1. The Modern Comprehensive Approach for Treating Type 2 Diabetes
Josephine Carlos-Raboca M.D.

2. Diabetes Pathophysiology
Table of Contents
Diabetes Pathophysiology
Comprehensive Approach is Pathophysiology Based
Therapy with DPP-4 Inhibitor
Table of Contents
Module 1—Clinical Background
The Need for Early Treatment
Diabetes Pathophysiology
Rationale for Combined Therapy With Metformin and a DPP-4 Inhibitor

3. The Pathophysiology of Type 2 Diabetes Involves Multiple Organ Systems
Pancreatic Beta Cells
Decreased insulin secretion
Pancreatic Alpha Cells
Excessive glucagon secretion
Peripheral Tissues
Liver
Increased Glucose Production
Decreased Glucose Uptake
Increased Lipolysis
The Pathophysiology of Type 2 Diabetes Involves Multiple Organ Systems
Type 2 diabetes is a complex metabolic disorder involving multiple organ sites.1
In the pancreas, insulin production from pancreatic beta cells is diminished, while the production of glucagon from alpha cells is excessive.1,2
Skeletal muscle demonstrates insulin resistance, with higher concentrations of insulin being required for glucose to enter muscle cells.1
Adipose tissue also demonstrates insulin resistance, leading to increased lipolysis and elevated circulating free fatty acids. These further reduce the response of skeletal muscle to insulin and the ability of the pancreas to secrete insulin, a process referred to as lipotoxicity.1
Insulin resistance also affects the liver. This, along with the combined effects of diminished insulin secretion and excessive glucagon, leads to elevated hepatic glucose production.1,2
Diminished glucose uptake by the muscle and elevated hepatic glucose production both contribute to the development of hyperglycemia.
Thus, coexisting defects at multiple organ sites, including the pancreas, muscle tissue, adipose tissue, and the liver, are to blame for the development and progression of hyperglycemia in type 2 diabetes.1
Insulin
resistance
Islet cell
dysfunction
Combined islet cell dysfunction
and insulin resistance
HYPERGLYCEMIA
Adapted with permission from Inzucchi SE. JAMA 2002;287:360–372; Porte D Jr, Kahn SE. Clin Invest Med 1995;18:247–254.
References:
1. Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes. JAMA 2002;287:360–372.
2. Porte D Jr, Kahn SE. The key role of islet cell dysfunction in type II diabetes mellitus. Clin Invest Med 1995;18:247–254.

4. Physiologic Glucose Control
Incretins Modulate Insulin and Glucagon to Decrease Blood Glucose During Hyperglycemia
Meal
Muscle
Peripheral glucose uptake
Increased insulin
(beta cells)
Adipose tissue
Glucose
Dependent
GIP
Gut
Incretins Modulate Insulin and Glucagon to Decrease Blood Glucose Levels During Hyperglycemia
This schematic summarizes the pathways related to the observed effects of glucagon-like peptide-1(GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) on insulin and GLP-1 on glucagon.
Following a meal, the release of incretins is stimulated: GLP-1 from L cells located primarily in the distal gut (ileum and colon) and GIP from K cells in the proximal gut (duodenum).1
Together, these incretins enhance the insulin response of the pancreatic beta cells to an oral glycemic challenge.1 GLP-1 helps suppress glucagon secretion from pancreatic alpha cells when glucose levels are elevated.2-5
The subsequent insulin-induced increase in glucose uptake by muscles and other tissues and the reduced glucose output (the result of increased insulin and decreased glucagon) from the liver result in better physiologic control of glucose levels.2-5
GLP-1
Pancreas
Physiologic Glucose Control
Glucose
Dependent
Decreased glucagon
(alpha cells)
Liver
Glucose
production
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.
Brubaker PL et al. Endocrinology 2004;145:2653–2659; Zander M et al. Lancet 2002;359:824–930; Ahren B. Curr Diab Rep 2003;3:365–372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:1427–1483; Drucker DJ. Diabetes Care 2003;26:2929–2940.
References
Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003;26:2929–2940
Brubaker PL, Drucker DJ. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology 2004;145: 2653–2659.
Zander M, Madsbad S, Madsen JL et al. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: A parallel-group study. Lancet 2002;359:824–830.
Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep 2003;3:365–372.
Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR, Kronenberg HM, Melmed S et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:1427–1483.

