Sitagliptin Slide Set Specialist_1

8/10/2019 Sitagliptin Slide Set Specialist_1

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Table of Contents

Module 1Clinical Background

The Need for Early Treatment

Diabetes Pathophysiology

Rationale for Combined Therapy With Metformin and a DPP-4 Inhibitor


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The Global Burden of Diabetes and

Its Complications Is Increasing

Fourth leading cause of

death from disease

Leading cause of blindnessand amputation in developed

countries

Risk of developing cardiovascular

disease is 2 to 4 times higher

Adapted from International Diabetes Foundation. http://www.idf.org/home/index.cfm?node=37. Accessed on January 24, 2007.

Increasing Prevalence of Diabetes Complications of Diabetes Worldwide

246

380

0

50

100

150

200

250

300

350

400

Prevalence

Number(millions)

2007 2025


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UKPDS: The Percent of Overweight Patients at HbA1cGoal

After Up to 9 Years of Monotherapy Is Low

0

10

20

30

40

50

60

3 6 9

Years from randomization

Metformin

Sulfonylurea

Pe

rcen

tageo

fpa

tien

ts

withHbA

1c

120%) patients.

Adapted from Turner RC et al. JAMA1999;281:20052012.

Monotherapy With Sulfonylurea or Metformin


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STENO-2: The Majority of Patients

Did Not Achieve HbA1CGoal (


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EVERY 1%

reduction in HbA1c

REDUCED RISK

(P


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ADOPT: At the 4-Year Evaluation Most Patients

Receiving Monotherapy Were Not at Goal HbA1c(


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ADOPT: Monotherapy With Rosiglitazone or Glyburide

Resulted in Weight Gain vs Weight Loss With Metformin

Adapted with permission from Kahn SE et al. NEJM2006;355:2427-2443.

Years

Treatment difference (95% CI)

Rosiglitazone vs metformin, 6.9 (6.3 to 7.4); P


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Summary: Glycemic Control in Type 2 Diabetes

The prevalence of diabetes and its complications is growing rapidly

Glycemic control is often inadequate

With monotherapy, many patients do not reach goals

With monotherapy, glycemic control has been shown to fail with time

Complications are reduced with improved glycemic control

The nearer to normal HbA1C(


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HYPERGLYCEMIA

Islet cell

dysfunction

PancreaticBeta CellsDecreased

insulin secretion

PancreaticAlpha CellsExcessive

glucagon secretion

Insulin

resistance

Adapted with permission from Inzucchi SE. JAMA2002;287:360372; Porte D Jr, Kahn SE. Clin Invest Med1995;18:247254.

LiverIncreased

Glucose Production

Peripheral TissuesDecreased

Glucose UptakeIncreasedLipolysis

Combined islet cell dysfunctionand insulin resistance

The Pathophysiology of Type 2 Diabetes Involves

Multiple Organ Systems


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Late Stage T2DMIGT

Insulin resistance

T2D DiagnosisNGT

Beta-cell dysfunction

100%

100%

Relative Contributions of Diabetic

Pathophysiologies Over Time

Those who develop

diabetes have typically

lost ~50% of beta-cell

function

Beta-cell dysfunction ultimately determines

the onset of hyperglycemia and is a major

factor associated with progressively rising

plasma glucose levels and disease

progression, not insulin resistance

Both beta-cell dysfunction

+ insulin resistance start

many years before

diagnosis

Hepatic glucose over-production

NGT = normal glucose tolerance, IGT = impaired glucose tolerance, T2D = type 2 diabetesBell D. Treat Endocrinol2006; 5:131-137; Butler AE et al. Diabetes2003;52:102-110; Del Prato S and Marchetti P. Diabetes Tech Therp2004;6:719-731

Gastaldelli A, et al Diabetologia2004:47:31-39; Mitrakou A, et al. N Engl J Med1992; 326:22-29; Halter JB, et al.Am J Med1985;79S2B:6-12


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Islet Cell Dysfunction in Type 2 Diabetes

Normal

Alpha cellsGlucagon

Beta cellsInsulin

Cell Type Hormone Physiologic Action Abnormality in Type 2 Diabetes

Alpha cell Glucagon Stimulates hepatic glucoseoutput to avoid hypoglycemia

Glucagon not suppressed after eating;

worsens hyperglycemia

Beta cell Insulin Increases glucose uptake in theliver and peripheral tissues

Inadequate and delayed insulin

response contributes to hyperglycemia

Adapted with permission from Rhodes CJ. Science2005; 307:380-384; Gerich JE. International Rev Phys1981; 24:243-275; Muller WA et al. N Engl JMed1970: 283:109-115.

