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Table of Contents
Diabetes Pathophysiology
HYPERGLYCEMIA
Adapted with permission from Inzucchi SE. JAMA 2002;287:360372; Porte D Jr, Kahn SE. Clin Invest Med 1995;18:247254.
3
Incretins Modulate Insulin and Glucagon to Decrease Blood Glucose During Hyperglycemia
Meal
Muscle
Adipose tissue
GIP
Gut
Glucose Dependent
GLP-1
Pancreas
Glucose Dependent
Liver
Glucose production
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide. Brubaker PL et al. Endocrinology 2004;145:26532659; Zander M et al. Lancet 2002;359:824930; Ahren B. Curr Diab Rep 2003;3:365372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:14271483; Drucker DJ. Diabetes Care 2003;26:29292940.
Insulin Resistance
Insulin resistance begins years before diagnosis After diagnosis of type 2 diabetes there is little worsening of insulin resistance
0.6 0.5
IR Insulin, mU/L
60
IR Insulin, mU/L
0.4
60
0.4
nmol/L
nmol/L
40
0.3 0.2
40
0.3 0.2
Time, min
Oral glucose load
Time, min
Intravenous (IV) glucose infusion
7
IR = immunoreactive Adapted with permission from Nauck M et al. Diabetologia 1986;29:4652. Copyright 1986 Springer-Verlag. Vilsbll T, Holst JJ. Diabetologia 2004;47:357366.
Does not increase risk of hypoglycemia Does not cause edema or congestive heart failure
DPP-4 Inhibitors Improve Glucose Control by Increasing Incretin Levels in Type 2 Diabetes
Ingestion of food
Glucose dependent
Insulin
from beta cells (GLP-1 and GIP)
GI tract
Pancreas
-cells -cells
Improved Hyperglycemia Physiologic Glucose Control insulin and glucagon reduce hepatic glucose output
DPP-4 Enzyme
Glucagon
from alpha cells (GLP-1) Glucose dependent
Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:26532659; Zander M et al Lancet 2002;359:824830; Ahrn B Curr Diab Rep 2003;3:365372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:14271483.
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DPP-4 Inhibitors
Chemical Class Generic Name -phenethylamines1 Sitagliptin Vildagliptin4 Cyanopyrrolidines Saxagliptin6 Aminopiperidine8 Alogliptin
Molecular Structure
H F F F N H2 O N N N N CF3 NC N O N H HO NC N
H NH2
O H 3C N
N N
CN
HO
Selectivity Half-life
9.96 1.03
nM2
NH 2
~12.4 h3
12.521.1 h10
1. Kim D et al. J Med Chem. 2005;48(1):141151. 2. Matsuyama-Yokono A et al. Biochem Pharmacol. 2008;76(1):98107. 3. Data on file, MSD. 4. Villhauer EB et al. J Med Chem. 2003;46(13):27742789. 5. EMEA approval and SPC for Galvus. http://www.emea.europa.eu/humandocs/Humans/EPAR/galvus/galvus.htm. Accessed on July 8, 2009. 6. Augeri DJ et al. J Med Chem. 2005;48(15):50255037. 7. Fura A et al. Drug Metab Dispos. 2009;37(6):11641171. 8. Feng J et al. J Med Chem. 2007;50(10):22972300. 9. Lee B et al. Eur J Pharmacol. 2008;589(13):30614. 11 10.Covington P et al. Clin Ther. 2008;30(3):499512.
Sitagliptin
Sitagliptin is a DPP-4 inhibitor that improves glycemic control in patients with type 2 diabetes.1 Sitagliptin is a potent, highly selective, once-daily oral therapy.1
Sitagliptin is >2,600 times more selective for DPP-4 in vitro than DPP-8, DPP-9, and other related enzymes.2
Sitagliptin 100 mg once daily has shown near maximal and sustained DPP-4 inhibition (97%) over 24 hours.3
DPP-4=dipeptidyl peptidase-4. 1. Data on file, MSD. 2. Kim D et al. J Med Chem. 2005;48(1):141151. 3. Alba M et al. Curr Med Res Opin. 2009;25(10):25072514. eAppendix. doi: 10.1185/03007990902109514.
