Download Core Defects of Type 2 Diabetes

Core Defects of Type 2 Diabetes
Targeting Mechanisms for a
Comprehensive Approach
1
Objectives
•
Discuss challenges in treating type 2 diabetes and rationale
for earlier and more aggressive treatment approaches
•
Review the physiologic regulation of glucose homeostasis,
the role of incretins, and core defects of type 2 diabetes
•
Describe the complementary MOAs of agents used in the
treatment of type 2 diabetes to address the 3 core defects
•
Provide a clinical overview of JANUVIA™ (sitagliptin)
•
Provide an overview of the prescribing information for
JANUMET™ (sitagliptin/metformin HCl)
2
Insulin Resistance:
An Underlying Cause of Type 2 Diabetes
Obesity and
inactivity
Genetic
abnormalities
Type 2
diabetes
Aging
Medications
INSULIN
RESISTANCE
Rare
disorders
PCOS
Hypertension
Atherosclerosis
Dyslipidemia
Reaven GM. Physiol Rev. 1995;75:473-486
Clauser, et al. Horm Res. 1992;38:5-12.
3
Development and Progression of Type 2
Diabetes (Conceptual Representation)
NGT  Insulin  IGT/ IFG  Type 2 Diabetes
Resistance
Postprandial glucose
Glucose
Regulation
Fasting glucose
–10
Metabolic
Activity
–5
0
5
Insulin level
10
15
20
25
30
Insulin resistance—
hepatic and peripheral
Beta-cell function
–10
–5
0
5
10
15
20
Years From Diabetes Diagnosis
25
NGT=normal glucose tolerance; IGT=impaired glucose tolerance; IFG=impaired fasting glucose.
Kendall DM, Bergenstal RM. ©2005 International Diabetes Center, Minneapolis, MN. All rights reserved.
Adapted from Ferrannini E. Presentation at 65th ADA in Washington, DC, 2006.
30
4
UKPDS: -Cell Loss Over Time
-Cell Function (%)*
100
75
Patients treated
with insulin,
metformin,
sulfonylureas‡
50
25
IGT†
0
-12 -10
Type 2
Postprandial
Diabetes
Hyperglycemia
Phase I
-6
-2 0
Type 2
Diabetes
Phase II
2
6
Type 2 Diabetes
Phase III
10
14
Years From Diagnosis
*Dashed
line shows extrapolation forward and backward from years 0 to 6 from diagnosis based on Homeostasis Model
Assessment (HOMA) data from UKPDS.
†IGT=impaired glucose testing
‡The data points for the time of diagnosis (0) and the subsequent 6 years are taken from a
subset of the UPKDS population
and were determined by the HOMA model.
Lebovitz HE. Diabetes Rev. 1999;7:139-153.
5
Intensive Treatments and Increase in
HbA1c Over Time
United Kingdom Prospective Diabetes Study (UKPDS)
Median HbA1c (%)
9
8
ADA action
7
ADA goal
6
0
Conventional
Insulin
Chlorpropamide
Glibenclamide
(glyburide)
Metformin
Upper limit of normal range (6.2%)
0
3
6
9 10
Time From Randomization (years)
UK Prospective Diabetes Study (UKPDS 34) Group. Lancet. 1998;352:854-65.
6
Guideline Recommendations Are Becoming
More Aggressive
• 2007 ADA standards1
– “The A1C goal for patients in general is an A1C goal
of <7%.”
– “The A1C goal for the individual patient is an A1C as close
to normal (<6%) as possible without significant
hypoglycemia.” [boldface added]
• ADA/EASD consensus statement2
– “If lifestyle intervention and maximal tolerated dose of
metformin fail to achieve or sustain glycemic goals, another
medication should be added within 2–3 months of the
initiation of therapy or at any time when A1C goal is not
achieved.” [boldface added]
ADA=American Diabetes Association; EASD=European Association for the Study of Diabetes.
1. American Diabetes Association. Diabetes Care. 2007;30(suppl 1):S4–S41.
2. Nathan DM et al. Diabetes Care. 2006;29:1963–1972.
7
Most Patients With Type 2 Diabetes May Fail to Attain
A1C Goal With Conventional Treatment Paradigm
Published Conceptual Approach
Mean A1C
of patients
Diet and
OAD
exercise monotherapy
OAD
OAD
up-titration combination
OAD +
basal insulin
OAD +
multiple daily
insulin
injections
10
A1C, 9
%
8
7
6
Duration of Diabetes
OAD=oral antihyperglycemic drug.
Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.
8
Earlier and More Aggressive Intervention May Improve
Treating to Target Compared With Conventional Therapy
Published Conceptual Approach
Diet and
OAD
exercise monotherapy
OAD
OAD
up-titration combination
OAD +
basal insulin
OAD +
multiple daily
insulin
injections
10
A1C, 9
%
8
Mean A1C
of patients
7
6
Duration of Diabetes
Adapted from Del Prato S et al. Int J Clin Pract. 2005;59:1345–1355.
9
Challenges in Achieving Glycemic Goals
in Diabetes
• Less aggressive treat-to-target approach by
some clinicians1
• Suboptimal use of available therapies1
• Inability of any single agent’s MOA to address all core
defects of type 2 diabetes2
• Potential for increased side effects with use of
multiple agents3
• Suboptimal adherence to lifestyle measures1
• Underuse of medications as a result of
– Cost4
– Complexity of therapy5
1. Blonde L. Clin Cornerstone. 2005;7(suppl 3):S6–S17.
2. Van Gaal LF et al. Diabetologia. 2003;46(suppl 1):M44–M50.
3. McDonald HP et al. JAMA. 2002;288:2868–2879.
4. Piette JD et al. Diabetes Care. 2004;27:384–391.
5. Donnan PT et al. Diabet Med. 2002;19:279–284.
10
Major Pathophysiologic Defects
in Type 2 Diabetes
Islet-cell dysfunction
Glucagon
(alpha cell)
Pancreas
Hepatic
glucose
output
Insulin
(beta cell)
Insulin
resistance
Glucose uptake in
muscle and fat
Hyperglycemia
Liver
Muscle
Liver
Adapted with permission from Kahn CR, Saltiel AR. Joslin’s Diabetes Mellitus. 14th ed.
Lippincott Williams & Wilkins; 2005:145–168.
Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781.
Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.
Adipose
tissue
11
Major Targeted Sites of Oral Drug Classes
The glucose-dependent
mechanism of DPP-4 inhibitors
targets 2 key defects: insulin
release and unsuppressed
hepatic glucose production.
Liver
Pancreas
Beta-cell
dysfunction
Sulfonylureas
Meglitinides
Muscle
and fat
DPP-4 inhibitors
GLP-1
Hepatic glucose
overproduction
Biguanides
↓Glucose level
Insulin
resistance
Gut
TZDs
TZDs
Biguanides
DPP-4 inhibitors
Glucose
absorption
Alphaglucosidase
inhibitors
Biguanides
DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones.
DeFronzo RA. Ann Intern Med. 1999;131:281–303.
Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:1427–1483.
12
No Single Class of Oral Antihyperglycemic
Monotherapy Targets All Key Pathophysiologies
Major Pathophysiologies
AlphaGlucosidase
Inhibitors1,2
Insulin
deficiency
Meglitinides3
SUs4,5


TZDs6,7
Metformin8

Insulin
resistance


Excess hepatic
glucose output


Intestinal
glucose
absorption

DPP-4
Inhibitors


1. Glyset [package insert]. New York, NY: Pfizer Inc; 2004. 2. Precose [package insert]. West Haven, Conn: Bayer; 2004.
3. Prandin [package insert]. Princeton, NJ: Novo Nordisk; 2006. 4. Diabeta [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2007.
5. Glucotrol [package insert]. New York, NY: Pfizer Inc; 2006. 6. Actos [package insert]. Lincolnshire, Ill: Takeda Pharmaceuticals; 2004.
7. Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2005.
8. Glucophage [package insert]. Princeton, NJ: Bristol-Myers Squibb; 2004.
13
The Role of Incretins in Type 2 Diabetes
14
The Incretin Effect Is Diminished in Subjects
With Type 2 Diabetes
Control Subjects
(n=8)
Subjects With Type 2 Diabetes
(n=14)
Normal Incretin Effect
Diminished Incretin Effect
80
IR Insulin, mU/L
IR Insulin, mU/L
80
60
40
20
0
60
40
20
0
0
60
120
180
Time, min
Oral glucose load
0
60
120
180
Time, min
Intravenous (IV) glucose infusion
Adapted with permission from Nauck M et al. Diabetologia 1986;29:46–52. Copyright © 1986 Springer-Verlag.