Type 2 diabetes Fewer islets

Fewer beta cells/islet

Pancreas Pancreas


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Islet Cell Dysfunction Leads to Abnormal Insulin

and Glucagon Dynamics in Type 2 Diabetes

*Insulin measured in 5 patients.

Adapted with permission from Mller WA et al. N Engl J Med1970;283:109115.

Copyright 1970 Massachusetts Medical Society. All rights reserved.

Glucose(mg/dL)

Insulin*(/mL)

from beta cells

Glucagon(/mL)

from alpha cells

Time (minutes)

Type 2 diabetes (n=12)

Normal patients (n=11)

60 0 60 120 180 240

360

330

300

270

240

110

80

140130

120

110

100

90

120

90

60

30

0

Meal


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0 60 120 180 240 300 360 420

4

2

0

Glucose Production Is Elevated

in Type 2 Diabetes

Mean

SEM

mg

/kgm

in

EndogenousGlucose Production

Oralglucose

Nondiabetic (n=7)

Diabetic (n=13)

Time, min

Adapted with permission from Firth RG et al. J Clin Invest1986;77:15251532. Buse JB et al. In: Williams Textbook of

Endocrinology.10th ed. Philadelphia, Pa: Saunders, 2003:14271483.


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Decreased glucagon

(alpha cells)

Increasedinsulin(beta cells)

Pancreas

Liver

Muscle

Adiposetissue

Incretins Modulate Insulin and Glucagon to Decrease

Blood Glucose During Hyperglycemia

Gut

Peripheral

glucose

uptake

Glucose

production

GIP

GLP-1

Glucose

Dependent

GlucoseDependent

Meal

PhysiologicGlucoseControl

GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

Brubaker PL et al. Endocrinology2004;145:26532659; Zander M et al. Lancet2002;359:824930; Ahren B. Curr Diab Rep2003;3:365372;Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:14271483; Drucker DJ. Diabetes Care

2003;26:29292940.


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Time, min

IRInsu

lin,

mU/L n

mol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

The Incretin Effect Is Diminished

in Individuals With Type 2 Diabetes

Control Subjects

(n=8)

Patients With Type 2 Diabetes

(n=14)

Time, min

IRInsu

lin,

mU/L n

mol/L

0.6

0.5

0.4

0.3

0.2

0.1

0

80

60

40

20

0

18060 1200

Oral glucose load Intravenous (IV) glucose infusion

Normal Incretin Effect DiminishedIncretin Effect

IR = immunoreactive

Adapted with permission from Nauck M et al. Diabetologia1986;29:4652. Copyright 1986 Springer-Verlag.Vilsbll T, Holst JJ. Diabetologia2004;47:357366.


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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


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Target Sites for Different Oral Drug ClassesUsed in Type 2 Diabetes

Ways to reducehyperglycemia

Biguanides (eg metformin)

TZDs (eg, rosiglitazone)

TZDs (eg rosiglitazone)

Biguanides (eg, metformin)

GutDelay intestinal

carbohydrate absorption

Sulfonylureas (eg glimepiride)

Meglitinides/D-Phenylalanine derivatives

(eg, repaglinide, nateglinide)

Pancreatic -cellsIncrease insulin secretion

Liver

Decrease glucoseproduction

-glucosidase inhibitors(eg, acarbose)

TZD = thiazolidinediones

Adapted from Inzucchi SE. JAMA2002;287:360372.

Muscle and Adipose Tissue

Increase glucose uptake


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Glucose dependent

Insulinfrom beta cells

(GLP-1 and GIP)

Adapted from Brubaker PL, Drucker DJ Endocrinology 2004;145:26532659; Zander M et al Lancet 2002;359:824830; Ahrn B CurrDiab Rep2003;3:365372; Buse JB et al. In Williams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders, 2003:14271483.

