1. Incretin Based Therapy in Diabetes Mellitus Type 2
JOSEPHINE CARLOS-RABOCA,M.D.,F.P.S.E.M.
ENDOCRINOLOGY,DIABETES AND METABOLISM
DIABETES CARE CENTER
WEIGHT WELLNESS CENTER
MAKATI MEDICAL CENTER

2. Outline Review of Incretins and Diabetes
Goals of Treatment for Diabetes
Treatment Options
Sitagliptin Studies(Case/Clinical trials)
Monotherapy Use
Combination Use
Cardiovascular Benefits
Outline

3. GLP-1: effects in humans
Stimulates glucose-dependent insulin secretion
Suppresses glucagon secretion
Slows gastric emptying
Leads to reduction of food intake
Improves insulin sensitivity
Longtime effects in animal models:
Increase of β-cell mass and improved β-cell function
After food ingestion
GLP-1 is secreted from the
L-cells of the jejunum
& ileum
That in turn…
Drucker. Curr Pharm Des. 2001
Drukcer. Mol. Endocrinol. 2003

4. GLP-1: Biological Activity
CVD
Fasting
hyperglycemia
Postprandial hyperglycemia /
hypertriglyceridemia
Obesity
Insulin
Resistance
Impaired insulin secretion
Hyperglucagonemia
b-cell mass i
LL Baggio and DJ Drucker. Gastroenterology 2007; 132: 4

5. GLP-1 Enhancenent Injectables Oral agents
GLP-1 Secretion is impaired in Type 2 Diabetes
Natural GLP-1 has extremely short half-life
Add GLP-1 analogues
with longer half-life:
exenatide
liraglutide
Block DPP-4, the enzyme
that degrades GLP-1:
sitagliptin
vildgaliptin
Injectables
Oral agents
DPP-4= Dipeptidyl Peptidase-4 ; GLP=Glucagpn like peptide-1
Drucker. Curr. Pharm. Des. 200; Drucker. Mol. Endocrinol. 2003

6. Incretin Mimetics and DPP-4 Inhibitors: Major Differences
Gallwitz. European Endocrine Diseases. 2003

7. Type 2 Diabetes arises when a pancreatic islet cell dysfunction occurs alongside insulin resistance

8. Outline Incretins and Diabetes Goals of Treatment for Diabetes
Treatment Options
Role of incretins in diabetes treatment
Sitagliptin Studies
Monotherapy Use
Combination Use

9. Goals of Therapy in Type 2 Diabetes
To lower the incidence of microvascular disease
To reduce the excess of cardiovascular disease
To improve the quality of life
To limit the burden of treatment
Goals of Therapy in Type 2 Diabetes1
In the management of type 2 diabetes, the goal is to achieve glycemic control. Appropriate therapy for those with diabetes should include a serious effort to achieve levels of blood glucose as close to those in the individual without diabetes.
There is a strong correlation between hyperglycemia and microvascular complications and cardiovascular disease (CVD). Achieving glycemic control could reduce the risk of microvascular and macrovascular complications related to diabetes.
Achieving and maintaining long-term optimal glycemic control can improve patients’ quality of life, reduce morbidity and mortality, and limit the burden of the disease.
Reference:
1. Del Prato S. Unlocking the opportunity of tight glycaemic control. Far from goal. Diabetes Obes Metab ;7:S1–S4.