5. Summary of Diabetic Pathophysiologies
Islet-cell dysfunction
Dysfunction of both beta cells (insulin production) and alpha cells (glucagon production) occur
Dysfunction begins years before diagnosis of type 2 diabetes
Dysfunction is progressive both before and after diagnosis
Incretin defects contribute to islet cell dysfunction
Insulin Resistance
Insulin resistance begins years before diagnosis
After diagnosis of type 2 diabetes there is little worsening of insulin resistance
Insulin resistance reduces glucose uptake and utilization
Hepatic Glucose Overproduction
Overproduction is a result of islet-cell dysfunction and insulin resistance
Summary of Diabetic Pathophysiologies
Islet-cell dysfunction
Dysfunction of both beta cells (insulin production) and alpha cells (glucagon production) occur
Dysfunction begins years before diagnosis of type 2 diabetes
Dysfunction is progressive both before and after diagnosis
Incretin defects contribute to islet cell dysfunction
Insulin Resistance
Insulin resistance begins years before diagnosis
After diagnosis of type 2 diabetes there is little worsening of insulin resistance
Insulin resistance reduces glucose uptake and utilization
Hepatic Glucose Overproduction
Overproduction is a result of islet-cell dysfunction and insulin resistance
References:
Porte DJr, Kahn SE The key role of islet dysfunction in type II diabetes mellitus Clin Invest Med 1995;18:
Bell DSH. The case for combination therapy as first-line treatment for type 2 diabetic patients. Treat Endocrinol 2006;5:131–137.
Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep 2003;3:365–372.
Del Prato S and Marchetti P. Targeting insulin resistance and beta-cell dysfunction: The role of thiazolidinediones. Diabetes Tech Ther 2004;6:719–131.
Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR, Kronenberg HM, Melmed S et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:1427–1483.

6. Management of Type 2 Diabetes
Hormones involved in glucose regulation
Insulin
Glucagon
Incretins
Insulin Resistance
islet cell
skeletal muscle
adipose tissue
liver 6

7. The Incretin Effect Is Diminished in Individuals With Type 2 Diabetes
Control Subjects (n=8)
Patients With Type 2 Diabetes (n=14)
Diminished Incretin Effect
Normal Incretin Effect
0.6
0.5
0.4
0.3
0.2
0.1
0.6
0.5
0.4
0.3
0.2
0.1 80 60 40 20 80 60 40 20
The Incretin Effect Was Diminished in Individuals With Type 2 Diabetes
When glucose is administered orally, insulin secretion is stimulated much more than it is when glucose is given intravenously, even with similar glucose concentrations.1
This is called the incretin effect and suggests that the ingestion of glucose leads the gut to produce substances that enhance insulin secretion beyond the release caused by the glucose itself.1
The incretin effect is caused mainly by the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).1
The incretin effect has been studied in patients with type 2 diabetes (n=14) compared with healthy control subjects (n=8). Glucose profiles were matched after oral versus intravenous (IV) glucose administration in both control subjects and patients with diabetes.2
Plasma insulin peaks were delayed in patients with type 2 diabetes. Although insulin levels were greater after oral glucose ingestion versus IV administration in both groups, the incretin effect was substantially less in diabetic patients.2
nmol/L
nmol/L
IR Insulin, mU/L
IR Insulin, mU/L 60
120
180 60
120
180
Time, min
Time, min
Oral glucose load
Intravenous (IV) glucose infusion
IR = immunoreactive
Adapted with permission from Nauck M et al. Diabetologia 1986;29:46–52. Copyright © 1986 Springer-Verlag.
Vilsbøll T, Holst JJ. Diabetologia 2004;47:357–366.
References:
1. Vilsbøll T, Holst JJ. Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia 2004;47:357–366.
2. Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 1986;29:46–52.

