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The Need for a More Comprehensive

Approach for Treating Type 2 Diabetes


Module 1
(For Health Care Practitioners Only)

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

The Global Burden of Diabetes and


Its Complications Is Increasing
Increasing Prevalence of Diabetes
2007

2025

400
380

Number (millions)

350
300
250
200

Complications of Diabetes Worldwide

246

150

Fourth leading cause of


death from disease
Leading cause of blindness
and amputation in developed
countries
Risk of developing cardiovascular
disease is 2 to 4 times higher

100

50
0
Prevalence

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

UKPDS: Glycemic Control With Monotherapy


Worsens Over Time
Monotherapy With Insulin, Sulfonylurea (SU), or Metformin

Median HbA1c (%)

9
8
7

Conventional (n=200)
Chlorpropamide (n=129)
Glibenclamide (n=149)
Metformin (n=181)
Insulin (n=199)

6
0
0

3
6
Years from randomization

Newly diagnosed overweight patients with type 2 diabetes. Data shown are medians for cohorts of patients
followed for up to 10 years. Patient numbers shown are at 10 years.
Conventional therapy = diet alone; UKPDS = UK Prospective Diabetes Study
Adapted with permission from UKPDS Group. Lancet 1998;352:854865.

UKPDS: The Percent of Overweight Patients at HbA1c Goal


After Up to 9 Years of Monotherapy Is Low

Percentage of patients
with HbA1c <7%

60

Monotherapy With Sulfonylurea or Metformin


Metformin

50

Sulfonylurea

40
30
20
10
0
3

Years from randomization


Patients (N=4075 median baseline HbA1c 9.1%; range 7.5% to 10.7%) with newly diagnosed type 2 diabetes from the UKPDS
population. Data are shown for overweight (ideal body weight>120%) patients.
Adapted from Turner RC et al. JAMA 1999;281:20052012.

STENO-2: The Majority of Patients


Did Not Achieve HbA1C Goal (<6.5%)
Mean Duration 7.8 years

Intensive therapy (n=67)


Conventional therapy (n=63)

Patients achieving goal (%)

80
70
60
50
40
30
20
10
0
Glycosylated Cholesterol Triglycerides Systolic BP
hemoglobin <175 mg/dL <150 mg/dL <130 mmHg
<6.5%

Diastolic BP
<80 mmHg

Conventional therapy was treatment for multiple risk factors from their general practitioner according to the 1988
recommendations of the Danish Medical Association. Intensive therapy was multifactorial intervention involving strict
treatment goals by behavior modification and a stepwise introduction of pharmacologic therapy overseen by a project team
at the Steno Diabetes Center.
Reprinted with permission from Gaede P et al. N Engl J Med 2003;348:383393.

UKPDS: Improving HbA1c Control


Reduced Diabetes-Related Complications
Incidence of Complications

Relative Risk

N=4585

N=3642
EVERY 1%
reduction in HbA1c

160

Adjusted incidence
per 1000 person years (%)

Diabetesrelated
deaths

Any diabetes endpoint

140

Microvascular endpoint
120

REDUCED RISK
(P<0.0001)

Myocardial infarcation

100

1%

80
60

Myocardial
infarctions

Microvascular
complications

40
20
0
5

Mean HbA1c (%)

10

11

Amputations or
deaths from
peripheral vascular
disorders

Data adjusted for age, sex, and ethnic group, expressed for white men aged 5054 years at diagnosis and with mean duration of diabetes of 10 years.
Adapted with permission from Stratton IM et al. UKPDS 35. BMJ 2000;321:405412.

ADOPT: Monotherapy Failure Over Time


was Progressive
Cumulative Incidence of
Monotherapy Failures (%)

Kaplan-Meier Estimates of the Cumulative Incidence of Monotherapy


Failures (FPG>180 mg/dL) at 5 years
40
Hazard ratio (95% CI)
Rosiglitazone vs metformin, 0.68 (0.55-0.85); P<0.001
Rosiglitazone vs glyburide, 0.37 (0.30--.45); P<0.001

30

Glyburide

Metformin

20

Rosiglitazone

10

0
0

Years

No. at Risk
Rosiglitazone

1393

1207

1078

957

844

324

Metformin

1397

1205

1076

950

818

311

Glyburide

1337

1114

958

781

617

218

FPG = fasting plasma glucose


Adapted with permission from Kahn SE et al. NEJM 2006;355:2427-2443.