10. Treatment Guidelines for Type 2 Diabetes
*Capillary glucose
† May not be achievable with as manyt as 5 anytihypertensive drugs in some individuals; use higher targets
where there is a risk of postural hypertension
‡With statin treatment for patients>40 y.o. or with evidence of cardiovascular disease
§Consider use of fibrates to achieve thee goals once LDL-C is controlled

11. Outline Incretins and Diabetes Goals of Treatment for Diabetes
Treatment Options
Role of incretins in diabetes treatment
Sitagliptin Studies
Monotherapy Use
Combination Use

12. Efficacy and tolerability of existing anti-diabetic agents
Class
Primary therapeutic effect
Limitations
Sulfonylureas
 HbA1c
Hypoglycemia, weight gain
Meglitinides
 PPG
Biguanides (metformin)
GI adverse effects, lactic acidosis (rare)
PPARs
Weight gain, edema, anemia, potential for liver toxicity
Alpha-glucosidase inhibitors
GI adverse effects
Insulin
Injectable route, hypoglycemia, weight gain
Adapted from DeFronzo RA Ann Intern Med 1999;131:281–303; Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004; Holz GG, Chepurny OG Curr Med Chem 2003;10(22):2471–2483; Meneilly GS Diabetes Care 2003;26(10): 2835–2841; Ahrén B et al Diabetes Care 2002;25(5):869–875; Moller DE Nature 2001;414:821–828.

13. Sitagliptin - Overview
DPP-4 inhibitor for the treatment of patients with type 2 diabetes
Provides potent and highly selective inhibition of the DPP-4 enzyme
Fully reversible and competitive inhibitor
ADA 2006 Late Breaking Clinical Presentation (Stein).

14. Sitagliptin Is Potent and Highly Selective (>2500x) for the DPP-4 Enzyme
IC50 (nM)
DPP-4 18
DPP-8
48,000
DPP-9
>100,000
DPP-2, DPP-7
FAP
PEP
APP
ADA 2006 Late Breaking Clinical Presentation (Stein).

15. Pharmacokinetics of Sitagliptin Supports Once-Daily Dosing
With once-daily administration, trough (at 24 hrs) DPP-4 inhibition is ~80%
≥80% inhibition provides full enhancement of active incretin levels
No effect of food on pharmacokinetics
Well absorbed following oral dosing
Low protein binding
Primarily renal excretion as parent drug
Approximately 80% of a dose recovered as intact drug in urine
No clinically important drug-drug interactions
No meaningful P450 system inhibition or activation
ADA 2006 Late Breaking Clinical Presentation (Stein).

16. Incretin based therapy in diabetes
Incretin hormone secretion and actions are impaired in type 2 diabetes.
Although β-cell responsiveness to GLP-1 is reduced, exogenous GLP-1 can still restore β-cell sensitivity to glucose and improve glucose-induced insulin secretion.
A GLP-1 based therapy of type 2 diabetes may therefore be expected to
Reduce hyperglycaemia and HbA1c levels
Improve β-cell function
Improve insulin sensitivity
Improve metabolism

17. ADA-EASD –Algorithm for Control of Type 2 Diabetes (2008)
Tier 1 : Well-validated core therapies
Lifestyle + Metformin +
Intensive Insulin
At diagnosis:
Lifestyle +
Metformin
Lifestyle + Metformin +
Basal Insulin
Lifestyle + Metformin +
Sulfonylurea
STEP 1
STEP 2
STEP 3
Tier 2 : Less well-validated therapies
Lifestyle + Metformin +
Pioglitazone
Sulfonylurea
Lifestyle + Metformin +
Pioglitazone
No hypoglycemia
Weight loss
Nausea/Vomiting
Lifestyle + Metformin +
Basal Insulin
Lifestyle + Metformin +
GLP-1 agonist
No hypoglycemia
Weight loss
Nausea/Vomiting
Nathan, D et al. Diabetes Care 2009; 32(1): 1-11 17

18. Recent Clinical Studies of Sitagliptin
Monotherapy use
Combination use with metformin or a PPAR agent
Combination use with sulfonylurea with / without metformin
With adjusted doses in patients with diabetes and renal insufficiency
ADA 2006 Late Breaking Clinical Presentation (Stein).