8. Characteristics of an Ideal Therapy
Characteristics of an ideal oral antidiabetic agent
Lowers HbA1c to normal levels
Decreases insulin resistance and hepatic glucose production and increases or preserves beta-cell mass while restoring first-phase insulin response
Does not cause weight gain
Does not increase risk of hypoglycemia
Does not cause edema or congestive heart failure
Rationale for Combination Therapy
An ideal oral antidiabetic agent would lower HbA1c to normal levels while independently decreasing insulin resistance and hepatic glucose production. The ideal agent would decrease cardiac risk factors, increase or preserve the beta-cell mass, and restore first-phase insulin release.
With an ideal agent there would be no hypoglycemia; the agent would not promote weight gain and preferably would cause weight loss; it would not cause edema, anemia, or congestive heart failure; and could be used safely in renal or hepatic decompensation.

9. Therapy with DPP-4 Inhibitor=
Therapy with DPP-4 Inhibitor
Table of Contents
Module 1—Clinical Background
The Need for Early Treatment
Diabetes Pathophysiology
Rationale for Combined Therapy With Metformin and a DPP-4 Inhibitor

10. 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)
Insulin increases peripheral glucose uptake
GI tract
Pancreas
Release of incretins from the gut
The presence of nutrients in the gastrointestinal tract rapidly stimulates the release of incretins: GLP-1 from L cells located primarily in the distal gut (ileum and colon), and GIP from K cells in the proximal gut (duodenum).1,2
Collectively, these incretins exert several beneficial actions, including stimulating the insulin response in pancreatic beta cells and reducing glucagon production from pancreatic alpha cells when glucose levels are elevated in a glucoxse dependent manner.3,4 Increased insulin levels improve glucose uptake by peripheral tissues; the combination of increased insulin and decreased glucagon reduces hepatic glucose output.5 The incretins are rapidly inactivated by the dipeptidyl peptidase 4 (DPP-4) enzyme.  
Patients with type 2 diabetes have a diminished incretin effect as a consequence of reduced GLP-1 levels3 and reduced GIP effect.3 Preventing the degradation  of the incretins by inhibiting DPP-4 enhances the level of active incretins.3 This in turn enhances the body’s own ability to control glucose. 
β-cells
Improved Physiologic
Glucose Control
Hyperglycemia
α-cells
DPP-4
Inhibitor X
DPP-4 Enzyme
↑insulin and ↓glucagon reduce hepatic glucose
output
Glucagon
from alpha cells (GLP-1) Glucose dependent
Inactive incretins
DPP-4 = dipeptidyl peptidase 4
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.
References
Brubaker PL, Drucker DJ. Minireview: Glucagon-like peptides regulate cell proliferation and apoptosis in the pancreas, gut, and central nervous system. Endocrinology 2004;145: 2653–2659.
Zander M, Madsbad S, Madsen JL et al. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: A parallel-group study. Lancet 2002;359:824–830.
Ahrén B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep 2003;3:365–372.
Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 2002;122:531–544.
Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Larsen PR, Kronenberg HM, Melmed S et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: Saunders, 2003:1427–1483.

