Core Defects of Type 2 Diabetes

Targeting Mechanisms for a Comprehensive Approach

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: An Underlying Cause of Type 2 Diabetes

Obesity and inactivity Genetic abnormalities Aging Medications

INSULIN RESISTANCE

Rare disorders

Type 2 diabetes

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

10

15

20

25

30

Metabolic Activity

Insulin level Beta-cell function 10 5

Insulin resistance hepatic and peripheral

0 5 10 15 20 Years From Diabetes Diagnosis

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.

UKPDS: -Cell Loss Over Time

100
-Cell Function (%)*

75

50
IGT Type 2 Postprandial Diabetes Hyperglycemia Phase I

Patients treated with insulin, metformin, sulfonylureas

25

Type 2 Diabetes Phase II

Type 2 Diabetes Phase III

0 -12 -10
*Dashed

-6

-2 0

10

14

Years From Diagnosis

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.

Intensive Treatments and Increase in HbA1c Over Time

United Kingdom Prospective Diabetes Study (UKPDS)
9 Median HbA1c (%)

ADA action

7
ADA goal

Conventional Insulin Chlorpropamide Glibenclamide (glyburide) Metformin

6 0

Upper limit of normal range (6.2%)

3 6 9 10 Time From Randomization (years)

6

UK Prospective Diabetes Study (UKPDS 34) Group. Lancet. 1998;352:854-65.

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 23 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):S4S41. 2. Nathan DM et al. Diabetes Care. 2006;29:19631972.

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;59:13451355.
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;59:13451355.
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 agents 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):S6S17. 2. Van Gaal LF et al. Diabetologia. 2003;46(suppl 1):M44M50. 3. McDonald HP et al. JAMA. 2002;288:28682879. 4. Piette JD et al. Diabetes Care. 2004;27:384391. 5. Donnan PT et al. Diabet Med. 2002;19:279284.

10

Major Pathophysiologic Defects in Type 2 Diabetes

Islet-cell dysfunction Glucagon (alpha cell)

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.

Hepatic glucose output

Liver Muscle 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.

Pancreas
Beta-cell dysfunction

Sulfonylureas Meglitinides DPP-4 inhibitors GLP-1

Liver

Muscle and fat

Hepatic glucose overproduction

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.

12

No Single Class of Oral Antihyperglycemic Monotherapy Targets All Key Pathophysiologies

AlphaGlucosidase Inhibitors1,2 Meglitinides3 SUs4,5 TZDs6,7 Metformin8 DPP-4 Inhibitors

Major Pathophysiologies

Insulin deficiency

Insulin resistance

Excess hepatic glucose output

Intestinal glucose absorption

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) Normal Incretin Effect
80 80

Subjects With Type 2 Diabetes (n=14) Diminished Incretin Effect

IR Insulin, mU/L

60

IR Insulin, mU/L
0 60 120 180

60

40

40

20

20

0 0 60 120 180

Time, min Oral glucose load

Time, min Intravenous (IV) glucose infusion

Adapted with permission from Nauck M et al. Diabetologia 1986;29:4652. Copyright 1986 Springer-Verlag.

15

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

200 150 100 50 0

GLP-1

*P <0.05 Patients with type 2 diabetes (N=10)

GLP-1 Infusion mU/L

Insulin

40 30 20 10 0 20 15

When glucose levels approach normal values, insulin levels decrease. *

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

Adapted from Nauck MA et al. Diabetologia. 1993;36:741744. 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

Glucose
uptake by peripheral tissue2,4

Pancreas2,3
Beta cells Alpha cells

Active GLP-1 & GIP

DPP-4 enzyme

Blood glucose Glucose

Glucose Dependent
Glucagon from alpha cells (GLP-1)

production by liver

Inactive Inactive GLP-1 GIP

1. Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876913. 2. Ahrn B. Curr Diab Rep. 2003;2:365372. 3. Drucker DJ. Diabetes Care. 2003;26:29292940. 4. Holst JJ. Diabetes Metab Res Rev. 2002;18:430441.

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: Can Cause Hypoglycemia:

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

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*

8.0
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

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.

23

rosiglitazone Medication (DREAM)

Primary Outcome: Rosiglitazone

0.6
Cumulative Hazard

0.5 0.4 0.3 0.2 0.1 0 0

HR = 0.40 (0.35-0.46); P<0.0001

Placebo

Rosiglitazone

1
2538 217 2470

No. at Risk Rosiglitazone Placebo 2635 2634

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

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

Insulin (GLP-1 and GIP)

Pancreas
Beta cells Alpha cells

Glucose uptake by peripheral tissue

Blood glucose
Glucose production by liver

JANUVIA (DPP-4 inhibitor)

DPP-4 enzyme

Glucose dependent
Glucagon (GLP-1)

Inactive Inactive GLP-1 GIP

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.

PPAR=peroxisome proliferator-activated receptor gamma.

26

JANUVIA (sitagliptin): Significant A1C Reductions as Monotherapy

Placebo-adjusted results
A1C Mean Baseline: 8.0% P<0.001*
0.0 Mean Change in A1C, %
0.0

Inclusion Criteria: 7%10% Prespecified Pooled Analysis at 18 Weeks|| Baseline A1C, %

Mean Change in A1C, %

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.

27

JANUVIA (sitagliptin) Monotherapy Significantly Lowers FPG and PPG Levels

24-week placebo-adjusted results
FPG
Mean Change in 2-Hour PPG, mg/dL

2-Hour PPG Mean Baseline: 257 mg/dL P<0.001*

0 10 20 30 40 50 60
n = 201

Mean Baseline: 170 mg/dL P<0.001*

Mean Change in FPG, mg/dL 0 10 20 30 40 50 60
(95% CI: 24, 10)

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.

28

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, %

Add-on to pioglitazone study2

Mean Change in A1C From Baseline, %

0 0.2 0.4 0.6 0.8 1.0

Metformin + Placebo
n=224

Metformin + JANUVIA
n=453

Mean Baseline A1C: 8.0%, 8.1% Pioglitazone Pioglitazone + Placebo + JANUVIA

0 0.2
n=174 n=163

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.

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
CrCl 30 to <50 mL/min (~Serum Cr levels [mg/dL] Men: >1.73.0; Women: >1.52.5)

Severe and ESRD

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 insufficiency100 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
Glucose uptake in muscle and fat by increasing insulin sensitivity5
36

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.
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 ~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
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
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

Mean Change in FPG, mg/dL

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)

(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.

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

50

47%
n=453

Percentage of patients

40 30 20 10 0

18%
n=224

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
Placebo + metformin (n=169) Sitagliptin + metformin (n=399)

Hypoglycemia
Placebo + metformin (n=169)

Mean Change in Body Weight From Baseline, lb

2 1
Patients, %

10 8 6 4

Sitagliptin + metformin (n=399)

0 1 2 3

1.3

2.1%
2 0

1.5

1.3%

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
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

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.
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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 patients current regimen Available dosage forms: 50 mg sitagliptin/500 mg metformin 50 mg sitagliptin/1,000 mg metformin Patients inadequately controlled on metformin:
Starting dose equal to 100 mg sitagliptin daily plus current metformin dose

Tablets not shown at actual size.

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
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Case Study: Caroline D.

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

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

Considerations for next treatment decision: Mechanism of action Efficacy Tolerability

Current Lab Results: A1C = 7.7% FPG = 150 mg/dL

A1C, %

Treatment: Metformin initiated

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.

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

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