15
GLP-1 Infusion Has Glucose-Dependent Effects on
Insulin and Glucagon in Patients With Type 2 Diabetes
GLP-1 Infusion
Glucose
mg/dL
250
Placebo
200
150
100
50
*
*
*
GLP-1
*
*
*
*
0
*P <0.05
Patients with type 2
diabetes (N=10)
Glucagon
pmol/L
Insulin
mU/L
GLP-1 Infusion
40
30
20
10
0
*
*
*
*
*
*
When glucose levels
approach normal values,
insulin levels decrease.
*
*
GLP-1 Infusion
20
15
10
5
0
–30 0
*
60
*
*
120
When glucose levels
approach normal values,
glucagon levels rebound.
*
180
240
Time, min
Adapted from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag.
16
Incretins Play an Important Role
in Glucose Homeostasis
Food ingestion
Glucose Dependent
 Insulin from beta cells
(GLP-1 and GIP)
Release of gut
hormones—
Incretins1,2
GI tract
Active
GLP-1 & GIP
Pancreas2,3
↑Glucose
uptake by
peripheral
tissue2,4
↓ Blood
glucose
Beta cells
Alpha cells
↓Glucose
DPP-4
enzyme
Glucose Dependent
 Glucagon from
alpha cells
(GLP-1)
production
by liver
Inactive Inactive
GLP-1
GIP
1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913.
2. Ahrén B. Curr Diab Rep. 2003;2:365–372.
3. Drucker DJ. Diabetes Care. 2003;26:2929–2940.
4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441.
17
Tips for Diabetes treatment
 Reduced HBA1C as low as possible at least below
6.5% without hypoglycemia
 Use DM meds that shows benefit beyound glycemic
control(Heart , vascular inflamation,
microalbuminuria)
 Medications that showed sustained effect and
preservation of B-cell function
 Use meds that have the least side effect.
18
Pills available for DM 2
• No hypoglycemia:
• TZD(Actos, Avandia)
• Metformin/glucophage)
• Alpha glucosidase
inhibitor(Precose,
Glyset)
• Combo(avandamet,
actoplusmet, janumet
• DPP IV inhibitor:
– Januvia
– Galvus
• Can Cause
Hypoglycemia:
• SU(glyburide,Amaryl)
• Prandin/Starlix
• Combo(glucovance,
avandaryl, duetact)
19
Non insulin injection for DM2
GLP-1 analog(byetta)
Amylin(Symlin)
20
Metformin
•+
insulin sensitizer

Less cardiac event by UKPDS

Weight reduction

Dm prevention data
 __ ____
______
 contraindicated in renal failure
 GI side effect

had to be stopped 48 hors before and after contrast
21
TZD( actos , Avandia)
•Plus:
•
•
•
•
Insulin Sensitizer
Heart and vascular benefit (Proactive ,Chicago)
Preservation of B- cell( dream , Adopt)
DM prevention data
•
(-): contraindicated in heart failure Stage 3- 4, or
liver failure
 Edema, weight gain
 ? Bone density
22
ADOPT: A Diabetes Outcome Progression Trial
Avandia Sustained A1C Over Time*
Treatment Difference at 4 Years
RSG vs MET –0.13 (–0.22 to –0.05), P=.002
RSG vs SU –0.42 (–0.50 to –0.33), P<.001
8.0
SU
HbA1C%
7.5
MET
RSG
7.0
6.5
6.0
0
0
1
2
3
4
5
Time (years)
Number of patients: 4012
3308
2991
2583
* Mean A1C values per visit are based on a repeated measures mixed model.
Kahn SE et al. N Engl J Med. 2006;355:2427-2443.
2197
822
23
rosiglitazone Medication (DREAM)
Primary Outcome: Rosiglitazone
Cumulative Hazard
0.6
HR = 0.40 (0.35-0.46); P<0.0001
0.5
0.4
Placebo
0.3
0.2
0.1
Rosiglitazone
0
0
1
2
No. at Risk
Years
3
4
5
Rosiglitazone
2635
2538
2414
1310
217
Placebo
2634
2470
2150
1148
177
 60% risk reduction of development of diabetes or death was seen with rosiglitazone
 This reduction was additive to standard counseling on healthy eating and exercise
The DREAM Trial Investigators. Lancet. 2006;368:1096-1105.