19. Physical Examination was normal
CASE # 1
R.M. 43 year old Filipino saw you because he wanted to know if he had diabetes because his parents are diabetic. He had no polyuria, polydipisia, no weight loss.
He didn’t smoke but had no exercise. Past medical history was unremarkable.
Physical Examination was normal
Lab exams: FBS 116 2h post 75 gm ,OGTT 283 HBa1c 7.6 %
Creatinine 1.0 SGOT 71 SGPT 146 cholesterol 226 triglyceride 213 HDL 45 LDL 139
Hb HCT 45 WBC Seg 51 Lympho 40 Mono 6 platelet
Urine wbc 5-10/hpf rbc 0-1 protein trace sugar negative
Contents
The next section will focus on the clinical overview of combination therapy with sitagliptin and metformin (as add-on or initial therapy) and combination therapy of sitagliptin and sulfonylurea (as add-on to sulfonylurea alone or sulfonylurea plus metformin).
Purpose:
To review with the audience the clinical data of combination therapy with sitagliptin and metformin (as add-on or initial therapy) and combination therapy of sitagliptin and sulfonylurea (as add-on to sulfonylurea alone or sulfonylurea plus metformin) 26 26

20. What would be your initial treatment plan? a. Insulin b. Sitagliptin
c. Exenatide
d. TZD
e. Sulfonylurea
f. Metformin
Contents
The next section will focus on the clinical overview of combination therapy with sitagliptin and metformin (as add-on or initial therapy) and combination therapy of sitagliptin and sulfonylurea (as add-on to sulfonylurea alone or sulfonylurea plus metformin).
Purpose:
To review with the audience the clinical data of combination therapy with sitagliptin and metformin (as add-on or initial therapy) and combination therapy of sitagliptin and sulfonylurea (as add-on to sulfonylurea alone or sulfonylurea plus metformin) 26 26

21. Sitagliptin Consistently and Significantly Lowers A1C With Once-Daily Dosing in Monotherapy
change vs placebo*
18-week Study
Placebo (n=74)
Sitagliptin 100 mg (n=168)
Time (weeks) 6 12 18
A1C (%)
7.2
7.6
8.0
8.4
-0.6%
(p<0.001) =
Placebo (n=244)
Sitagliptin 100 mg (n=229)
24-week Study
Time (weeks) 5 10 15 20 25
-0.79%
(p<0.001)
Japanese Study
-1.05%
(p<0.001)
Placebo (n=75)
Sitagliptin 100 mg (n=75)
Time (weeks) 4 8 12
A1C (%)
7.6
8.0
8.4
7.2
6.8
8.4
8.0
7.6
7.2

22. Sitagliptin 100 mg Once-daily Provides Significant and Progressively Greater Reductions in A1C With Progressively Higher Baseline A1C
Inclusion Criteria: 7%–10%+
18-week Study
-0.44
-0.61
-1.2
-1.8
-1.6
-1.4
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
24-week Study
-0.57
-0.8
-1.52
-1.8
-1.6
-1.4
-1.2
-1.0
-0.6
-0.4
-0.2
0.0
Baseline A1C (%)
Mean (%)
Reduction in A1C (%)
<8% 8–<9% ≥9%
Reduction in A1C (%)
Reductions are placebo-subtracted.
Adapted from Raz I, et al. Protocol 023; Aschner P, et al. Protocol 021. Abstracts presented at ADA2006.
ADA 2006 Late Breaking Clinical Presentation (Stein).

