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

Table of Contents

–Diabetes Pathophysiology

–Comprehensive Approach is Pathophysiology Based –Therapy with DPP-4 Inhibitor

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The Pathophysiology of Type 2 Diabetes Involves Multiple Organ Systems
Peripheral Tissues Decreased Increased Glucose Uptake Lipolysis Liver Increased Glucose Production Pancreatic Beta Cells Decreased insulin secretion

Pancreatic Alpha Cells Excessive glucagon secretion

Insulin resistance Combined islet cell dysfunction and insulin resistance

Islet cell dysfunction

HYPERGLYCEMIA
Adapted with permission from Inzucchi SE. JAMA 2002;287:360–372; Porte D Jr, Kahn SE. Clin Invest Med 1995;18:247–254.
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GIP=glucose-dependent insulinotropic polypeptide. Brubaker PL et al. Diabetes Care 2003. Drucker DJ. In Williams Textbook of Endocrinology. 4 . 10th ed.Incretins Modulate Insulin and Glucagon to Decrease Blood Glucose During Hyperglycemia Meal Increased insulin (beta cells) Muscle Adipose tissue Peripheral glucose uptake GIP Gut Glucose Dependent GLP-1 Pancreas Glucose Dependent Physiologic Glucose Control Decreased glucagon (alpha cells) Liver Glucose production GLP-1=glucagon-like peptide-1. Zander M et al. Lancet 2002.3:365–372. Saunders.359:824–930. Curr Diab Rep 2003. Ahren B. Endocrinology 2004.145:2653–2659. Philadelphia. 2003:1427–1483.26:2929–2940. Buse JB et al.

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 5 .

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

.29:46–52.1 0 0 60 120 180 0 Time.5 IR Insulin.4 nmol/L nmol/L 40 0.2 40 0.6 0.2 20 0.The Incretin Effect Is Diminished in Individuals With Type 2 Diabetes Control Subjects (n=8) 80 Patients With Type 2 Diabetes (n=14) 0. mU/L 60 IR Insulin. Diabetologia 2004. Copyright © 1986 Springer-Verlag.1 0 0 60 120 180 0 20 0. min Oral glucose load Time. min Intravenous (IV) glucose infusion 7 IR = immunoreactive Adapted with permission from Nauck M et al. Diabetologia 1986.4 60 0. mU/L 0. Vilsbøll T.3 0.47:357–366.3 0. Holst JJ.5 80 Normal Incretin Effect Diminished Incretin Effect 0.6 0.

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 8 .

= –Therapy with DPP-4 Inhibitor 9 .

2003:1427–1483.145:2653–2659.3:365–372.359:824–830. Ahrén B Curr Diab Rep 2003. 10 . Buse JB et al. Zander M et al Lancet 2002.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 Release of incretins from the gut Pancreas β-cells α-cells Insulin increases peripheral glucose uptake Improved Hyperglycemia Physiologic Glucose Control ↑insulin and ↓glucagon reduce hepatic glucose output DPP-4 Enzyme X  Glucagon from alpha cells (GLP-1) Glucose dependent DPP-4 Inhibitor Inactive incretins DPP-4 = dipeptidyl peptidase 4 Adapted from Brubaker PL. Saunders. Drucker DJ Endocrinology 2004. 10th ed. In Williams Textbook of Endocrinology. Philadelphia.

37(6):1164–1171.5 nM9 NH 2 ~12. J Med Chem.9 ± 1. 2005.emea. 7. 2003. Clin Ther.50(10):2297–2300. http://www. 5. Eur J Pharmacol. 8.europa.4 h3 12. 2008. MSD. 2007. Augeri DJ et al.48(1):141–151. 2005. 9. Biochem Pharmacol. Fura A et al.589(1–3):306–14.eu/humandocs/Humans/EPAR/galvus/galvus. Data on file.30(3):499–512. 4. J Med Chem. 11 10.1 h10 1.90 nM2 ~2–2. J Med Chem. Feng J et al. Villhauer EB et al. Drug Metab Dispos. Kim D et al.htm.76(1):98–107. EMEA approval and SPC for Galvus. 2.5–21.37 ± 0. .Covington P et al. 2008. J Med Chem. 2008.03 nM2 5. 6. 2009. Lee B et al. 2009.04 nM2 ~2–3 h5 3. 3.DPP-4 Inhibitors Chemical Class Generic Name β-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 O HO O Selectivity Half-life 9. Matsuyama-Yokono A et al.46(13):2774–2789. Accessed on July 8.48(15):5025–5037.8 h7 6.96 ± 1.28 ± 1.