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Placebo
Sitagliptin 100 mg qd
Time (hr)
Insulinogenic Index (U/mg)
0.5 0.4 0.3 0.2 0.1 0 Week 0 Week 12 Placebo Sitagliptin 100 mg qd
Placebo
Sitagliptin 100 mg qd
0.5 1.0
2.0
Time (hr)
Nonaka K et al. A201. Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC.
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Sitagliptin Consistently and Significantly Lowers A1C With Once-Daily Dosing in Monotherapy
18-Week study
Change vs placebo* 8.4
24-Week study
-0.79%
8.4 (P<.001)
-0.6%
(P<.001)
8.0
A1C (%)
A1C (%)
A1C (%)
Placebo (n=244) Sitagliptin 100 mg (n=229)
8.0
8.0
7.6
7.6
7.6
7.2
Placebo (n=74) Placebo (n=75) Sitagliptin 100 mg (n=75)
7.2
7.2
6.8
Time (wk)
12
18
10
Time (wk)
15
20
25
Time (wk)
12
HOMA-
0.36
0.34 0.32 0.3 from baseline vs pbo = 0.078
Hatched = Baseline Solid = Week 24
Placebo
Sitagliptin
* P value for change from baseline compared to placebo Aschner P et al. PN021; Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC.
In vivo low potential of drug interactions with substrates of CYP3A4, 2C8, and 2C9
No meaningful alteration of the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives
Digoxin
No dosage adjustment of digoxin or sitagliptin is recommended
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Summary
Sitagliptin is a potent, highly selective once-daily oral therapy.1 Sitagliptin enhances incretin levels through inhibition of DPP-4.1 Sitagliptin is a DPP-4 inhibitor that is not covalently bound.2 It rapidly dissociates and has a prolonged half-life that supports once- daily dosing.1 Sitagliptin 100 mg has shown near maximal and sustained DPP-4 inhibition over 24 hours, resulting in increases in active GLP-1 and GIP.3,4
1. Data on file, MSD. 2. Wallace MB et al. Bioorg Med Chem Lett. 2008;18:23622367. 3. Herman GA et al. J Clin Endocrinol Metab. 2006;91(11):46124619. 4. Alba M et al. Curr Med Res Opin. 2009;25(10):25072514. eAppendix. doi: 10.1185/03007990902109514.
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Initial Combination Therapy with Sitagliptin and Metformin: Effective and Durable Glycemic Control Over 1 Year in Patients With T2DM
Proportion of patients achieving an A1C target of <7%
90 80
Proportion of patients achieving an A1C target of <7% at Week 24 remaining at <7% at Week 54
90 80 70 60 50 40 30 20 10 0
Sitagliptin 100 mg qd (n=33) Metformin 500 mg bid (n=34) Metformin 1000 mg bid (n=63) Sitagliptin 50 mg + metformin 500 mg bid (n=65) Sitagliptin 50 mg + metformin 1000 mg bid (n=96)
18
77
70 60 50 40 30 20 10 0
67 57 44 48 41 35 23 25
79 70 59
80
85
63
APT
Week 54 Completers
Sitagliptin 100 mg qd (n=106/58) Metformin 500 mg bid (n=117/77) Metformin 1000 mg bid (n=134/101) Sitagliptin 50 mg + metformin 500 mg bid (n=147/106) Sitagliptin 50 mg + metformin 1000 mg bid (n=153/124)
Williams-Herman D et al. Poster presented at 2007 ADA Annual Meeting; Chicago, IL.