11. DPP-4 Inhibitors N O H C N O H C H O N C F O N H C
Chemical Class
β-phenethylamines1
Cyanopyrrolidines
Aminopiperidine8
Generic Name
Sitagliptin
Vildagliptin4
Saxagliptin6
Alogliptin
Molecular Structure
Selectivity
9.96 ± 1.03 nM2
5.28 ± 1.04 nM2
3.37 ± 0.90 nM2
6.9 ± 1.5 nM9
Half-life
~12.4 h3
~2–3 h5
~2–2.8 h7
12.5–21.1 h10 N O H 3 C 2 N O H C 2 H O N C F O N H 2 C 3
DPP-4 Inhibitors
Several DPP-4 inhibitors either are approved or are awaiting approval for use in patients with type 2 diabetes.
Sitagliptin is a member of the β-phenethylamine chemical class1 and has an inhibitory concentration (IC50) of 9.96 ± 1.03 nM against DPP-4.2 Its half-life is approximately 12.4 hrs.3
Vildagliptin is a member of the cyanopyrrolidine chemical class,4 and has an IC50 of 5.28 ± 1.04 nM against DPP-4.2 It has a half-life of approximately 2 to 3 hours.5
Saxagliptin is also a member of the cyanopyrrolidine chemical class6 and its IC50 against DPP-4 is 3.37 ± 0.90 nM.2 It has a half-life of approximately 2 to 2.8 hours.7
Alogliptin, a member of the aminopiperidine chemical class,8 has an IC50 of 6.9 ± 1.5 nM9, and its half-life is approximately 12.5 to 21.1 hours.10
Purpose
To outline characteristics of various DPP-4 inhibitors that have been approved or that are awaiting approval.
1. Kim D et al. J Med Chem. 2005;48(1):141– Matsuyama-Yokono A et al. Biochem Pharmacol. 2008;76(1):98–107.
3. Data on file, MSD Villhauer EB et al. J Med Chem. 2003;46(13):2774–2789.
5. EMEA approval and SPC for Galvus. Accessed on July 8, Augeri DJ et al. J Med Chem. 2005;48(15):5025– Fura A et al. Drug Metab Dispos. 2009;37(6):1164–1171.
8. Feng J et al. J Med Chem. 2007;50(10):2297–2300.
9. Lee B et al. Eur J Pharmacol. 2008;589(1–3):306– Covington P et al. Clin Ther. 2008;30(3):499–512.
References
1. Kim D, Wang L, Beconi M, et al. (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl) butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem. 2005;48(1):141– Matsuyama-Yokono A, Tahara A, Nakano R, et al. ASP8497 is a novel selective and competitive dipeptidyl peptidase-IV inhibitor with antihyperglycemic activity. Biochem Pharmacol. 2008;76(1):98–107.
3. Data on file, MSD Villhauer EB, Brinkman JA, Naderi GB, et al. 1-[[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective,
and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J Med Chem. 2003;46(13):2774–2789.
5. EMEA approvals and SPC for Galvus. Accessed on July 8, Augeri DJ, Robl JA, Betebenner DA, et al. Discovery and preclinical profile of Saxagliptin (BMS ): a highly potent, long-acting,
orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem. 2005;48(15):5025– Fura A, Khanna A, Vyas V, et al. Pharmacokinectics of the dipeptidyl peptidase 4 inhibitor saxagliptin in rats, dogs, and monkeys and
clinical projections. Drug Metab Dispos. 2009;37(6):1164–1171.
8. Feng J, Zhang Z, Wallace MB, et al. Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV J Med Chem. 2007;50(10):2297–2300.
9. Lee B, Shi L, Kassel DB, Asakawa T, Takeuchi K, Christopher RJ. Pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel inhibitor
of dipeptidyl peptidase-4, in rats, dogs, and monkeys. Eur J Pharmacol. 2008;589(1–3):306–14.
10.Covington P, Christopher R, Davenport M, et al. Phamacokinetic, pharmacodynamic, and tolerability profiles of dipeptidyl peptidase-4
inhibitor alogliptin: a randomized, double-blind, placebo-controlled, multi-dose study in adult patients with type 2 diabetes. Clin Ther. 2008;30(3):499–512.

12. 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
Sitagliptin
Sitagliptin is a DPP-4 inhibitor that provides glucose-dependent control for patients with type 2 diabetes.1 Sitagliptin, administered orally once-daily, is potent and highly selective for the DPP-4 enzyme.1 It is >2,600 times more selective for DPP-4 in vitro than DPP-8, DPP-9, and other related enzymes.2 It also has shown near maximal and sustained DPP-4 inhibition (97%) over 24 hours in healthy subjects.3
Purpose
To provide an overview of sitagliptin, a therapy for the treatment of type 2 diabetes.
Takeaway
Sitagliptin is an orally-active, potent, highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor administered once daily for the treatment of type 2 diabetes.
DPP-4=dipeptidyl peptidase-4.
1. Data on file, MSD. 2. Kim D et al. J Med Chem. 2005;48(1):141– Alba M et al. Curr Med Res Opin. 2009;25(10):2507–2514. eAppendix. doi: /
References
1. Data on file, MSD.
2. Kim D, Wang L, Beconi M, et al. (2R)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5- trifluorophenyl)butan-2-amine: A potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem. 2005;48(1):141–151.
3. Alba M, Sheng D, Guan Y, et al. Sitagliptin 100 mg daily effect on DPP-4 inhibition and compound-specific glycemic improvement. Curr Med Res Opin. 2009;25(10):2507–2514. Electronic supplementary data published in conjunction with Alba M, Sheng D, Guan Y, et al. Curr Med Res Opin. 2009;25(10):2507–2514. doi: /

