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
2
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;287:360–372; Porte D Jr, Kahn SE. Clin Invest Med 1995;18:247–254.
3
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;145:2653–2659; 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.
4
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
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;29:46–52. Copyright © 1986 Springer-Verlag.
Vilsbøll T, Holst JJ. Diabetologia 2004;47:357–366.
7
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
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
X
DPP-4
Enzyme
Pancreas
β-cells
α-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;145:2653–2659; 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.
10
DPP-4 Inhibitors
Chemical Class
β-phenethylamines1
Generic Name
Sitagliptin
Aminopiperidine8
Cyanopyrrolidines
Vildagliptin4
Saxagliptin6
H
Molecular Structure
F
N
F NH2 O
N
F
N
N N
NC
HO
H 3C N
N
NC
O
HO
CF3
Selectivity
Half-life
9.96 ± 1.03
nM2
~12.4 h3
O
H NH2
N
H
O
Alogliptin
O
CN
N
N
NH 2
5.28 ± 1.04 nM2
3.37 ± 0.90 nM2
6.9 ± 1.5 nM9
~2–3 h5
~2–2.8 h7
12.5–21.1 h10
1. Kim D et al. J Med Chem. 2005;48(1):141–151.
2. Matsuyama-Yokono A et al. Biochem Pharmacol. 2008;76(1):98–107.
3. Data on file, MSD.
4. Villhauer EB et al. J Med Chem. 2003;46(13):2774–2789.
5. EMEA approval and SPC for Galvus. http://www.emea.europa.eu/humandocs/Humans/EPAR/galvus/galvus.htm. Accessed on July 8, 2009.
6. Augeri DJ et al. J Med Chem. 2005;48(15):5025–5037.
7. 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):306–14.
11
10.Covington P et al. Clin Ther. 2008;30(3):499–512.
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
DPP-4=dipeptidyl peptidase-4.
1. Data on file, MSD.
2. Kim D et al. J Med Chem. 2005;48(1):141–151.
3. Alba M et al. Curr Med Res Opin. 2009;25(10):2507–2514. eAppendix. doi: 10.1185/03007990902109514.
12
Sitagliptin Lowers Post-meal Glucose
Excursion and Enhances Insulin Secretion
P<0.05 for between group difference
Japanese Monotherapy Study
Baseline
Week 12
280
11.7
mg/dL
-69.2
mg/dL
240
60
Sitagliptin 100 mg qd
Placebo
50
40
30
20
10
0
0 0.5 1.0
2.0
0 0.5 1.0
2.0
Time (hr)
200
160
Placebo
Sitagliptin 100 mg qd
120
0
0.5 1.0
2.0
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
Insulinogenic Index (µU/mg)
Plasma Glucose (mg/dL)
320
Plasma Insulin (µU/mL)
Baseline
Week 12
70
0.5
Placebo
0.4
Sitagliptin 100 mg qd
0.3
0.2
0.1
0
Week 0
Week 12
Between group difference (P<0.001)
Nonaka K et al. A201. Abstract presented at: American Diabetes Association; June 10, 2006; Washington, DC.
13
Sitagliptin Consistently and Significantly Lowers A1C With Once-Daily
Dosing in Monotherapy
18-Week study
Change vs
placebo*
8.4
Japanese study
24-Week study
-0.6%
-0.79%
(P<.001)
-1.05%
(P<.001)
8.4
(P<.001)
8.4
7.6
8.0
A1C (%)
8.0
A1C (%)
A1C (%)
8.0
7.6
7.6
7.2
Placebo (n=74)
7.2
Sitagliptin 100 mg (n=168)
0
6
12
Time (wk)
18
Placebo (n=244)
7.2
Sitagliptin 100 mg (n=229)
0
5
10
15
20
Time (wk)
25
Placebo (n=75)
6.8
Sitagliptin 100 mg (n=75)
0
4
8
Time (wk)
12
*Between group difference in LS means.
Raz I et al; PN023; Aschner P et al. PN021; Nonaka K et al; A201. Abstracts presented at: 66 th Scientific Sessions of the American
14
Diabetes Association; June 9-13, 2006; Washington, DC.
Sitagliptin Improved Markers of Beta-Cell
Function: 24-Week Monotherapy Study
HOMA-β
Proinsulin/insulin ratio
0.48
75
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
0.3
30
Placebo
∆ from baseline vs pbo
Placebo
Sitagliptin
= 0.078
(95% CI -0.114, -0.023)
p< 0.001*
Hatched = Baseline
Solid = Week 24
Sitagliptin
∆ from baseline vs pbo
* 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.