23. Sitagliptin Once Daily Significantly Improves Both Fasting and Post-meal Glucose In Monotherapy
Fasting Glucose
Post-meal Glucose
 FPG* = –17.1 mg/dL (p<0.001)
in 2-hr PPG* = –46.7 mg/dL (p<0.001)
144
180
216
252
288 60
120
180
170
Fasting Glucose (mg/dL)
160
Plasma Glucose (mg/dL)
Baseline
24 Weeks
Baseline
24 Weeks
150
Placebo (n=247)
Sitagliptin 100 mg (n=201)
Sitagliptin 100 mg (n=234)
Placebo (N=204)
140 3 6 12 18 24
* LS mean difference from placebo after 24 weeks.
Aschner P, et al. Protocol 021. Abstract presented at American Diabetes Association; June 10, 2006; Washington, DC.
ADA 2006 Late Breaking Clinical Presentation (Stein).
Weeks
Time (minutes)

24. Add-On to Metformin Study
Sitagliptin Once Daily Significantly Increases Proportion of Patients Achieving Goal in Monotherapy or Combination Therapy
Goal A1C <7%
P<0.001
P<0.001
P<0.001
47%
45%
41%
Percentage
Percentage
Percentage
23%
18%
17%
Monotherapy Study
Add-On to Metformin Study
Add-On to TZD Study
Placebo
Sitagliptin
Aschner P, et al. Protocol 021. Rosenstock J, et al. Protocol 019. Karacik A, et al. Protocol 020. ADA 2006.
ADA 2006 Late Breaking Clinical Presentation (Stein).

25. Hypoglycemia Weight Changes
Sitagliptin Once-daily Lowers A1C Without Increasing the Incidence of Hypoglycemia or Leading to Weight Gain
Hypoglycemia
0.9
Placebo
1.2
Sitagliptin 100 mg
Sitagliptin 200 mg
Hypoglycemia
Proportion of patients with (%)
Pooled Phase III Population Analysis: no statistically significant difference in incidence for either dose vs. placebo
Weight Changes
Neutral effect on body weight
In monotherapy studies, small decreases from baseline (~0.1 to 0.7 kg) with sitagliptin; slightly greater reductions with placebo (~0.7 to 1.1 kg)
In combination studies, weight changes with sitagliptin similar to placebo-treated patients

27. Safety laboratory mean changes
Small rise in WBC – largely due to slight increase in absolute neutrophil count (ANC)
~ 0.2 K/mm3 maximum difference from placebo in WBC with baseline mean of 6.7 K/mm3
No increase in patients meeting PDLC (> 20% increase and > ULN) for WBC or ANC; no increase in bands/earlier WBC forms
No associated laboratory AEs of increased WBC
Slight increase in uric acid ~ 0.2 mg/dL (baseline ~ 5.3 mg/dL)
No increase in gout AEs
Decrease in alk phosphatase – ~ 4-5 IU/mL (baseline of ~ 55 IU/mL)
Small decrease ALT (-1 mIU/mL), small/variable decrease in bili
In Phase II studies – similar reduction in total AP with metformin (-6.4 IUI/mL) and glipizide (-2.4 IU/mL) comparator groups
Literature suggests decrease AP occurs with improved glycemic control

28. Combination Treatment

29. CASE # 2
R. C. M 61 y/o consulted for diabetes mellitus of 8 years. Medications include glimepiride 2 mg BID, Metformin 100 mg BID.
FPG 154 mg/dl
His mother, brother and sister are diabetic. He does not smoke nor drink alcohol. His past medical history was unremarkable.
Physical examination: Height cm weight 88.5 kg BP 140/80 BMI WC 38 inches. He had no retinopathy on funduscopy. The rest of the physical examination was normal.
Lab work up: 2hour PPBS 240 Hba1c of 7.8%. uric acid 5.51 cholesterol 294 triglyceride 387 VLDL LDL 145 SGPT 36 Serum creatinine 1.22, urine microalbumin 64mg/dl; urine creatinine 118 mgdl ; UAC 54
ECG, sinus bradycardia incomplete RBBB, Treadmill stress test: Exaggerated BP response to exercise
Contents
The next section will focus on the clinical overview of combination therapy with sitagliptin and metformin (as add-on or initial therapy) and combination therapy of sitagliptin and sulfonylurea (as add-on to sulfonylurea alone or sulfonylurea plus metformin).
Purpose:
To review with the audience the clinical data of combination therapy with sitagliptin and metformin (as add-on or initial therapy) and combination therapy of sitagliptin and sulfonylurea (as add-on to sulfonylurea alone or sulfonylurea plus metformin) 26 26

