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)
INSULIN RESISTANCE
Rare disorders
Type 2 diabetes
PCOS
Postprandial glucose
Glucose Regulation
Fasting glucose
10
10
15
20
25
30
Metabolic Activity
25
30
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.
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50
IGT Type 2 Postprandial Diabetes Hyperglycemia Phase I
25
0 -12 -10
*Dashed
-6
-2 0
10
14
ADA action
7
ADA goal
6 0
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
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;59:13451355.
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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
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;59:13451355.
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10
Pancreas Insulin (beta cell) Insulin resistance Glucose uptake in muscle and fat Hyperglycemia Liver
Adapted with permission from Kahn CR, Saltiel AR. Joslins Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145168. Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775781. Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247254.
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Pancreas
Beta-cell dysfunction
Liver
Glucose level
Insulin resistance
Biguanides
Gut
Alphaglucosidase inhibitors Biguanides
TZDs
TZDs
DPP-4 inhibitors
Glucose absorption
Biguanides
DPP-4=dipeptidyl peptidase-4; TZDs=thiazolidinediones. DeFronzo RA. Ann Intern Med. 1999;131:281303. Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:14271483.
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Major Pathophysiologies
Insulin deficiency
Insulin resistance
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.
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14
IR Insulin, mU/L
60
IR Insulin, mU/L
0 60 120 180
60
40
40
20
20
0 0 60 120 180
Adapted with permission from Nauck M et al. Diabetologia 1986;29:4652. Copyright 1986 Springer-Verlag.
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GLP-1 Infusion Has Glucose-Dependent Effects on Insulin and Glucagon in Patients With Type 2 Diabetes
250 GLP-1 Infusion
Placebo
Glucose
mg/dL
GLP-1
Insulin
40 30 20 10 0 20 15
GLP-1 Infusion When glucose levels approach normal values, glucagon levels rebound.
Glucagon
pmol/L
10
5 0 30 0
60
120
Time, min
180
240
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Glucose Dependent
Insulin from beta cells (GLP-1 and GIP)
Release of gut hormones Incretins1,2
GI tract
Glucose
uptake by peripheral tissue2,4
Pancreas2,3
Beta cells Alpha cells
Glucose Dependent
Glucagon from alpha cells (GLP-1)
production by liver
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TZD(Actos, Avandia) Metformin/glucophage) Alpha glucosidase inhibitor(Precose, Glyset) Combo(avandamet, actoplusmet, janumet DPP IV inhibitor:
SU(glyburide,Amaryl)
Prandin/Starlix
Combo(glucovance, avandaryl, duetact)
Januvia Galvus
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20
Metformin
insulin sensitizer
Less cardiac event by UKPDS Weight reduction Dm prevention data
__ ____ ______
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Plus:
Insulin Sensitizer Heart and vascular benefit (Proactive ,Chicago) Preservation of B- cell( dream , Adopt) DM prevention data
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SU
7.5
HbA1C%
MET
7.0
RSG
6.5
6.0 0 0
Number of patients: 4012
1
3308
2
2991
3
2583
4
2197
5
822
Time (years)
* 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.
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Placebo
Rosiglitazone
1
2538 217 2470
Years
2414 2150
3
1310 1148
60% risk reduction of development of diabetes or death was seen with rosiglitazone 177 This reduction was additive to standard counseling on healthy eating and exercise
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
Blood glucose
Glucose production by liver
DPP-4 enzyme
Glucose dependent
Glucagon (GLP-1)
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.
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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.
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Overall
<8
8<9
0.2 0.4
n=193
0.2
0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8
n=119 n=769 n=411
n=239
0.6
0.7
0.6
0.7
0.6
0.8
1.0
n=229
0.8
18-week monotherapy (95% CI: 0.8, 0.4) study1 24-week monotherapy study2 (95% CI: 1.0, 0.6)
1.4
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;49:25642571. 2. Aschner P et al. Diabetes Care. 2006;29:26322637.
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17
n = 234
47
(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;29:26322637.