1  Sitagliptin is a potent.1185/03007990902109514.1 – Sitagliptin is >2. 2005.25(10):2507–2514.Sitagliptin  Sitagliptin is a DPP-4 inhibitor that improves glycemic control in patients with type 2 diabetes. Curr Med Res Opin. 2. 2009. 1. Kim D et al. DPP-9.48(1):141–151. 12 .2  Sitagliptin 100 mg once daily has shown near maximal and sustained DPP-4 inhibition (97%) over 24 hours. MSD.600 times more selective for DPP-4 in vitro than DPP-8. Alba M et al. 3. doi: 10.3 DPP-4=dipeptidyl peptidase-4. and other related enzymes. highly selective. J Med Chem. once-daily oral therapy. eAppendix. Data on file.

Washington. A201.05 for between group difference 70 60 50 40 30 20 10 0 0 0.0 2. June 10.4 0. Abstract presented at: American Diabetes Association. DC.5 1.Sitagliptin Lowers Post-meal Glucose Excursion and Enhances Insulin Secretion Japanese Monotherapy Study Baseline Week 12 320 Baseline Week 12 Plasma Insulin (µU/mL) P<0.0 Placebo Sitagliptin 100 mg qd Plasma Glucose (mg/dL) 280 240 200 160 120 0 0.3 0.5 1.5 0.0 2.0 2.5 1.0 P<0.0 11.001) Nonaka K et al. 13 .0 2.2 mg/dL Time (hr) Insulinogenic Index (µU/mg) 0.001 for difference in change from baseilne in 2-hr PPG Time (hr) Insulinogenic index = ∆ I30 / ∆ G30 Between group difference (P<0.0 0 0. 2006.7 mg/dL -69.5 1.1 0 Week 0 Week 12 Placebo Sitagliptin 100 mg qd Placebo Sitagliptin 100 mg qd 0 0.2 0.

PN021. PN023.8 0 Time (wk) 6 12 18 0 5 10 Time (wk) 15 20 25 0 Time (wk) 4 8 12 *Between group difference in LS means. June 9-13.79% 8. Washington.6 7. A201. 2006.001) 8.2 Placebo (n=74) Placebo (n=75) Sitagliptin 100 mg (n=75) 7.4 24-Week study -0.4 (P<.05% 8.0 7.2 Sitagliptin 100 mg (n=168) 7.Sitagliptin Consistently and Significantly Lowers A1C With Once-Daily Dosing in Monotherapy 18-Week study Change vs placebo* 8. Abstracts presented at: 66 th Scientific Sessions of the American 14 Diabetes Association. Nonaka K et al.4 (P<.2 6.6% (P<. DC. Raz I et al. Aschner P et al.0 A1C (%) A1C (%) A1C (%) Placebo (n=244) Sitagliptin 100 mg (n=229) 8.6 7.001) -0.001) Japanese study -1.0 8.6 7. .

Abstract presented at: American Diabetes Association.36 0. . June 10. 21.4 0.023) p< 0.44 0.38 p< 0.32 0. 2006.3 (95% CI 3. PN021.46 0.42 0.114.078 Hatched = Baseline Solid = Week 24 Placebo Sitagliptin ∆ from baseline vs pbo = 13.2 +/. -0. Washington.3 ∆ from baseline vs pbo = 0.Sitagliptin Improved Markers of Beta-Cell Function: 24-Week Monotherapy Study Proinsulin/insulin ratio 0.9) 15 * P value for change from baseline compared to placebo Aschner P et al.34 0.9.48 0. DC.001* 75 70 65 60 55 50 45 40 35 30 Placebo Sitagliptin (95% CI -0.3.001* HOMA-β 0.