24
JANUVIA™ (sitagliptin) Targets 2 Physiologic
Glucose-Lowering Actions With a Single Oral Agent
Food ingestion
Glucose dependent
Release of
active incretins
GLP-1 and GIP
GI tract
JANUVIA
(DPP-4 inhibitor)
X
 Insulin
(GLP-1 and GIP)
Pancreas
Beta cells
Alpha cells
DPP-4
enzyme
Inactive Inactive
GLP-1
GIP
Glucose
uptake by
peripheral tissue
Glucose dependent
 Glucagon
(GLP-1)
Blood
glucose
Glucose
production
by liver
•
Incretin hormones GLP-1 and GIP are released by the intestine throughout the day;
their levels increase in response to a meal.
•
JANUVIA blocks DPP-4 to enhance the level of active incretins for 24 hours.
25
JANUVIA™ (sitagliptin):
Indications and Usage
• Monotherapy
– JANUVIA is indicated as an adjunct to diet and exercise to
improve glycemic control in patients with type 2 diabetes mellitus.
• Combination therapy
– JANUVIA is indicated in patients with type 2 diabetes mellitus to
improve glycemic control in combination with metformin or a
PPAR agonist (eg, thiazolidinediones) when the single agent
alone, with diet and exercise, does not provide adequate glycemic
control.
• Important limitations of use
– JANUVIA should not be used in patients with type 1 diabetes or
for the treatment of diabetic ketoacidosis, as it would not be
effective in these settings.
PPARγ=peroxisome proliferator-activated receptor gamma.
26
JANUVIA™ (sitagliptin):
Significant A1C Reductions as Monotherapy
Placebo-adjusted results
A1C
Mean Baseline: 8.0%
P<0.001*
Inclusion Criteria: 7%–10%
Prespecified Pooled Analysis at 18 Weeks||
<8
≥8–<9
≥9
Baseline A1C, % Overall
0.0
–0.2
–0.2
–0.4
n=193
–0.6
–0.8
–1.0
–0.6†
n=229
–0.8†
18-week monotherapy
(95% CI: –0.8, –0.4)
study1
24-week monotherapy study2
(95% CI: –1.0, –0.6)
Mean Change in A1C, %
Mean Change in A1C, % ‡
0.0
–0.4
n=411§
–0.6
n=769§
–0.8
–0.7
–0.6
n=239§
–0.7
–1.0
–1.2
–1.4
–1.6
n=119§
–1.4
–1.8
CI=confidence interval. *Compared with placebo. †Least-squares means adjusted for prior antihyperglycemic
therapy status and baseline value. ‡Difference from placebo. §Combined number of patients on JANUVIA or
placebo. ||P<0.001 overall and for treatment-by-subgroup interactions.
1. Raz I et al. Diabetologia. 2006;49:2564–2571.
2. Aschner P et al. Diabetes Care. 2006;29:2632–2637.
27
JANUVIA™ (sitagliptin) Monotherapy
Significantly Lowers FPG and PPG Levels
FPG
2-Hour PPG
Mean Baseline: 170 mg/dL
P<0.001*
Mean Baseline: 257 mg/dL
P<0.001*
0
–10
–20
–17†
n = 234
–30
–40
–50
–60
(95% CI: –24, –10)
Mean Change in 2-Hour PPG, mg/dL‡
Mean Change in FPG, mg/dL‡
24-week placebo-adjusted results
0
–10
n = 201
–20
–30
–40
–50
–47†
–60
(95% CI: –59, –34)
*Compared with placebo.
†Least-squares means adjusted for prior antihyperglycemic therapy status and baseline value.
‡Difference from placebo.
CI=confidence interval; FPG=fasting plasma glucose; PPG=postprandial plasma glucose (meal challenge test).
Aschner P et al. Diabetes Care. 2006;29:2632–2637.