Hyperglycemia

DPP-4 Inhibitors Improve Glucose Control by

Increasing Incretin Levels in Type 2 Diabetes

Glucagonfrom alpha cells(GLP-1)

Glucose dependent

Release of

incretins fromthe gut

Pancreas

-cells

-cells

Insulin

increases

peripheral

glucose

uptake

Ingestionof food

GI tract

insulin and

glucagonreduce hepatic

glucose

output

Inactive

incretins

Improved

Physiologic

Glucose Control

DPP-4

Enzyme

DPP-4

Inhibitor

X

DPP-4 = dipeptidyl peptidase 4


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Characteristics of an Ideal Therapy

Characteristics of an ideal oral antidiabetic agent

Lowers HbA1cto 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


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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 patientsachieve their HbA1cgoal without increasing side effects

1

1Adapted from Del Prato Int J Clin Pract2005;59:1345-1355.


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Rationale for Combining Metformin

With a DPP-4 Inhibitor (Incretin Enhancer)

Metformin

DPP-4

Inhibitor

Improves insulin

production through

incretin action

Improves insulin

resistance

Suppresses glucagon

production through

incretin action

Lowers hepatic

glucose production

Hypoglycemic risk

Edema CHF risks Weight gain,

weight loss,

or weight neutralLoss Neutral

GI effects + rare

lacticacidosis

Mecha

nism

Side

Effec

ts

= low risk or no effect

Targeted Pathophysiologies

Benefits and Tolerability Issues


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The Rationale for More Comprehensive Therapy

With Sitagliptin and Metformin

Improved glycemic efficacy, better than either agent alone

Complementary mechanisms and targets of action Metformin reduces hepatic glucose overproduction and improves peripheral

insulin resistance

Sitagliptin lowers hepatic glucose overproduction through the distinct

mechanism of increasing GLP-1 levels to reduce glucagon concentrations

Sitagliptin also improves glucose-dependent insulin release

Weight gain is not expected for both agents

Incidence of hypoglycemia is expected to be low

Adapted from Williams-Herman et al, Poster presentation IDF 19thWorld Diabetes Congress, South Africa, 2006;Nauck MA, et al Diabetes Obes Metab2007;9:194205.


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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

control1

Combination therapy with a DPP-4 inhibitor and metformin offersopportunity 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

1Adapted from Del Prato Int J Clin Pract2005;59:1345-1355.


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Bibliography

Ahrn B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep2003;3:365372.

Bailey CJ, Del Prato S, Eddy D, Zinman B. Earlier intervention in type 2 diabetes: The case forachieving early and sustained glycemic control. Int J Clin Pract2005;59:13091316

Bell D. The case for combination therapy as first-line treatment for the type diabetic patient. TreatEndocrinol2006;5:131137.

Brazg R, Xu L, Dalla Man C, et al. Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, tometformin on 24-h glycaemic control and -cell function in patients with type 2 diabetes. DiabetesObes Metab2007;9:186193.

Brubaker PL, Drucker DJ. Minireview: Glucagon-like peptides regulate cell proliferationand apoptosis in the pancreas, gut, and central nervous system. Endocrinology 2004;145:26532659.

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, Pa: Saunders,2003:14271483.

Butler AE, Jansen J, Bonner-Weir S, et al. Beta-cell deficit and increased beta-cell apoptosis inhumans with type 2 diabetes.Diabetes2003;52:102-110.

Charbonnel B, Karasik A, Liu J, et al for the Sitagliptin Study 020 Group. Efficacy and safety ofthe dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients withtype 2 diabetes inadequately controlled with metformin alone. Diabetes Care2006;29:26382643.

Del Prato S and Marchetti P. Targeting insulin resistance and beta-cell dysfunction: The role ofThiazolidinediones. Diabetes Tech Therp2004; 6:719-131.


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Bibliography (continued)

1Del Prato S, Felton-A-M, Munro et al. Improving glucose management: Ten steps to get morepatients with type 2 diabetes to glycaemic goal. Int J Clin Pract2005;59:1345-1355.

Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care2003;26:29292940.

Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides.Gastroenterology 2002;122:531544.

Firth RG, Bell PM, Marsh HM, et al. Postprandial hyperglycemia in patients with noninsulin-

dependent diabetes mellitus: Role of hepatic and extra hepatic tissues. J Clin Invest1986;77:15251532.

Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease inpatients with type 2 diabetes. N Engl J Med2003;348:383393.

Gastaldelli A, Ferranninni E, Miyazaki Y, et al. Beta-cell dysfunction and glucose intolerance:Results from the San Antonio metabolism (SAM) study. Diabetologia2004; 47:31-39.

Gerich JE. Physiology of Glucagon. International Review of Physiology1981;24:243-275.

Halter JB, Ward WK, Porte D, et al. Glucose regulation in non-insulin-dependent diabetesmellitus: Interaction between pancreatic islets and the liver.Am J Med1985; 79S2B:6-12

International Diabetes Foundation (IDF). Facts and figures.http://www.idf.org/home/index.cfm?node=37. Accessed on January 24, 2007.

Inzucchi S. Oral antihyperglycemic therapy for type 2 diabetes. JAMA2002;287:360372.

Jiang G and Zhang BB. Glucagon and regulation of glucose metabolismAm J Physiol EndocrinolMetab2003;284:E671-E678.


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Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin,or glyburide monotherapy. The ADOPT study group. N EnglJ Med2006;355:24272443.

Mitrakou A, Kelley D, Mokan M, et al. Role of reduced suppression of glucoseproduction and diminished early insulin release in impaired glucose tolerance. N EnglJMed1992; 326:2229.

Mller WA, Faloona GR, Aguilar-Parada E et al. Abnormal alpha-cell function in

diabetes. Response to carbohydrate and protein ingestion. N Engl J Med1970;283:109115.

Nauck MA, Meininger G, Sheng D, et al for the Sitagliptin Study 024 Group. Efficacyand safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with thesulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled onmetformin alone: A randomized, double-blind, non-inferiority trial. Diabetes ObesMetab2007;9:194205.

Nauck M, Stckmann F, Ebert R et al. Reduced incretin effect in type 2 (non-insulin-

dependent) diabetes. Diabetologia1986;29:4652. Porte D Jr. Clinical importance of insulin secretion and its interaction with insulin

resistance in the treatment of type 2 diabetes mellitus and its complications. DiabetesMetab Res Rev2001;17:181188.

Porte D Jr, Kahn SE. The key role of islet cell dysfunction in type II diabetes mellitus.Clin Invest Med1995;18:247254.

Rhodes CJ. Type 2 diabetesA matter of -cell life and death? Science2005;

307:380384.


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Stratton MI, Adler AI, Neil AW et al. Association of glycaemia with macrovascular and micro-

vascular complications of type 2 diabetes (UKPDS 35): Prospective observational study. BMJ

2000;321:405412.

Stumvoli M, Nurjhan N, Perriello G, et al Metabolic effects of metformin in non-insulin-dependent

diabetes mellitus. N Engl J Med1995;333:550554.

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. JAMA1999;281:20052012.

UKPDS Group. Effect of intensive blood-glucose control with metformin on complications in

overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS)

Group. Lancet1998;352:854865.

Vilsbll T, Holst JJ. Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia

2004;47:357366.

Williams-Herman D. et al, Poster presentation at International Diabetes Federation (IDF) 19thWorld Diabetes Congress in Cape Town, South Africa, 37 December 2006.

Zander M, Madsbad S, Madsen JL, et al. Effect of 6-week course of glucagon-like peptide 1 on

glycaemic control, insulin sensitivity, and -cell function in type 2 diabetes: A parallel-group study.

Lancet2002;359:824830.


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MSD does not recommend the use of any product

in any different manner than as described

in the prescribing information.

Before prescribing, please consult the complete manufacturers'

prescribing information

Copyright 2007 Merck & Co., Inc., Whitehouse Station, NJ, USA. All rights reserved.

3-08 JMT 2006-W-577005-SC (31-Jan-2010 JMT-09-ID-068-SS)

PT Merck Sharp & Dohme Indonesia

27thFloor, Wisma BNI 46, Jl. Jend. Sudirman Kav. 1, Jakarta 10220, Indonesia

Phone: (62 21) 5789-7000

The Need for a More Comprehensive Approach for

the Treatment of Type 2 Diabetes

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Sitagliptin Slide Set Specialist_1