30. Diagnosis: Diabetes Mellitus Type 2 Diabetic nephropathy , stage 2
Dyslipidemia
Hypertension
How will modify treatment to reach target goals for his diabetes?
a. Insulin
b. Sitagliptin 100 mg OD
c. Sulfonylurea
d. Pioglitazone
Contents
The next section will focus on the clinical overview of combination therapy with sitagliptin and metformin (as add-on or initial therapy) and combination therapy of sitagliptin and sulfonylurea (as add-on to sulfonylurea alone or sulfonylurea plus metformin).
Purpose:
To review with the audience the clinical data of combination therapy with sitagliptin and metformin (as add-on or initial therapy) and combination therapy of sitagliptin and sulfonylurea (as add-on to sulfonylurea alone or sulfonylurea plus metformin) 26 26

31. Other treatment? a. Fenofibrate b. Statin c. Aspirin d. ARB
e. Vaccination
Contents
The next section will focus on the clinical overview of combination therapy with sitagliptin and metformin (as add-on or initial therapy) and combination therapy of sitagliptin and sulfonylurea (as add-on to sulfonylurea alone or sulfonylurea plus metformin).
Purpose:
To review with the audience the clinical data of combination therapy with sitagliptin and metformin (as add-on or initial therapy) and combination therapy of sitagliptin and sulfonylurea (as add-on to sulfonylurea alone or sulfonylurea plus metformin) 26 26

32. Summary: Mechanism of Action of the Co-administration of Sitagliptin Plus Metformin
Co-administration of sitagliptin and metformin addresses the 3 core defects of type 2 diabetes in a complementary manner
Sitagliptin and metformin have different but complementary mechanisms of action
Metformin increases total GLP-1 → likely by enhancing GLP-1 release
By inhibition of DPP-4, sitagliptin increases levels of active GLP-1
Co-administration of these drugs results in higher GLP-1 levels than when either drug is administered alone
Co-administration of sitagliptin and metformin results in a more than additive effect on both pre- and post-prandial active GLP-1 concentrations
Summary: Mechanism of Action of the Co-administration of Sitagliptin Plus Metformin
This study provides evidence to support the hypothesis that the co-administration of sitagliptin with metformin has complementary mechanisms of action.1
This study showed that metformin increased total GLP-1.1
The increase in active GLP-1 concentrations observed with metformin was similar to the increase observed in total GLP-1 concentrations. This finding suggests that the effect of metformin on active GLP-1 is likely a result of increasing the amount of total GLP-1.1
The investigators of this study suggest that metformin increases total GLP-1 by enhancing GLP-1 release.1
Sitagliptin, a DPP-4 inhibitor, is believe to increase active peptide concentrations by preventing inactivation of active GLP-1.1
When co-administered, sitagliptin with metformin appear to have complementary MOAs resulting in a more than additive effect on increasing active GLP-1 concentrations.1
In summary, these results provide evidence to support the hypothesis that the co-administration of sitagliptin and metformin has complementary mechanisms of action to enhance active GLP-1 concentrations. It is unclear what these findings mean for changes in glycaemic control in patients with type 2 diabetes.
Purpose:
To summarise the mechanisms of action of sitagliptin and metformin in support of the additive effects of sitagliptin and metformin co-administration on GLP-1.
Take-away:
Co-administration of sitagliptin and metformin addresses the 3 core defects of type 2 diabetes and may have complementary effects on GLP-1.
1/O431_050_11
_Discussion and Conclusions
p.1 P1 L14-22
p.1 P2 L1-4
p.3 P1 L24-30
p.4 P2 L1-4
1/O431_050_02
_Synopsis
p.10 Conclusions
L3-8 25
1/O431_050_11
_Discussion and Conclusions
p.2 Pcont L2-9
p.2 P1 L7-10
1/WPC-JMT Mechanism of Action, p.21 Pcont L4-5, L12
Reference
1. Data on file, MSD. 25