13. Japanese Monotherapy Study
Sitagliptin Lowers Post-meal Glucose Excursion and Enhances Insulin Secretion
Japanese Monotherapy Study
Time (hr)
Plasma Insulin (µU/mL) 10 20 30 40 50 60 70
0.5
1.0
2.0
Sitagliptin 100 mg qd
Placebo
P<0.05 for between group difference
Baseline
Baseline
Week 12
Week 12
320
11.7
mg/dL
280
-69.2
Plasma Glucose (mg/dL)
240
mg/dL
200
Insulinogenic Index (µU/mg)
160
Placebo
Sitagliptin 100 mg qd
120
0.5
1.0
2.0
0.5
1.0
2.0
Time (hr)
P<0.001 for difference in change from baseilne in 2-hr PPG
Insulinogenic index = ∆ I30 / ∆ G30
Nonaka K et al. A201. Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC. 13

14. Sitagliptin Consistently and Significantly Lowers A1C With Once-Daily Dosing in Monotherapy
18-Week study
Placebo (n=244)
Sitagliptin 100 mg (n=229)
24-Week study
Time (wk) 5 10 15 20 25
-0.79%
(P<.001)
A1C (%)
7.2
7.6
8.0
8.4
Placebo (n=75)
Sitagliptin 100 mg (n=75)
Time (wk)
Japanese study
-1.05%
(P<.001)
A1C (%)
7.2
7.6
8.0
8.4
6.8 4 8 12
Change vs placebo*
-0.6%
(P<.001)
8.4
8.0
A1C (%)
7.6
Placebo (n=74)
Sitagliptin 100 mg (n=168)
7.2 6 12 18
Time (wk)
*Between group difference in LS means.
Raz I et al; PN023; Aschner P et al. PN021; Nonaka K et al; A201. Abstracts presented at: 66th Scientific Sessions of the American Diabetes Association; June 9-13, 2006; Washington, DC. 14

15. * P value for change from baseline compared to placebo
Sitagliptin Improved Markers of Beta-Cell Function: 24-Week Monotherapy Study
Proinsulin/insulin ratio
HOMA-β
0.48 75
p< 0.001*
p< 0.001*
0.46 70
0.44 65
0.42 60
0.4 55
0.38 50
0.36 45
0.34 40
0.32 35 30
0.3
Placebo
Sitagliptin
Placebo
Sitagliptin
∆ from baseline vs pbo =
(95% CI , )
Hatched = Baseline
Solid = Week 24
∆ from baseline vs pbo
= /- 3.3
(95% CI 3.9, 21.9)
* 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. 15

16. Assessment of Drug Interactions With Sitagliptin
In vitro  unlikely to cause interactions with other drugs
No inhibition of CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19, or 2B6
No induction of CYP3A4
Not extensively bound to plasma proteins
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
Assessment of Drug Interactions With Sitagliptin
Based on in vitro data, sitagliptin is unlikely to cause interactions with other drugs. Indeed, sitagliptin does not inhibit CYP isozymes CYP3A4, 2C8, 2C9, 2D6, 1A2, 2C19, or 2B6; does not induce CYP3A4; and is not extensively bound to plasma proteins.1
Based on in vivo assessment, sitagliptin has a low propensity for causing drug interactions with substrates of CYP3A4, 2C8, and 2C9. In drug interaction studies, sitagliptin did not have clinically meaningful effects on the pharmacokinetics of metformin, glyburide, simvastatin, rosiglitazone, warfarin, or oral contraceptives.1
A slight increase in area under the curve (AUC) (11%) and mean peak drug concentrations (Cmax) (18%) of digoxin when coadministered with sitagliptin 100 mg for 10 days was observed. No dosage adjustment of digoxin or sitagliptin is recommended.1
Purpose
To show the assessment of drug interactions with sitagliptin.
Takeaway
In vitro studies have shown that sitagliptin is unlikely to cause interactions with other drugs. In vivo assessments support the low potential of drug interactions with sitagliptin.
Data on file, MSD.
Reference
1. Data on file, MSD.