28
JANUVIA™ (sitagliptin): Significant A1C Reductions
From Baseline When Added to Metformin or Pioglitazone
0
–0.2
Add-on to metformin study1
Add-on to pioglitazone study2
Mean Baseline A1C: 8.0%
Mean Baseline A1C: 8.0%, 8.1%
Pioglitazone Pioglitazone
+ Placebo + JANUVIA
Metformin
+ Placebo
Metformin
+ JANUVIA
n=224
n=453
–0.0%
–0.4
–0.6
P<0.001*
–0.8
–0.7%
–1.0
0.7% placebosubtracted result
*Compared with placebo.
1. Charbonnel B et al. Diabetes Care. 2006;29:2638–2643.
2. Rosenstock J et al. Clin Ther. 2006;28:1556–1568.
Mean Change in A1C From Baseline, %
Mean Change in A1C From Baseline, %
24-week change from baseline
0
n=174
n=163
–0.2
–0.2%
–0.4
–0.6
–0.8
–1.0
P<0.001*
–0.9%
0.7% placebosubtracted result
29
JANUVIA™ (sitagliptin):
Effect on Body Weight
• Monotherapy studies
– No increase in body weight from baseline with
JANUVIA compared with a small reduction in the
placebo group
• Add-on to metformin
– A similar decrease in body weight for both treatment
groups
• Add-on to pioglitazone
– No significant difference in body weight change
between treatment groups
30
JANUVIA™ (sitagliptin):
Adverse Reactions
Overall:
• Adverse reactions and discontinuation rates were similar to
placebo (both as monotherapy and as combination therapy)
• Incidence of hypoglycemia with JANUVIA was similar
to placebo (1.2% vs 0.9%)
• The adverse reactions, reported regardless of investigator
assessment of causality in ≥5% of patients treated with
JANUVIA 100 mg daily as monotherapy or in combination with
pioglitazone and more commonly than in patients treated with
placebo, were upper respiratory tract infection, nasopharyngitis,
and headache.
• Incidence of selected GI adverse reactions in patients treated
with JANUVIA vs placebo was as follows:
– Abdominal pain (2.3%, 2.1%)
– Nausea (1.4%, 0.6%)
– Diarrhea (3.0%, 2.3%)
31
JANUVIA™ (sitagliptin): Once-Daily Dosing—
Proven 24-Hour Glycemic Control
Usual Dosing for JANUVIA*
The recommended dose of JANUVIA is 100 mg once daily
as monotherapy or as combination therapy with
metformin or a PPAR agonist.
Patients With Renal Insufficiency*,†
A dosage adjustment is recommended in patients with moderate or severe
renal insufficiency and in patients with end-stage renal disease requiring
hemodialysis or peritoneal dialysis.
50 mg once daily
25 mg once daily
Moderate
Severe and ESRD‡
CrCl 30 to <50 mL/min
(~Serum Cr levels [mg/dL]
Men: >1.7–≤3.0; Women: >1.5–≤2.5)
CrCl <30 mL/min
(~Serum Cr levels [mg/dL]
Men: >3.0; Women: >2.5)
Assessment of renal function is recommended prior to JANUVIA
initiation and periodically thereafter.
*JANUVIA can be taken with or without food.
†Patients with mild renal insufficiency—100 mg once daily.
‡ESRD=end-stage renal disease requiring hemodialysis or peritoneal dialysis.
32
JANUVIA™ (sitagliptin):
Contraindications/Warnings and Precautions
• Contraindications
– None
• Warnings and Precautions
– Use in patients with renal insufficiency:
A dosage adjustment is recommended in patients with moderate
or severe renal insufficiency and in patients with ESRD requiring
hemodialysis or peritoneal dialysis.
– Use with medications known to cause hypoglycemia:
As monotherapy and as part of combination therapy with
metformin or pioglitazone, rates of hypoglycemia were similar to
rates in patients taking placebo.
The use of JANUVIA in combination with medications known to
cause hypoglycemia, such as sulfonylureas or insulin, has not
been adequately studied.
33
Summary of JANUVIA™ (sitagliptin)
• JANUVIA is an oral, selective inhibitor of the DPP-4 enzyme
• Indication:
– Indicated as monotherapy and in combination with metformin
or TZDs
– Usual recommended dose is 100 mg once daily
• In clinical studies:
– JANUVIA significantly improved A1C, FPG, and PPG
– Mean A1C response with JANUVIA appears to be related to
baseline A1C level
• Overall:
– Incidence of adverse reactions was similar to that with placebo
 Overall incidence of hypoglycemia similar to that with placebo
 A neutral effect on weight relative to that with placebo
• Before prescribing JANUVIA, please read the full Prescribing
Information, available at this presentation.