1A2. rosiglitazone. or 2B6 No induction of CYP3A4 Not extensively bound to plasma proteins  In vivo  low potential of drug interactions with substrates of CYP3A4. warfarin.Assessment of Drug Interactions With Sitagliptin  In vitro  unlikely to cause interactions with other drugs – – – No inhibition of CYP isozymes CYP3A4. glyburide. MSD. 2C9. 2C19. or oral contraceptives  Digoxin – No dosage adjustment of digoxin or sitagliptin is recommended 16 Data on file. 2C8. 2D6. simvastatin. . 2C8. and 2C9 – No meaningful alteration of the pharmacokinetics of metformin.

Data on file.18:2362–2367.1  Sitagliptin is a DPP-4 inhibitor that is not covalently bound.25(10):2507–2514. highly selective once-daily oral therapy.4 1.2 It rapidly dissociates and has a prolonged half-life that supports once. 2006.daily dosing.1185/03007990902109514.91(11):4612–4619. doi: 10. eAppendix. J Clin Endocrinol Metab.Summary  Sitagliptin is a potent.1  Sitagliptin 100 mg has shown near maximal and sustained DPP-4 inhibition over 24 hours. Bioorg Med Chem Lett. MSD.1  Sitagliptin enhances incretin levels through inhibition of DPP-4. 17 . 3. resulting in increases in active GLP-1 and GIP. 4.3. Curr Med Res Opin. Herman GA et al. Wallace MB et al. 2. 2008. Alba M et al. 2009.

Chicago.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 Proportion of patients (%) Proportion of patients (%) 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. IL.

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

Sitagliptin Added to Ongoing Metformin Therapy: Sustained Glycemic Control Over 54-weeks With Weight Loss A1C (%) Phase A 7.0 Weight (kg) Phase A Interim Phase B LS mean change from baseline at week 54 -0. -0.0 -1.5 7.3 7.7% (95% CI: -0.5.0 -2.2) 0. -0.9 6. Poster presented at 2007 ADA Annual Meeting.1 6.6) 1.7 6.6 kg (95% CI: -1. 20 .5 LS mean chance from baseline in body weight (kg) Interim Phase B 2.0 0 6 12 18 24 30 38 46 54 0 12 24 Weeks 38 54 Weeks Karasik A et al.0 LS mean change from baseline at week 54 -0.7 Mean A1C (%) 7.9 7.8.

4%) 9% and <10% (mean 9.Initial Combination Therapy with Sitagliptin and Metformin: Change From Baseline in A1C at Week 54 by Baseline A1C Subgroups* HbA1C Change from baseline at Week 54 (%) 0.5 -1.5 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) -2.0 -1.5 -1. Chicago. 21 .6%) 8% and <9% (mean 8.4%) 0. Williams-Herman D et al. Poster presented at 2007 ADA Annual Meeting. IL.0 -3.0 -1.0 -2.0 -0.0 -3.5 *Mean change  SE: APT Population.4%) 10% (mean 10.5 -3.5 -3.5 <8% (mean 7.5 -2.0 -0.0 -2.

5 Additive to 100% 2. 2006.3)=100% FDC=fixed-dose combination.0 P<.5 Combination Metformin Sita 50 mg/ 500 mg bid Met 500 mg bid Combination Sitagliptin Metformin Sita 50 mg/ 100 mg qd 1000 mg bid Met 1000 mg bid -0.5 -1.1 -2.3 -1.0 -1.8 + 1.8 -1 -0. Presented at: 19th World Diabetes Congress (IDF) in South Africa.8 -1.1/(0.0)89% P<.Effect of FDC Sitagliptin/Metformin on A1C Reduction Is Higher Than Monotherapy Placebo-Subtracted Data in 24-Week Study Sitagliptin 100 mg qd A1C reduction from baseline (%) -0 -0.6 -2.001 Additive to 89% 1.8 + 1.001 -2. Williams-Herman D et al.6/(0. 22 .

