or additional agent added.Brown JB et al. Diabetes Care. 2004;27:1535–1540; American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41; Nathan DM et al. Diabetologia. 2006 Aug;49(8):1711–21.
First HbA1c on Treatment
Best HbA1c on Treatment
Last HbA1c before Switch or Additionc
ADA goal
EASD goal
27b
months
35b
months
8.2
7.7
8.8
7.6
7.1
9.1
6
7
8
9
10
Metformin monotherapy (n=513 episodes)
Sulfonylurea monotherapy (n=3394 episodes)
0
HbA
1c, %
ADA=American Diabetes Association.EASD=European Association for the Study of Diabetes.
11
Traditional Type 2 Diabetes Management: A “Treat-to-Fail Approach”
OAD=oral anti-hyperglycaemic drug.Adapted from Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol. 2000;7(10):625–631.Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.
7
8
6
9
10
OAD monotherapy
Diet andexercise
OAD combination
OAD up-titration
OAD plus multiple daily
insulininjections
OAD plus basal insulin
HbA
1c, %
Mean HbA1cof patients
Duration of Diabetes
Published Conceptual Approach
Time
12
Less than 50% of Adults With Type 2Diabetes Have Achieved HbA1cGoals
NHANES=National Health and Nutrition Examination Survey of a US population.Adapted from Saydah SH et al. JAMA. 2004;291:335–342.
HbA1c level<7%
Blood pressure <130/80 mmHg
Total cholesterol<200 mg/dl
Achieved all 3 treatment goals
CV Risk Factors
44.3
29.033.9
5.2
37.0 35.8
48.2
7.3
0
10
20
30
40
50
60
Adu
lts, %
NHANES III (1988–1994) (n=1204)NHANES 1999–2000 (n=370)
US Population
13
UKPDS: Improving HbA1c Control Reduced Diabetes-Related Complications
UKPDF=United Kingdom Prospective Diabetes Study. Data adjusted for age, sex, and ethnic group, expressed for white men aged 50–54 years at diagnosis and with mean duration of diabetes of 10 years. Stratton IM et al. UKPDS 35. BMJ 2000;321:405–412.
EVERY 1% reduction in HbA1c
REDUCED RISK(P<0.0001)
1%
Diabetes-related deaths
Myocardial infarctions
Microvascular complications
Amputations or deaths from peripheral
vascular disorders
21%
14%
37%
43%
Relative RiskN=3642
14
Major Targeted Sites of Oral Drug Classes
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483; DeFronzo RA. Ann Intern Med. 1999;131:281–303; Inzucchi SE. JAMA 2002;287:360-372; Porte D et al. Clin Invest Med. 1995;18:247–254.
DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.
Glucose Glucose absorptionabsorption
Hepatic glucoseHepatic glucoseoverproductionoverproduction
Impaired insulinImpaired insulinsecretionsecretion
InsulinInsulinresistanceresistance
Pancreas
↓Glucose level
Muscle and fatLiver
BiguanidesTZDs Biguanides
Sulfonylureas
Meglitinides
TZDs
α-Glucosidase inhibitors
Gut
DPP-4 inhibitors
DPP-4 inhibitors
Biguanides
15
Mechanisms of Action of Major Oral Monotherapies Are Unable to Address the 3 Core Defects in Type 2 Diabetes
Oral Monotherapies
SUs Meglitinides TZDs Metforminα-Glucosidase
Inhibitors
Lowers hepatic glucose production
DPP-4 Inhibitors
Improves insulin secretion
Improves insulin resistance
SUs=sulfonylureas; TZD=thiazolidinediones; DPP-4=dipeptidyl peptidase 4.Inzucchi SE. JAMA 2002;287:360–372; Gallwitz B. Minerva Endocrinol. 2006;31:133–147; Nathan DM et al. Diabetologia. 2006;49:1711–1721.