Sitagliptin Add-on to Metformin Improved 24-Hour Glucose Profile in Patients With Type 2 Diabetes
Post Prandial
Fasting/Pre-Prandial
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Sitagliptin Added to Ongoing Metformin Therapy: Sustained Glycemic Control Over 54-weeks With Weight Loss
A1C (%)
Phase A 7.9 7.7 Mean A1C (%) 7.5 7.3 7.1 6.9 6.7 6.5 LS mean chance from baseline in body weight (kg) Interim Phase B 2.0
Weight (kg)
Phase A Interim Phase B
LS mean change from baseline at week 54 -0.7% (95% CI: -0.8, -0.6)
1.0
LS mean change from baseline at week 54 -0.6 kg (95% CI: -1.5, -0.2)
0.0
-1.0
-2.0
12
18
24
30
38
46
54
12
24
Weeks
38
54
Weeks
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Initial Combination Therapy with Sitagliptin and Metformin: Change From Baseline in A1C at Week 54 by Baseline A1C Subgroups*
0.0 -0.5
-1.0
-1.5 -2.0 -2.5
Sitagliptin 100 mg (28/43/19/16) Metformin 500 mg bid (32/39/30/16) Metformin 1000 mg bid (40/53/33/8) Sitagliptin 50 mg + metformin 500 mg bid (39/49/38/21) Sitagliptin 50 mg + metformin 1000 mg bid (33/60/43/17)
-3.0
-3.5
*Mean change SE: APT Population. Williams-Herman D et al. Poster presented at 2007 ADA Annual Meeting; Chicago, IL.
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Combination Sitagliptin Metformin Sita 50 mg/ 100 mg qd 1000 mg bid Met 1000 mg bid
-0.8 -1
-2.0
P<.001
-2.1
-2.5
Additive to 100% 2.1/(0.8 + 1.3)=100%
FDC=fixed-dose combination. Williams-Herman D et al. Presented at: 19th World Diabetes Congress (IDF) in South Africa, 2006.
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30 25 20 15 10 5 0
8.41 * 14.81 * 16.37
Placebo
*P<.001 vs placebo. Migoya EM et al. Presented at 2007 ADA Annual Meeting. Abstract # 286-OR.
Incidence of Hypoglycemia With Sitagliptin With Metformin Was Similar to Placebo With Metformin
5.0
4.0
Patients (%)
3.0
2.1%
2.0
1.3%
1.0
Sitagliptin With Metformin Provided Weight Loss Similar to Placebo With Metformin at Week 24
0 Change in Body Weighta from baseline (kg)b -0.1 -0.2 -0.3 -0.4 -0.5 -0.6 -0.7 -0.8
0.6
P=0.017 vs baseline
0.7
P<0.001 vs baseline
aExcluding cSitagliptin
data after initiation of glycemic rescue therapy; bleast squares means; 100 mg/day; dMetformin 1500 mg/day
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JANUVIA (sitagliptin) Indications and Contraindications: Based on the Worldwide Product Circular
Indications
JANUVIA is indicated as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus as:
Monotherapy Initial combination therapy with metformin Initial combination therapy with a PPAR agonist (TZD) Combination therapy with metformin, sulfonylurea, or PPAR, when the single agent alone with diet and exercise does not provide adequate glycemic control Combination therapy with metformin and a sulfonylurea, when dual therapy with these agents with diet and exercise does not provide adequate glycemic control Combination therapy with metformin and a PPAR agonist, when dual therapy with these agents with diet and exercise does not provide adequate glycemic control
Combination with Insulin JANUVIA is indicated in patients with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control in combination with insulin (with or without metformin).
Contraindications
JANUVIA is contraindicated in patients who are hypersensitive to any components of this product
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Because there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter
aMild=CrCl
50 mL/min. 30 to <50 mL/min. cSevere=CrCl <30 mL/min. dRequiring hemodialysis or peritoneal dialysis. JANUVIA may be administered without regard to the timing of hemodialysis.
bModerate=CrCl
28
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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
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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. 31 2. Data on file, MSD.
Conclusions
Treatment to achieve glycemic control early is important to help reduce complications of type 2 diabetes1 Many patients on current monotherapies do not achieve glycemic control2 Combination therapy with a DPP-4 inhibitor and metformin offers opportunity for improved glycemic efficacy, complementary mechanisms of action, and a low risk of hypoglycemia without weight gain Sitagliptin/metformin provides a more comprehensive approach for addressing the key pathophysiologies of type 2 diabetes
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