001 vs placebo. .81 * 16. Migoya EM et al.37 Placebo Metformin Sitagliptin Sitagliptin + metformin 23 *P<. Abstract # 286-OR. Presented at 2007 ADA Annual Meeting.68 Active GLP-1 (pM) 30 25 20 15 10 5 0 8.Complementary Effect of Sitagliptin + Metformin on Active GLP-1 40 35 * 34.41 * 14.

0 Patients (%) 3.24-Week Add-on Therapy to Metformin Study Incidence of Hypoglycemia With Sitagliptin With Metformin Was Similar to Placebo With Metformin 5.29:2638–2643. Diabetes Care.0 Patients with at least one episode of hypoglycemia over 24 weeks All-patients-as-treated population aSitagliptin 100 mg/day.0 0. 24 . bMetformin ≥1500 mg/day Adapted from Charbonnel B et al.0 1.1% 2.0 2.0 Placebo + metforminb (n=237) Sitagliptina + metforminb (n=464) 4.3% 1. 2006.

dMetformin ≥1500 mg/day 25 Adapted from Charbonnel B et al.2 -0.4 -0. . 100 mg/day. 2006.6 -0.7 P<0.001 vs baseline aExcluding cSitagliptin data after initiation of glycemic rescue therapy.017 vs baseline Placebo + metformind (n=169) Sitagliptinc + metformind (n=399) –0.8 –0. bleast squares means. Diabetes Care.29:2638–2643.5 -0.7 -0.6 P=0.1 -0.3 -0.24-Week Add-on Therapy to Metformin Study Sitagliptin With Metformin Provided Weight Loss Similar to Placebo With Metformin at Week 24 0 Change in Body Weighta from baseline (kg)b -0.

26 .59:1345-1355.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 Adapted from Del Prato Int J Clin Pract 2005.

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 PPARγ agonist (TZD) Combination therapy with metformin. when the single agent alone with diet and exercise does not provide adequate glycemic control Combination therapy with metformin and a sulfonylurea. or PPARγ. Contraindications – JANUVIA is contraindicated in patients who are hypersensitive to any components of this product 27 . sulfonylurea. 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). when dual therapy with these agents with diet and exercise does not provide adequate glycemic control Combination therapy with metformin and a PPARγ agonist.

dRequiring hemodialysis or peritoneal dialysis. bModerate=CrCl 28 . assessment of renal function is recommended prior to initiation of JANUVIA and periodically thereafter aMild=CrCl ≥50 mL/min.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. JANUVIA may be administered without regard to the timing of hemodialysis. a lower dose of the sulfonylurea or insulin may be considered to reduce the risk of sulfonylurea.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. ≥30 to <50 mL/min. cSevere=CrCl <30 mL/min.

sitagliptin.JANUMET™ (sitagliptin/metformin. or 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. 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. thiazolidinediones) 29 . 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. sitagliptin.

acute myocardial infarction.g. because the use of such products may result in acute alteration of renal function 30 . and septicemia. – JANUMET should be temporarily discontinued in patients undergoing radiologic studies involving intravascular administration of iodinated contrast materials. • Known hypersensitivity to sitagliptin phosphate.5 mg/dL [males].4 mg/dL [females]. or abnormal creatinine clearance. with or without coma. which may also result from conditions such as cardiovascular collapse (shock). as suggested by serum creatinine levels ≥1. ≥1. metformin hydrochloride or any other component of JANUMET • Acute or chronic metabolic acidosis. e.JANUMET™ (sitagliptin/metformin.. including diabetic ketoacidosis. MSD) Contraindications: Based on the Worldwide Product Circular Contraindications – JANUMET is contraindicated in patients with: • Renal disease or renal dysfunction.

Data on file. 2009. LA. MSD. Poster presented at: American Diabetes Association 69th Scientific Sessions. .Initial Fixed-Dose Combination Therapy With JANUMET™ vs Metformin Monotherapy: Conclusions Compared with metformin alone. and lower incidences of abdominal pain and diarrhea compared with metformin alone. June 5 –9. 31 2. Reasner C et al. FDC=fixed-dose combination. 1. New Orleans. 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.

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. 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 32 . complementary mechanisms of action.