Mec
hani
sms
of A
ctio
n
16
7
6
9
8
10
Mean HbA1cof patients
HbA
1c, %
Duration of Diabetes
OAD monotherapy
Diet andexercise
OAD combination
OAD up-titration
OAD plus multiple daily
insulininjections
OAD plus basal insulin
Published Conceptual Approach
Earlier Use of Combination Therapy May Improve Treating to Target Compared With Conventional Therapy
Time
18OAD=oral anti-hyperglycaemic drug.Adapted from Campbell IW. Need for intensive, early glycaemic control in patients with type 2 diabetes. Br J Cardiol. 2000;7(10):625–631.Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.
Summary—Complexities of Getting Patients to Goal:A Rationale for Earlier Combination Therapy
Percentage of patients with type 2 diabetes getting to glycaemic goal is far from optimalCurrent conventional treatment paradigm has been characterised by ‘treatment to failure’ rather than ‘treatment to success’
Physicians see adverse events and adherence as the main barriersto earlier use of current combination therapy regimens
Revised/proactive treatment paradigm for type 2 diabetes, involving earlier use of combination therapy, is urgently needed to be more effective in reaching and maintaining HbA1c goals
Saydah SH et al. JAMA. 2004;291:335–342; Brown JB et al. Diabetes Care. 2004;27:1535–1540; Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355; Campbell IW. Br J Cardiol. 2000;7:625–631; Grant RW, et al. Diabetes Care. 2003;26:1408–1412; Dailey G et al. Clin Ther. 2001;23:1311–1320. 19
Contents
Pathophysiology of type 2 diabetes and mechanism of action of sitagliptin
Clinical data overview of sitagliptin:Monotherapy (PN021, 023, A201)
Complexities of getting patients to goal: a rationale for earlier combination therapy
Mechanism of action of the co-administration of sitagliptin plus metformin
Clinical data overview of combination therapy with sitagliptin and metformin (PN024) 8
The Combination of Sitagliptin and Metformin Addresses the 3 Core Defects of Type 2 Diabetes
in a Complementary Manner
Sitagliptin improvesmarkers of β-cell function andincreases insulin synthesis and release
Sitagliptin indirectly reducesHGO through suppression ofglucagon from α cells
Metformin significantlydecreases HGO by directly
targeting the liver to decreasegluconeogenesis and
glycogenolysis
Metformin acts as aninsulin sensitiser(liver>muscle/fat)
β-Cell Dysfunction
Insulin Resistance
Hepatic Glucose OverproductionHepatic Glucose Overproduction
HGO=hepatic glucose overproduction.Aschner P et al. Diabetes Care. 2006;29:2632–2637; Abbasi F et al. Diabetes Care. 1998;21:1301–1305; Inzucchi SE. JAMA 2002;287:360–372; Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33; Zhou G et al. J Clin Invest. 2001;108:1167–1174.
22
Contents
Pathophysiology of type 2 diabetes and mechanism of action of sitagliptin
Clinical data overview of sitagliptin:Monotherapy (PN021, 023, A201)
Complexities of getting patients to goal: a rationale for earlier combination therapy
Mechanism of action of the co-administration of sitagliptin plus metformin
Clinical data overview of combination therapy with sitagliptin and metformin (PN024) 8
HbA1c With Sitagliptin or Glipizide as Add-on Combination With Metformin: Comparable Efficacy
LSM change from baseline (for both groups): –0.7%
Achieved primary hypothesis of non-
inferiority to sulfonylurea
Sulfonylureaa + metformin (n=411)Sitagliptinb + metformin (n=382)
HbA
1c, %
±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
aSpecifically glipizide ≤20 mg/day;bSitagliptin 100 mg/day with metformin (≥1500 mg/day).
Per-protocol population; LSM=least squares mean.SE=standard error.
27
Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes ObesMetab. 2007;9:194–205 with permission from Blackwell Publishing Ltd., Boston, MA.