17. 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
Summary
Purpose
To summarize the pharmacodynamic properties of sitagliptin and their clinical implications.
Takeaway
Sitagliptin is a potent, highly selective once-daily oral therapy.
Sitagliptin enhances incretin levels through inhibition of DPP-4.
Sitagliptin is a DPP-4 inhibitor that is not covalently bound. It rapidly dissociates and has a prolonged half-life that supports once daily dosing.
Sitagliptin 100 mg has shown sustained DPP-4 inhibition over 24 hours, resulting in increases in active GLP-1 and GIP.
1. Data on file, MSD. 2. Wallace MB et al. Bioorg Med Chem Lett. 2008;18:2362–2367.
3. Herman GA et al. J Clin Endocrinol Metab. 2006;91(11):4612– Alba M et al. Curr Med Res Opin. 2009;25(10):2507–2514. eAppendix. doi: /

18. Initial Combination Therapy with Sitagliptin and Metformin: Effective and Durable Glycemic Control Over 1 Year in Patients With T2DM
Week 54 Completers
APT
Proportion of patients (%)
Proportion of patients achieving an A1C target of <7%
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)
Proportion of patients achieving an A1C target of <7% at Week 24 remaining at <7% at Week 54
Proportion of patients (%)
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)
Williams-Herman D et al. Poster presented at 2007 ADA Annual Meeting; Chicago, IL. 18

19. Fasting/Pre-Prandial
Sitagliptin Add-on to Metformin Improved 24-Hour Glucose Profile in Patients With Type 2 Diabetes
Post Prandial
Fasting/Pre-Prandial

20. Sitagliptin Added to Ongoing Metformin Therapy: Sustained Glycemic Control Over 54-weeks With Weight Loss
A1C (%)
Weight (kg)
Phase A
Interim Phase B
Phase A
Interim Phase B
2.0
7.9
7.7
LS mean change from baseline at week kg (95% CI: -1.5, -0.2)
LS mean change from baseline at week % (95% CI: -0.8, -0.6)
1.0
7.5
7.3
Mean A1C (%)
LS mean chance from baseline in body weight (kg)
0.0
7.1
6.9
-1.0
6.7
6.5
-2.0 6 12 18 24 30 38 46 54 12 24 38 54
Weeks
Weeks
Karasik A et al. Poster presented at 2007 ADA Annual Meeting. 20

21. HbA1C Change from baseline at Week 54 (%)
Initial Combination Therapy with Sitagliptin and Metformin: Change From Baseline in A1C at Week 54 by Baseline A1C Subgroups*
<8%
(mean 7.6%)
8% and <9% (mean 8.4%)
9% and <10%
(mean 9.4%)
10%
(mean 10.4%)
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
-3.5
-3.0
-2.5
-2.0
-1.5
-1.0
-0.5
0.0
HbA1C Change from baseline at Week 54 (%)
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)
*Mean change  SE: APT Population.
Williams-Herman D et al. Poster presented at 2007 ADA Annual Meeting; Chicago, IL. 21

22. Effect of FDC Sitagliptin/Metformin on A1C Reduction Is Higher Than Monotherapy
Placebo-Subtracted Data in 24-Week Study
Combination Sita 50 mg/ Met 500 mg bid
Combination Sita 50 mg/ Met 1000 mg bid
Sitagliptin 100 mg qd
Metformin 500 mg bid
Sitagliptin 100 mg qd
Metformin 1000 mg bid -0
-0.5
-1.0
A1C reduction from baseline (%)
-1.5
-2.0
Additive to 89% 1.6/( )89%
P<.001
-2.5
P<.001
Additive to 100% 2.1/( )=100%
FDC=fixed-dose combination.
Williams-Herman D et al. Presented at: 19th World Diabetes Congress (IDF) in South Africa, 2006. 22