34
Complementary Mechanisms of Action
Combining Sitagliptin and Metformin
35
Metformin Lowers Plasma Glucose by Lowering Hepatic
Glucose Production and by Improving Insulin Sensitivity
Liver
↓ Gluconeogenesis
↓ Glycogenolysis
↑ Glycogen synthesis
Metformin
Blood glucose
Muscle
Adipose
tissue
Liver
1. Kirpichnikov D et al. Ann Intern Med. 2002;137:25–33. 2. Setter SM et al. Clin Ther. 2003;25:2991–3026.
3. Hundal RS et al. Diabetes. 2000;49:2063–2069. 4. Chu CA et al. Metabolism. 2000;49:1619–1626.
5. Bailey CJ et al. N Engl J Med. 1996;334:574–579.
↑Glucose
uptake in
muscle and
fat by
increasing
insulin
sensitivity5
36
The Combination of Sitagliptin and Metformin
Addresses
the 3Reduces
Core Defects
of Type 2 Diabetes
Sitagliptin
Hyperglycemia
Metformin
in a Complementary Manner
Sitagliptin improves
beta-cell function and
increases insulin
Beta-Cell
synthesis and
Dysfunction
release.
Hepatic Glucose
Sitagliptin reduces HGO
through suppression of glucagon Overproduction
(HGO)
from alpha cells.
*Please see corresponding speaker note for references.
Metformin has insulinsensitizing properties.
Insulin
Resistance
Metformin decreases HGO by
targeting the liver to decrease
gluconeogenesis and
glycogenolysis.
37
JANUMET™ (sitagliptin/metformin HCl):
Indications and Usage
• Indication
– JANUMET is indicated as an adjunct to diet and
exercise to improve glycemic control in adult patients
with type 2 diabetes mellitus who are not adequately
controlled on metformin or sitagliptin alone or in
patients already being treated with the combination of
sitagliptin and metformin.
• Important limitations of use
– JANUMET should not be used in patients with type 1
diabetes or for the treatment of diabetic ketoacidosis.
38
JANUMET™ (sitagliptin/metformin HCl):
Boxed Warning: Lactic Acidosis
• The labeling for JANUMET contains a boxed warning for lactic
acidosis, a rare,* but serious, metabolic complication that can occur
due to metformin accumulation during treatment with JANUMET.
• The risk of lactic acidosis increases with conditions such as sepsis,
dehydration, excess alcohol intake, hepatic insufficiency, renal
impairment, and acute congestive heart failure.
• The onset is often subtle, accompanied only by nonspecific symptoms
such as malaise, myalgias, respiratory distress, increasing
somnolence, and nonspecific abdominal distress.
• Laboratory abnormalities include low pH, increased anion gap, and
elevated blood lactate.
• If acidosis is suspected, JANUMET should be discontinued and the
patient hospitalized immediately.
See the full Prescribing Information for the complete Boxed Warning.
*The reported incidence of lactic acidosis in patients receiving metformin hydrochloride is very low
(approximately 0.03 cases/1,000 patient-years, with approximately 0.015 fatal cases/1,000 patient-years). When
lactic acidosis occurs, it is fatal in approximately 50% of cases.
39
JANUMET™ (sitagliptin/metformin HCl):
Pharmacokinetics
• Bioequivalence: A clinical bioequivalence study has
demonstrated that JANUMET is bioequivalent to
corresponding doses of sitagliptin plus metformin as
individual tablets
• Bioavailability:
– Sitagliptin ~87%
– Metformin ~50–60%
• Metabolism: both sitagliptin and metformin are
predominantly excreted unchanged in the urine
• Pharmacokinetics: no meaningful changes in either
sitagliptin or metformin with co-administration
40
JANUMET™ (sitagliptin/metformin HCl) Label Data:
Sitagliptin Plus Metformin Provided Significant Improvements
in Glycemic Control Beyond Metformin Alone*
24-week placebo-adjusted results†
A1C
FPG
2-Hour PPG
Mean Baseline A1C: 8.0%
P <0.001*
Mean Baseline: 170 mg/dL
P <0.001*
Mean Baseline: 275 mg/dL
P <0.001*
–0.25
–0.50
–1.00
–0.7%‡
(95% CI: –0.8, –0.5)
n=454
–10
–20
–30
–25‡
–40
–50
–60
Mean Change in PPG, mg/dL §
n=453
–0.75
0
0
Mean Change in FPG, mg/dL §
Mean Change in A1C, % §
0.00
(95% CI: –31, –20)
*Compared with placebo plus metformin.