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JANUVIA (sitagliptin): Significant A1C Reductions From Baseline When Added to Metformin or Pioglitazone
24-week change from baseline
Add-on to metformin study1
Mean Baseline A1C: 8.0%
Mean Change in A1C From Baseline, %
Metformin + Placebo
n=224
Metformin + JANUVIA
n=453
0.0%
0.2%
0.4 0.6 0.8 1.0
P<0.001*
0.7%
0.7% placebosubtracted result
P<0.001*
0.9%
0.7% placebosubtracted result
*Compared with placebo. 1. Charbonnel B et al. Diabetes Care. 2006;29:26382643. 2. Rosenstock J et al. Clin Ther. 2006;28:15561568.
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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
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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
CrCl 30 to <50 mL/min (~Serum Cr levels [mg/dL] Men: >1.73.0; Women: >1.52.5)
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 insufficiency100 mg once daily. ESRD=end-stage renal disease requiring hemodialysis or peritoneal dialysis.
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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.
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Metformin Lowers Plasma Glucose by Lowering Hepatic Glucose Production and by Improving Insulin Sensitivity
Liver
Gluconeogenesis Glycogenolysis Glycogen synthesis
Metformin
Blood glucose
Glucose uptake in muscle and fat by increasing insulin sensitivity5
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Muscle
Adipose tissue
Liver
1. Kirpichnikov D et al. Ann Intern Med. 2002;137:2533. 2. Setter SM et al. Clin Ther. 2003;25:29913026. 3. Hundal RS et al. Diabetes. 2000;49:20632069. 4. Chu CA et al. Metabolism. 2000;49:16191626. 5. Bailey CJ et al. N Engl J Med. 1996;334:574579.
The Combination of Sitagliptin and Metformin Addresses the 3 Core Defects of Type 2 Diabetes Sitagliptin Metformin Reduces Hyperglycemia in a Complementary Manner
Sitagliptin improves beta-cell function and increases insulin Beta-Cell synthesis and Dysfunction release. Metformin has insulinsensitizing properties.
Insulin Resistance
Hepatic Glucose Sitagliptin reduces HGO through suppression of glucagon Overproduction (HGO) from alpha cells.
*Please see corresponding speaker note for references.
Metformin decreases HGO by targeting the liver to decrease gluconeogenesis and glycogenolysis.
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Bioavailability:
Sitagliptin ~87% Metformin ~5060%
Metabolism: both sitagliptin and metformin are predominantly excreted unchanged in the urine
Pharmacokinetics: no meaningful changes in either sitagliptin or metformin with co-administration
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JANUMET (sitagliptin/metformin HCl) Label Data: Sitagliptin Plus Metformin Provided Significant Improvements in Glycemic Control Beyond Metformin Alone*
24-week placebo-adjusted results
A1C
Mean Baseline A1C: 8.0% P <0.001*
0.00
Mean Change in A1C, %
FPG
Mean Baseline: 170 mg/dL P <0.001*
0 0
2-Hour PPG
Mean Baseline: 275 mg/dL P <0.001*
Mean Change in PPG, mg/dL
n=453
0.25
10 20 30 40 50 60
n=454
10 20 30 40 50 60
n=387
0.50
25
0.75
0.7%
(95% CI: 0.8, 0.5)
1.00
51
(95% CI: 61, 41)
*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.
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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
50
47%
n=453
Percentage of patients
40 30 20 10 0
18%
n=224
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.
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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
Placebo + metformin (n=169) Sitagliptin + metformin (n=399)
Hypoglycemia
Placebo + metformin (n=169)
2 1
Patients, %
10 8 6 4
0 1 2 3
1.3
2.1%
2 0
1.5
1.3%
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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.
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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
Other AEs Nausea
Vomiting Abdominal Pain Diarrhea Sitagliptin and Metformin, % Placebo and Metformin, %
1.3
1.1 2.2 2.4
0.8
0.8 3.8 2.5
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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.
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9.0% 8.8% 8.6% 8.4% 8.2% 8.0% 7.8% 7.6% 7.4% 7.2% 7.0%
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
A1C, %
2005
2006
2007
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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.
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