ADOPT: At the 4-Year Evaluation Most Patients


Receiving Monotherapy Were Not at Goal HbA1c (<7%)
Monotherapy with Rosiglitazone, Metformin, or Glyburide
Rosiglitazone (n=1456)

100

Percentage of patients
with HbA1c<7%

Metformin (n=1454)
Glyburide (n=1441)

80

P<0.001
P=0.03

60

40%

36%

40

26%
20

0
Rosiglitazone

Metformin

Adapted with permission from Kahn SE et al. NEJM 2006;355:2427-2443.

Glyburide

ADOPT: Monotherapy With Rosiglitazone or Glyburide


Resulted in Weight Gain vs Weight Loss With Metformin
100

Treatment difference (95% CI)


Rosiglitazone vs metformin, 6.9 (6.3 to 7.4); P<0.001
Rosiglitazone vs glyburide, 2.5 (2.0 to 3.1); P<0.001

Rosiglitazone (n=1456)
Metformin (n=1454)

98

Glyburide (n=1441)

Weight (kg)

96
94
92
90
88
0

2263

851

Years
No. of Patients

4117

3439

3068

Adapted with permission from Kahn SE et al. NEJM 2006;355:2427-2443.

2646

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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 (<6%) that can be achieved with therapy the
better

Unmet needs
A more comprehensive approach to treatment that will improve glycemic
control without increasing side effects
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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

Islet cell
dysfunction
Combined islet cell dysfunction
and insulin resistance

HYPERGLYCEMIA
Adapted with permission from Inzucchi SE. JAMA 2002;287:360372; Porte D Jr, Kahn SE. Clin Invest Med 1995;18:247254.

12

Relative Contributions of Diabetic


Pathophysiologies Over Time
Both beta-cell dysfunction
+ insulin resistance start
many years before
diagnosis

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

Hepatic glucose over-production

100%

Beta-cell dysfunction
Insulin resistance

NGT

IGT

T2D Diagnosis

100%

Late Stage T2DM

NGT = normal glucose tolerance, IGT = impaired glucose tolerance, T2D = type 2 diabetes
Bell D. Treat Endocrinol 2006; 5:131-137; Butler AE et al. Diabetes 2003;52:102-110; Del Prato S and Marchetti P. Diabetes Tech Therp 2004;6:719-731 13
Gastaldelli A, et al Diabetologia 2004:47:31-39; Mitrakou A, et al. N Engl J Med 1992; 326:22-29; Halter JB, et al. Am J Med 1985;79S2B:6-12

Islet Cell Dysfunction in Type 2 Diabetes


Normal

Type 2 diabetes

Alpha cells

Fewer islets
Fewer beta cells/islet

Glucagon

Pancreas

Pancreas
Beta cells
Insulin

Cell Type

Hormone

Physiologic Action

Abnormality in Type 2 Diabetes

Alpha cell

Glucagon

Stimulates hepatic glucose


output to avoid hypoglycemia

Glucagon not suppressed after eating;


worsens hyperglycemia

Beta cell

Insulin

Increases glucose uptake in the


liver and peripheral tissues

Inadequate and delayed insulin


response contributes to hyperglycemia

Adapted with permission from Rhodes CJ. Science 2005; 307:380-384; Gerich JE. International Rev Phys 1981; 24:243-275; Muller WA et al. N Engl J
14
Med 1970: 283:109-115.

Islet Cell Dysfunction Leads to Abnormal Insulin


and Glucagon Dynamics in Type 2 Diabetes

Glucose
(mg/dL)

Insulin*
(/mL)
from beta cells

360
330
300
270
240
110
80

Meal
Type 2 diabetes (n=12)
Normal patients (n=11)

120
90
60
30
0

140
Glucagon
130
(/mL)
120
from alpha cells
110
100
90
Time (minutes)

60

*Insulin measured in 5 patients.