23. Complementary Effect of Sitagliptin + Metformin on Active GLP-1
Active GLP-1 (pM)
Placebo
Metformin
Sitagliptin
Sitagliptin + metformin
*P<.001 vs placebo.
Migoya EM et al. Presented at 2007 ADA Annual Meeting. Abstract # 286-OR. 23

24. 24-Week Add-on Therapy to Metformin Study
Incidence of Hypoglycemia With Sitagliptin With Metformin Was Similar to Placebo With Metformin
R1-p2642-T2-L11
Patients with at least one episode of hypoglycemia over 24 weeks
Patients (%)
Placebo + metforminb (n=237)
Sitagliptina + metforminb (n=464)
2.1%
1.3%
0.0
1.0
2.0
3.0
4.0
5.0
R1-p2639-Col 3-Par. Last-L1-5
Incidence of Hypoglycemia With Sitagliptin With Metformin Is Similar to Placebo With Metformin
The incidence of hypoglycemia was low and similar between treatment groups (1.3% and 2.1% in the sitagliptin 100 mg once daily with metformin and placebo with metformin groups, respectively).1
There was no statistically significant difference in incidence of hypoglycemia between the sitagliptin with metformin and placebo with metformin groups.1
R1-p2642
T2-L11
R1-p2642-
Col 1
Par. cont-L1-L5
All-patients-as-treated population
aSitagliptin 100 mg/day; bMetformin ≥1500 mg/day
Adapted from Charbonnel B et al. Diabetes Care. 2006;29:2638–2643.
Reference:
1. Charbonnel B, Karasik A, Liu J, et al, for the Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006;29:2638–2643.

25. 24-Week Add-on Therapy to Metformin Study
Sitagliptin With Metformin Provided Weight Loss Similar to Placebo With Metformin at Week 24
R.1-CSR020-p168-
T L1,2,4
–0.6
P=0.017
vs baseline
–0.7
P<0.001
Placebo + metformind (n=169)
Sitagliptinc + metformind (n=399)
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
Change in Body Weighta
from baseline (kg)b
R.2-p2642-
Col 2
Par.1-L3-L10
R1/CSR020, p167-Par.6-L1-L3
R1-CSR020-p168-T L1,2,4
Sitagliptin With Metformin Provided Weight Loss Similar to Placebo With Metformin
Small but statistically significant decreases from baseline were observed in body weight at 24 weeks in both the sitagliptin 100 mg once daily with metformin (–0.7 kg, P<0.001) and placebo with metformin (–0.6 kg, P=0.017) treatment groups; however, there was no significant difference in weight loss between the two groups.1
R1-p2642-
Col 2
Par.1-L3-L10
aExcluding data after initiation of glycemic rescue therapy; bleast squares means;
cSitagliptin 100 mg/day; dMetformin ≥1500 mg/day
Adapted from Charbonnel B et al. Diabetes Care. 2006;29:2638–2643.
References:
1. Data on file, MSD___________
2. Charbonnel B, Karasik A, Liu J, et al, for the Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006;29:2638–2643.

26. Combination Therapy Offers Advantages Over Monotherapy
Combination therapy may provide more glycemic control than the individual monotherapies
Combination therapy may provide more comprehensive coverage of the key pathophysiologies of type 2 diabetes than monotherapy
An appropriately chosen combination therapy may help more patients achieve their HbA1c goal without increasing side effects1
Rationale for Combination Therapy
Combination therapy may provide more glycemic control than the individual monotherapies.
Combination therapy may provide more comprehensive coverage of the key pathophysiologies of type 2 diabetes than monotherapies.
An appropriately chosen combination therapy may help more patients achieve their HbA1c goal without increasing side effects.1
Adapted from Del Prato Int J Clin Pract 2005;59:
Reference:
1. Del Prato S, Felton-A-M, Munro et al. Improving glucose management: Ten steps to get more patients with type 2 diabetes to glycaemic goal Int J Clin Pract 2005;59:

27. JANUVIA™ (sitagliptin) Indications and Contraindications: Based on the Worldwide Product Circular
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 PPARγ agonist (TZD)
Combination therapy with metformin, sulfonylurea, or PPARγ, 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 PPARγ 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
Note : Please align to local approval and regulations
JANUVIA™ (sitagliptin) Indications and Usage:
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:1
Monotherapy
Initial combination therapy with metformin
Initial combination therapy with a PPARγ agonist (TZD)
Combination therapy with metformin, a sulfonylurea, or a PPARγ agonist 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 PPARγ 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.1
Reference
Data on file, MSD.