33. Sitagliptin Once Daily Significantly Lowers A1C When Added on to Metformin or Pioglitazone
Add-on to Metformin
 in A1C vs. Placebo* = –0.65% (p<0.001)
Add-on to Pioglitazone
 in A1C vs. Placebo* = –0.70% (p<0.001)
8.2
8.2
8.0
8.0
7.8
7.8
A1C (%)
7.6
A1C (%)
7.6
7.4
7.4
7.2
7.2
7.0
7.0 6 12 18 24 6 12 18 24
Weeks
Weeks
Placebo
Sitagliptin 100 mg
* Placebo Subtracted Difference in LS Means.
Rosenstock J, et al. Protocol 019. Karasik A, et al. Protocol 020. Abstracts presented at ADA 2006.
ADA 2006 Late Breaking Clinical Presentation (Stein).

34. Active GLP-1 Concentrations, pM Time (hours pre/post meal)
Co-administration of Sitagliptin and Metformin in Healthy Adults Increased Active GLP-1 Greater Than Either Agent Alone
Placebo
Metformin 1000 mg
Sitagliptin 100 mg
Co-administration of sitagliptin 100 mg plus metformin 1000 mg
Mean AUC ratio
Sita + Met: 4.12
Mean AUC ratios
Sita: Met: 1.76 –2 10 20 30 40 50 –1 1 2 3 4
Active GLP-1 Concentrations, pM
Meal
Morning Dose Day 2
Time (hours pre/post meal)
1/O431_050_09
_Efficacy
p.4 Figure 11-1
p.5 Table 11-1
Co-administration of Sitagliptin and Metformin in Healthy Adults Increased Active GLP-1 Greater Than Either Agent Alone
Among 18 healthy adults who were randomised in a double-blind, placebo-controlled, 4-period crossover, study that consisted of 2-day–long treatment periods with a 7-day washout period between them, 16 healthy adults completed the study. The objective of the study was to examine the effect of sitagliptin, metformin and the combination of sitagliptin with metformin on the post-meal incretin hormone concentrations, specifically GLP-1 and GIP.1
Subjects were randomly assigned to receive sitagliptin, metformin, co-administration of sitagliptin and metformin, or placebo. On the second day of each treatment period, blood samples were obtained for active and total GLP-1 and active and total GIP concentrations before and at specific time points after the post-dose meal was consumed.1
Results for the incremental 4-hour post-meal weighted averages showed that after administration of metformin alone or co-administration of sitagliptin and metformin, total GLP-1 concentrations were increased compared with placebo alone, whereas total GLP-1 concentrations were significantly decreased when sitagliptin was administered alone.1 On the other hand, administration of sitagliptin or metformin alone increased active GLP-1 to nearly double that seen with placebo. Moreover, active GLP-1 concentrations were increased by more than 2 times after concomitant administration of sitagliptin with metformin compared with either agent alone. Thus, there was a more than additive effect on active GLP-1 concentrations when sitagliptin and metformin were co-administered.1
Both sitagliptin and the combination of sitagliptin and metformin increased active GIP; however, metformin alone had no effect on active GIP, indicating that metformin is not a DPP-4 inhibitor.1 The increase in active GIP observed after the co-administration of metformin with sitagliptin likely resulted from the effect of sitagliptin.1
Purpose:
To show data in support of the additive effects of sitagliptin and metformin co-administration on active concentrations GLP-1.
Take-away:
Although sitagliptin increased active GLP-1 concentrations, as expected based on its MOA, the co-administration of metformin and sitagliptin have complementary MOAs to enhance active GLP-1 concentrations.
Values represent geometric mean±SE.
1/O431_050_02
_Synopsis
p.2 Study Design
p.3 Subject/Patient Disposition
N=16 healthy subjects.
AUC=area under the curve 24
1/O431_050_09
_Efficacy
Section
p.3 P3 L1-13
p.4 Figure 11-1
p.5 Table 11-1
Section
p.6 P1 L1-14
Figure 11-2
p.7 Table 11-2
1/O431_050_11
_Discussion and Conclusions
Section 13.1
p.2 Pcont L2-22 p.3, P1 L24-30
Reference
1. Data on file, MSD. 24