Adapted with permission from Mller WA et al. N Engl J Med 1970;283:109115.
Copyright 1970 Massachusetts Medical Society. All rights reserved.

60

120

180

240
15

Glucose Production Is Elevated


in Type 2 Diabetes
Oral
glucose

Endogenous
Glucose Production

4
Mean SEM
mg/kgmin

Diabetic (n=13)
Nondiabetic (n=7)

0
0

60

120

180

240

300

360

420

Time, min
Adapted with permission from Firth RG et al. J Clin Invest 1986;77:15251532. Buse JB et al. In: Williams Textbook of
Endocrinology. 10th ed. Philadelphia, Pa: Saunders, 2003:14271483.

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Incretins Modulate Insulin and Glucagon to Decrease


Blood Glucose During Hyperglycemia
Meal

Increased insulin
(beta cells)

GIP

Muscle
Adipose
tissue

Glucose
Dependent

Peripheral
glucose
uptake

Gut

GLP-1

Physiologic
Glucose
Control

Pancreas
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;145:26532659; 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.

17

The Incretin Effect Is Diminished


in Individuals With Type 2 Diabetes
Control Subjects
(n=8)

Patients With Type 2 Diabetes


(n=14)

Normal Incretin Effect

80

0.6

80

Diminished Incretin Effect

0.4

0.2
20
0.1
0

0
0

60

120

180

Time, min

60

0.4
0.3

40

nmol/L

0.3

40

IR Insulin, mU/L

60

0.5

nmol/L

IR Insulin, mU/L

0.5

0.6

0.2
20
0.1
0

0
0

60

120

180

Time, min
Oral glucose load

Intravenous (IV) glucose infusion

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.

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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 Classes


Used in Type 2 Diabetes
Pancreatic -cells
Increase insulin secretion

Sulfonylureas (eg glimepiride)


Meglitinides/D-Phenylalanine derivatives
(eg, repaglinide, nateglinide)

Muscle and Adipose Tissue

Liver

Increase glucose uptake

Decrease glucose production

Ways to reduce
hyperglycemia
TZDs (eg rosiglitazone)
Biguanides (eg, metformin)

Biguanides (eg metformin)


TZDs (eg, rosiglitazone)

Gut
Delay intestinal
carbohydrate absorption

-glucosidase inhibitors
(eg, acarbose)

TZD = thiazolidinediones
Adapted from Inzucchi SE. JAMA 2002;287:360372.

20

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

DPP-4
Enzyme

Pancreas
-cells
-cells

Glucagon
from alpha cells
(GLP-1)
Glucose dependent

DPP-4
Inhibitor
Inactive
incretins

Insulin
increases
peripheral
glucose
uptake

Improved
Hyperglycemia
Physiologic
Glucose Control
insulin and
glucagon
reduce hepatic
glucose
output

DPP-4 = dipeptidyl peptidase 4

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.

21

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

22

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

1Adapted

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

23

Rationale for Combining Metformin


With a DPP-4 Inhibitor (Incretin Enhancer)
Targeted Pathophysiologies

Mechanism

Metformin
Improves insulin
production through
incretin action
Improves insulin
resistance

Suppresses glucagon
production through
incretin action
Lowers hepatic
glucose production

DPP-4
Inhibitor

Side Effects

Benefits and Tolerability Issues

= low risk or no effect

Hypoglycemic risk

Edema CHF risks

Weight gain,
weight loss,
or weight neutral

Loss

Neutral

GI effects + rare
lacticacidosis

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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 19th World Diabetes Congress, South Africa, 2006;
Nauck MA, et al Diabetes Obes Metab 2007;9:194205.

25

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 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

1Adapted

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

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Brazg R, Xu L, Dalla Man C, et al. Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to
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27

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1Del

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29

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The Need for a More Comprehensive Approach for


the Treatment of Type 2 Diabetes
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