28. JANUVIA™ (sitagliptin) Recommended Dosing: Based on the Worldwide Product Circular
Dosage
Recommended dosage of JANUVIA is 100 mg once daily taken with or without food
When JANUVIA is used in combination with a sulfonylurea or with insulin, a lower dose of the sulfonylurea or insulin may be considered to reduce the risk of sulfonylurea- or insulin-induced hypoglycemia
For patients with renal insufficiency
Milda — no dosage adjustment is required
Moderateb — JANUVIA 50 mg once daily
Severec or end-stage renal diseased — JANUVIA 25 mg once daily
Because there is a dosage adjustment based upon renal function, assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter
Note : Please align to local approval and regulations
JANUVIA™ (sitagliptin) Recommended Dosing: Based on the Worldwide Product Circular
Recommended dosage of JANUVIA is 100 mg once daily taken with or without food.1
When JANUVIA is used in combination with a sulfonylurea or with insulin, a lower dose of sulfonylurea or insulin may be considered to reduce the risk of sulfonylurea- or insulin-induced hypoglycemia.1
For patients with mild renal insufficiency (creatinine clearance [CrCl] ≥50 mL/min), no dosage adjustment for JANUVIA is required.1
For patients with moderate renal insufficiency (CrCl ≥30 to <50 mL/min), the dosage of JANUVIA is 50 mg once daily.1
For patients with severe renal insufficiency (CrCl <30 mL/min) or end-stage renal disease requiring hemodialysis or peritoneal dialysis, the dosage of JANUVIA is 25 mg once daily. JANUVIA may be administered without regard to the timing of hemodialysis.1
Because there is a dosage adjustment based on renal function, assessment of renal function is recommended before the initiation of JANUVIA and periodically thereafter.1
aMild=CrCl ≥50 mL/min. bModerate=CrCl ≥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.
Reference
Data on file, MSD.

29. Note: Please align to local approval and regulations
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
WPC-JMT-T
p.2, A
Note: Please align to local approval and regulations
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:1
As initial therapy when diet and exercise do not provide adequate glycemic control
As an adjunct to diet and exercise in patients who had 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 had 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
WPC-JMT-T
p.2, A
Reference
1. Data on file, MSD.

30. JANUMET™ (sitagliptin/metformin, MSD) Contraindications: Based on the Worldwide Product Circular
WPC-JMT-T
p.4, A
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) Contraindications:
Based on the Worldwide Product Circular
Contraindications
JANUMET is contraindicated in patients with:1
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.1
WPC-JMT-T
p.4, A
Reference
1. Data on file, MSD.

31. 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.
Reasner 2009 L
079A CSR p.38, A
Initial Fixed-Dose Combination Therapy With JANUMET™ vs Metformin Monotherapy: Conclusions
Purpose To summarize the findings of the study.
Takeaway
In patients with type 2 diabetes and moderate to severe hyperglycemia on diet and exercise initial combination therapy with sitagliptin/metformin FDC (JANUMET) provided significant glycemic reductions, with similar weight loss, similar low incidence of hypoglycemia, and lower incidences of abdominal pain and diarrhea compared with metformin alone.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, Data on file, MSD.
References
1. 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.
2. Data on file, MSD.

32. 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
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 MOAs, 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.
References:
1. Bailey CJ, Del Prato S, Eddy D, Zinman B. Earlier intervention in type 2 diabetes: The case for achieving early and sustained glycemic control. Int J Clin Pract 2005;59:1309–1316.
2. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: Progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA 1999;281:2005–2012.