= 13.2 +/- 3.3
(95% CI 3.9, 21.9)
15
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
16
Data on file, MSD.
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
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):4612–4619.
4. Alba M et al. Curr Med Res Opin. 2009;25(10):2507–2514. eAppendix. doi: 10.1185/03007990902109514.
17
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
67
70
63
57
60
50
44
40
48
41
35
23 25
20
10
0
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)
Proportion of patients (%)
Proportion of patients (%)
90
77
80
30
Proportion of patients achieving an A1C target
of <7% at Week 24 remaining at <7% at Week 54
80
70
79
80
85
70
59
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)
Williams-Herman D et al. Poster presented at 2007 ADA Annual Meeting; Chicago, IL.
18
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
Weight (kg)
Interim Phase B
Phase A
2.0
Mean A1C (%)
7.7
LS mean change from baseline
at week 54
-0.7% (95% CI: -0.8, -0.6)
7.5
7.3
7.1
6.9
6.7
LS mean chance from baseline
in body weight (kg)
7.9
6.5
Interim Phase B
LS mean change from
baseline at week 54
-0.6 kg (95% CI: -1.5, -0.2)
1.0
0.0
-1.0
-2.0
0
6
12
18
24
30
38
46
54
Weeks
Karasik A et al. Poster presented at 2007 ADA Annual Meeting.
0
12
24
38
54
Weeks
20
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*
0.0
<8%
(mean 7.6%)
8% and <9%
(mean 8.4%)
9% and <10%
(mean 9.4%)
10%
(mean 10.4%)
0.0
-0.5
-0.5
-1.0
-1.0
-1.5
-1.5
-2.0
-2.5
-3.0
-3.5
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)
*Mean change  SE: APT Population.
Williams-Herman D et al. Poster presented at 2007 ADA Annual Meeting; Chicago, IL.
-2.0
-2.5
-3.0
-3.5
21
Effect of FDC Sitagliptin/Metformin on A1C Reduction Is
Higher Than Monotherapy
A1C reduction from baseline (%)
Placebo-Subtracted Data in 24-Week Study
-0
Sitagliptin
100 mg qd
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
-1.0
-0.8
-0.8
-1
-1.5
-1.3
-1.6
-2.0
P<.001
Additive to 89%
1.6/(0.8 + 1.0)89%
-2.1
-2.5
P<.001
Additive to 100%
2.1/(0.8 + 1.3)=100%
FDC=fixed-dose combination.
Williams-Herman D et al. Presented at: 19th World Diabetes Congress (IDF) in South Africa, 2006.
22
Complementary Effect of Sitagliptin
+ Metformin on Active GLP-1
*
34.68
40
Active GLP-1 (pM)
35
30
25
*
14.81
20
15
10
*
16.37
8.41
5
0
Placebo
Metformin Sitagliptin Sitagliptin +
metformin
*P<.001 vs placebo.
Migoya EM et al. Presented at 2007 ADA Annual Meeting. Abstract # 286-OR.
23
24-Week Add-on Therapy to Metformin Study
Incidence of Hypoglycemia With Sitagliptin With
Metformin Was Similar to Placebo With Metformin
Placebo + metforminb (n=237)
5.0
Sitagliptina + metforminb (n=464)
Patients (%)
4.0
3.0
2.1%
2.0
1.3%
1.0
0.0
Patients with at least one episode of hypoglycemia over 24 weeks
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.
24
24-Week Add-on Therapy to Metformin Study
Sitagliptin With Metformin Provided Weight Loss
Similar to Placebo With Metformin at Week 24
Change in Body Weighta
from baseline (kg)b
0
-0.1
-0.2
-0.3
-0.4
-0.6
-0.8
cSitagliptin
Sitagliptinc + metformind (n=399)
-0.5
-0.7
aExcluding
Placebo + metformind (n=169)
–0.6
P=0.017
vs baseline
–0.7
P<0.001
vs baseline
data after initiation of glycemic rescue therapy; bleast squares means;
100 mg/day; dMetformin ≥1500 mg/day
Adapted from Charbonnel B et al. Diabetes Care. 2006;29:2638–2643.
25
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;59:1345-1355.
26
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, 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
27
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
aMild=CrCl
≥50 mL/min.
≥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.
bModerate=CrCl
28
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)
29
JANUMET™ (sitagliptin/metformin, MSD) Contraindications: Based on
the Worldwide Product Circular
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
30
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.
FDC=fixed-dose combination.
1. Reasner C et al. Poster presented at: American Diabetes Association 69th Scientific Sessions. New Orleans, LA. June 5–9, 2009.
31
2. Data on file, MSD.
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
32