†In patients inadequately controlled on metformin monotherapy.
‡Least-squares means adjusted for prior antihyperglycemic therapy status and baseline value.
§Difference from placebo.
n=387
–10
–20
–30
–40
–50
–60
–51‡
(95% CI: –61, –41)
41
JANUMET™ (sitagliptin/metformin HCl) Label Data:
Percentage of Patients Achieving A1C <7.0% With the
Combination of Sitagliptin and Metformin
24-Week Study
P<0.001
47%
Percentage of patients
50
n=453
40
30
20
18%
n=224
10
0
Placebo
+
Placebo
metformin
Sitagliptin
JANUVIA+
metformin
A total of 41 (of 224) patients on placebo plus metformin and 213 (of 453) patients on sitagliptin plus
metformin achieved A1C <7.0%.
Intent-to-treat population using last observation on study before pioglitzone rescue therapy.
42
JANUMET™ (sitagliptin/metformin HCl) Label Data:
Weight Change and Hypoglycemia Incidence in Patients
Treated With the Combination of Sitagliptin and Metformin
24-Week Add-On Therapy to Metformin Study
Weight Change
Hypoglycemia
Placebo + metformin (n=169)
Placebo + metformin (n=169)
10
1
8
Patients, %
Mean Change in Body Weight
From Baseline, lb
Sitagliptin + metformin (n=399)
2
0
–1
–2
–3
–1.3
–1.5
Sitagliptin + metformin (n=399)
6
4
2.1%
2
1.3%
0
Patients with at least 1 episode of
hypoglycemia over 24 weeks
43
JANUMET™ (sitagliptin/metformin HCl) Label Data:
Overall Incidence of Selected Adverse Reactions in Patients
Treated With the Combination of Sitagliptin and Metformin
Overall:
• The incidence of side effects and discontinuation rates with sitagliptin and
metformin were similar to those with placebo and metformin.
• The incidence of hypoglycemia in patients treated with sitagliptin and
metformin was similar to that in patients treated with placebo and metformin
(1.3% vs 2.1%).
• The incidence of gastrointestinal disturbances in patients treated with
sitagliptin and metformin was similar to that in patients treated with placebo
and metformin (11.6% vs 9.7%).
• The most common adverse experience in sitagliptin monotherapy reported
regardless of investigator assessment of causality in ≥5% of patients and
more commonly than in patients given placebo was nasopharyngitis.
• The most common (>5%) established adverse reactions due to initiation of
metformin therapy are diarrhea, nausea/vomiting, flatulence, abdominal
discomfort, indigestion, asthenia, and headache.
44
JANUMET™ (sitagliptin/metformin HCl) Label Data:
Incidence of Selected Gastrointestinal Adverse Reactions in
Patients Treated With Sitagliptin and Metformin
Incidence in Patients With Sitagliptin or Placebo Added to
a Twice-Daily Metformin Regimen
Sitagliptin and Metformin,
%
Placebo and Metformin,
%
Nausea
1.3
0.8
Vomiting
1.1
0.8
Abdominal Pain
2.2
3.8
Diarrhea
2.4
2.5
Other AEs
45
JANUMET™ (sitagliptin/metformin HCl):
Contraindications
• JANUMET is contraindicated in patients with:
– Renal disease or renal dysfunction, eg, as suggested
by serum creatinine levels ≥1.5 mg/dL (males),
≥1.4 mg/dL (females) or abnormal creatinine clearance
– 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
use of such products may result in acute alteration of
renal function.
46
JANUMET™ (sitagliptin/metformin HCl):
Selected Warnings and Precautions
• Metformin and sitagliptin are known to be substantially
excreted by the kidney. The risk of metformin accumulation
and lactic acidosis increases with the degree of impairment of
renal function. Thus, patients with serum creatinine levels
above the upper limit of normal for their age should not
receive JANUMET.