Greater Reductions in HbA1c Associated With Higher Baseline HbA1c – 52-Week Post Hoc Analysis
n=117
Baseline HbA1c Category
Mea
n C
hang
e Fr
om B
asel
ine
in H
bA1c
, %
<7% ≥7 to <8% ≥8 to <9% ≥9%
− 0.1
− 0.6
−1.1
−1.8
− 0.3
−0.5
−1.1
−1.7
−2.0
−1.8
−1.6
−1.4
−1.2
−1.0
−0.8
−0.6
−0.4
−0.20.0
Sitagliptinb plus metformin
Sulfonylureaa plus metformin
n=33 n=21n=82 n=82n=179 n=167n=112
aSpecifically glipizide ≤20 mg/day.bSitagliptin 100 mg/day with metformin (≥1500 mg/day);
Per-protocol population. Add-on sitagliptin with metformin vs sulfonylurea
with metformin study.28
Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes ObesMetab. 2007;9:194–205 with permission from Blackwell Publishing Ltd., Boston, MA.
Sitagliptin With Metformin Provided Weight Reduction (vs Weight Gain) and a Much Lower Incidence of Hypoglycaemia
aSpecifically glipizide ≤20 mg/day; bSitagliptin (100 mg/day) with metformin (≥1500 mg/day);
cAll-patients-as-treated population.Least squares mean between-group difference at week 52 (95% CI):
change in body weight = –2.5 kg [–3.1, –2.0] (P<0.001);Least squares mean change from baseline at week 52:
glipizide: +1.1 kg; sitagliptin: –1.5 kg (P<0.001).Add-on sitagliptin with metformin vs sulfonylurea
with metformin study.
Δ between groups = –2.5 kg
Least squares mean change over timec
Bod
y W
eigh
t, kg
±SE
Sulfonylureaa plus metformin (n=416)
Sitagliptinb plus metformin (n=389)
−3
−2
−1
0
1
2
3
Weeks0 12 24 38 52
Hypoglycaemiac
P<0.001
32%
5%
0
10
20
30
40
50
Week 52Pa
tient
s W
ith ≥
1 Ep
isod
e, %
P<0.001
Sulfonylureaa plus metformin (n=584)
Sitagliptinb plus metformin (n=588)
29
Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes ObesMetab. 2007;9:194–205 with permission from Blackwell Publishing Ltd., Boston, MA.
Summary: Sitagliptin or Glipizide as Add-on Combination With Metformin
Efficacy profileComparable efficacy in lowering HbA1c
Both provided greater HbA1c reductions in patients with the highest baseline HbA1c
Safety profileBoth were generally well tolerated
Adverse event profiles (ie, serious and GI-related adverse events, those leading to discontinuation) were similar, with the exception of hypoglycaemia– Significantly lower incidence of hypoglycaemic episodes associated with
sitagliptin with metformin
Body weight significantly decreased for sitagliptin with metformin, but increased for glipizide with metformin
Nauck MA et al. Diabetes Obes Metab. 2007;9:194–205.30
Summary
Insulin resistance, β-cell dysfunction, and elevated hepatic glucose production are the 3 core pathophysiologies of type 2 diabetesIncretins positively affect glucose homeostasis by physiologically helping to regulate
Insulin secretion from β cells in a glucose-dependent mannerGlucagon secretion in a glucose-dependent manner
Getting patients to goal may be enhanced by targeting all 3 core defects and hyperglycaemia in the fasting and post-prandial states
Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781; Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254; Drucker DJ. Diabetes Care. 2003;26:2929–2940; Nauck MA et al. Diabetologia. 1993;36:741–744; Monnier L et al. Diabetes Care. 2003;26:881–885; American Diabetes Association. Diabetes Care. 2007;30(Suppl 1):S4–S41; International Diabetes Federation. 2008:1–32.
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Summary (Continued)
Sitagliptin and metformin have complementary mechanisms of action that address all 3 core defects of type 2 diabetes Sitagliptin as add-on combination with metformin provided HbA1c reductions comparable to adding an SU
With less hypoglycemiaWith weight loss
Nauck MA et al. Diabetes Obes Metab. 2007;9:194–205;; Goldstein BJ et al. Diabetes Care. 2007;30:1979–1987; Hermansen K et al. Diabetes Obes Metab. 2007;9:733–745. 42
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