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Module 1Clinical Background
The Need for Early Treatment
Diabetes Pathophysiology
Rationale for Combined Therapy With Metformin and a DPP-4 Inhibitor
2025
400
380
Number (millions)
350
300
250
200
246
150
100
50
0
Prevalence
Adapted from International Diabetes Foundation. http://www.idf.org/home/index.cfm?node=37. Accessed on January 24, 2007.
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.
Percentage of patients
with HbA1c <7%
60
50
Sulfonylurea
40
30
20
10
0
3
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.
Relative Risk
N=4585
N=3642
EVERY 1%
reduction in HbA1c
160
Adjusted incidence
per 1000 person years (%)
Diabetesrelated
deaths
140
Microvascular endpoint
120
REDUCED RISK
(P<0.0001)
Myocardial infarcation
100
1%
80
60
Myocardial
infarctions
Microvascular
complications
40
20
0
5
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.
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
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
Glyburide
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
2646
10
Unmet needs
A more comprehensive approach to treatment that will improve glycemic
control without increasing side effects
11
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
100%
Beta-cell dysfunction
Insulin resistance
NGT
IGT
T2D Diagnosis
100%
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
Type 2 diabetes
Alpha cells
Fewer islets
Fewer beta cells/islet
Glucagon
Pancreas
Pancreas
Beta cells
Insulin
Cell Type
Hormone
Physiologic Action
Alpha cell
Glucagon
Beta cell
Insulin
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.
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
60
120
180
240
15
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.
16
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
17
80
0.6
80
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
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.
18
Insulin Resistance
Insulin resistance begins years before diagnosis
After diagnosis of type 2 diabetes there is little worsening of insulin
resistance
Liver
Ways to reduce
hyperglycemia
TZDs (eg rosiglitazone)
Biguanides (eg, metformin)
Gut
Delay intestinal
carbohydrate absorption
-glucosidase inhibitors
(eg, acarbose)
TZD = thiazolidinediones
Adapted from Inzucchi SE. JAMA 2002;287:360372.
20
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
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
22
1Adapted
23
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
Hypoglycemic risk
Weight gain,
weight loss,
or weight neutral
Loss
Neutral
GI effects + rare
lacticacidosis
24
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
26
Bibliography
Ahrn B. Gut peptides and type 2 diabetes mellitus treatment. Curr Diab Rep 2003;3:365372.
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;59:13091316
Bell D. The case for combination therapy as first-line treatment for the type diabetic patient. Treat
Endocrinol 2006;5:131137.
Brazg R, Xu L, Dalla Man C, et al. Effect of adding sitagliptin, a dipeptidyl peptidase-4 inhibitor, to
metformin on 24-h glycaemic control and -cell function in patients with type 2 diabetes. Diabetes
Obes Metab 2007;9:186193.
Brubaker PL, Drucker DJ. Minireview: Glucagon-like peptides regulate cell proliferation
and 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 in
humans with type 2 diabetes. Diabetes 2003;52:102-110.
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;29:26382643.
Del Prato S and Marchetti P. Targeting insulin resistance and beta-cell dysfunction: The role of
Thiazolidinediones. Diabetes Tech Therp 2004; 6:719-131.
27
Bibliography (continued)
1Del
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;59:1345-1355.
Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care
2003;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 noninsulindependent diabetes mellitus: Role of hepatic and extra hepatic tissues. J Clin Invest
1986;77:15251532.
Gaede P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in
patients with type 2 diabetes. N Engl J Med 2003;348:383393.
Gastaldelli A, Ferranninni E, Miyazaki Y, et al. Beta-cell dysfunction and glucose intolerance:
Results from the San Antonio metabolism (SAM) study. Diabetologia 2004; 47:31-39.
Gerich JE. Physiology of Glucagon. International Review of Physiology 1981;24:243-275.
Halter JB, Ward WK, Porte D, et al. Glucose regulation in non-insulin-dependent diabetes
mellitus: Interaction between pancreatic islets and the liver. Am J Med 1985; 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. JAMA 2002;287:360372.
Jiang G and Zhang BB. Glucagon and regulation of glucose metabolism Am J Physiol Endocrinol
Metab 2003;284:E671-E678.
28
Bibliography (continued)
Kahn SE, Haffner SM, Heise MA, et al. Glycemic durability of rosiglitazone, metformin,
or glyburide monotherapy. The ADOPT study group. N EnglJ Med 2006;355:2427
2443.
Mitrakou A, Kelley D, Mokan M, et al. Role of reduced suppression of glucose
production and diminished early insulin release in impaired glucose tolerance. N EnglJ
Med 1992; 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 Med
1970;283:109115.
Nauck MA, Meininger G, Sheng D, et al for the Sitagliptin Study 024 Group. Efficacy
and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the
sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on
metformin alone: A randomized, double-blind, non-inferiority trial. Diabetes Obes
Metab 2007;9:194205.
Nauck M, Stckmann F, Ebert R et al. Reduced incretin effect in type 2 (non-insulindependent) diabetes. Diabetologia 1986;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. Diabetes
Metab Res Rev 2001;17:181188.
Porte D Jr, Kahn SE. The key role of islet cell dysfunction in type II diabetes mellitus.
Clin Invest Med 1995;18:247254.
Rhodes CJ. Type 2 diabetesA matter of -cell life and death? Science 2005;
307:380384.
29
Bibliography (continued)
Stratton MI, Adler AI, Neil AW et al. Association of glycaemia with macrovascular and microvascular 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 Med 1995;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. JAMA 1999;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. Lancet 1998;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) 19th
World 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.
Lancet 2002;359:824830.
30
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