• Before initiation of therapy with JANUMET and at least
annually thereafter, renal function should be assessed and
verified as normal.
• Concomitant medication(s) that may affect renal function or
result in significant hemodynamic change or may interfere with
the disposition of metformin, such as cationic drugs that are
eliminated by renal tubular secretion [see Drug Interactions
(7.1)], should be used with caution.
47
JANUMET™ (sitagliptin/metformin HCl):
Selected Warnings and Precautions
• Cardiovascular collapse (shock) from whatever cause, acute
congestive heart failure, acute myocardial infarction and other
conditions characterized by hypoxemia have been associated with
lactic acidosis and may also cause prerenal azotemia. When such
events occur in patients on JANUMET therapy, the drug should be
promptly discontinued.
• Use of JANUMET should be temporarily suspended for periods of
stress, trauma, infection, or any surgical procedure (except minor
procedures not associated with restricted intake of food and fluids)
and should not be restarted until the patient's oral intake has
resumed and renal function has been evaluated as normal.
• Patients should be warned against excessive alcohol intake, acute or
chronic, while receiving JANUMET.
• JANUMET should generally be avoided in patients with clinical or
laboratory evidence of hepatic disease.
• Hematologic parameters should be measured annually.
48
JANUMET™ (sitagliptin/metformin HCl):
Drug Interactions
• Drug Interactions
– Pharmacokinetic drug interaction studies with JANUMET
have not been performed; however, such studies have been
conducted with the individual components of JANUMET
(sitagliptin and metformin hydrochloride).
– Use cationic drugs with caution.
– There are no known clinically meaningful drug interactions
for sitagliptin.
• Use of Metformin With Other Drugs
– When drugs that tend to produce hyperglycemia are
administered to a patient receiving JANUMET, the
patient should be closely monitored to maintain adequate
glycemic control.
49
JANUMET™ (sitagliptin/metformin HCl):
Recommended Dosing
• In general: twice daily with meals, with gradual dose escalation, to
reduce the gastrointestinal side effects due to metformin
• Starting dose based on patient’s current regimen
• Available dosage forms:
– 50 mg sitagliptin/500 mg metformin
– 50 mg sitagliptin/1,000 mg metformin
Tablets not shown at actual size.
• Patients inadequately controlled on metformin:
– Starting dose equal to 100 mg sitagliptin daily plus current
metformin dose
• Patients inadequately controlled on sitagliptin:
– Starting dose 50 mg sitagliptin/500 mg metformin twice daily
– Titrated up to 50 mg sitagliptin/1,000 mg metformin twice daily
• Patients switching from sitagliptin coadministered with
metformin:
– Initiate at current doses of sitagliptin and metformin
50
Case Study: Caroline D.
9.0%
8.8%
8.6%
A1C, %
8.4%
Patient History:
45-year-old woman,
bus driver
BMI = 31 kg/m2
Borderline hypertension
Type 2 diabetes diagnosed
Lab Results:
A1C = 7.6%
FPG = 150 mg/dL
Serum creatinine = 0.9 mg/dL
(CrCl = 104 mL/min)
Treatment:
Diet and exercise
recommended
8.2%
Lab Results:
A1C = 8.0%
FPG = 170 mg/dL
Serum creatinine = 1.0 mg/dL
(CrCl = 100 mL/min)
Treatment:
Metformin up-titrated to
2,000 mg/day
Considerations for next
treatment decision:
• Mechanism of action
• Efficacy
• Tolerability
Current Lab Results:
A1C = 7.7%
FPG = 150 mg/dL
Treatment:
Metformin initiated
8.0%
7.8%
7.6%
7.4%
7.2%
7.0%
2005
2006
2007
51
Overall Summary
• A majority of patients with type 2 diabetes may fail to attain A1C
goal with the conventional treatment paradigm
• The components of JANUMET™ (sitagliptin/metformin HCl)
have complementary MOAs and comprehensively address
3 core pathophysiologic defects of type 2 diabetes.
• Coadministration of sitagliptin and metformin results in:
– Significant reductions in A1C, FPG, and PPG compared with
metformin alone
– Weight loss comparable to metformin alone
– Low incidence of hypoglycemia comparable to metformin alone
– Similar overall incidence of side effects to metformin alone
52