35. HbA1c With Sitagliptin or Glipizide as Add-on Combination With Metformin: Comparable Efficacy
1/Nauck p.201, Figure 2A p.197, C2 P3 L1-9
p.196, C1 Pcont L7-9
LSM change from baseline (for both groups): –0.7%
Achieved primary hypothesis of non-inferiority to sulfonylurea
Sulfonylureaa + metformin (n=411)
Sitagliptinb + metformin (n=382)
HbA1c, % ±SE
Weeks
6.2
6.4
6.6
6.8
7.0
7.2
7.4
7.6
7.8 6 12 18 24 30 38 46 52
8.0
8.2
HbA1c With Sitagliptin or Glipizide as Add-on Combination With Metformin: Comparable Efficacy
Sitagliptin 100 mg once daily with metformin was similar (non-inferior) to a sulfonylurea (glipizide) with metformin in lowering HbA1c, the primary efficacy end point of the study.1
At week 52, the least squares mean (LSM) change from baseline in HbA1c was –0.7% in both groups in the per-protocol population.1
The graph shows the reduction in HbA1c obtained with sitagliptin 100 mg once daily with metformin over the study period of 52 weeks.1
An estimate of durability from 24 to 52 weeks (coefficient of durability, [COD]) showed a lower COD for sitagliptin with metformin (0.008%/week) than for sulfonylurea (glipizide) with metformin (0.011%/week), indicating that durability was better for sitagliptin 100 mg once daily with metformin than for sulfonylurea with metformin (COD difference between treatments was –0.003%).1
Purpose:
To provide efficacy results of sitagliptin compared with the sulfonylurea glipizide in patients who had inadequate glycaemic control on metformin monotherapy.
Take-away:
Sitagliptin was shown to have efficacy comparable to that of a sulfonylurea when added to patients who had inadequate glycaemic control on metformin monotherapy.
1/Nauck p.197, C2 P3 L1-9 L14-18
p.198, C1 Pcont L1-7
p.198, C1 P1 L1-4
p.201, Figure 2A
Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205 with permission from Blackwell Publishing Ltd., Boston, MA.
aSpecifically glipizide ≤20 mg/day;
bSitagliptin 100 mg/day with metformin (≥1500 mg/day). Per-protocol population; LSM=least squares mean.
SE=standard error. 27
Reference
1. Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205. 27

36. Baseline HbA1c Category Mean Change From Baseline in HbA1c, %
Greater Reductions in HbA1c Associated With Higher Baseline HbA1c – 52-Week Post Hoc Analysis
n=117
Baseline HbA1c Category
Mean Change From Baseline in HbA1c, %
<7%
≥7 to <8%
≥8 to <9%
³9%
− 0.1
− 0.6
−1.1
−1.8
− 0.3
−0.5
−1.7
−2.0
−1.6
−1.4
−1.2
−1.0
−0.8
−0.6
−0.4
−0.2
0.0
Sitagliptinb plus metformin
Sulfonylureaa plus metformin
n=33
n=21
n=82
n=179
n=167
n=112
1/Nauck p.201 Figure 2B
p.196, C1 Pcont L7-9
Greater Reductions in HbA1c Associated With Higher Baseline HbA1c – 52-Week Post Hoc Analysis
In a post hoc analysis of the HbA1c data, both sitagliptin with metformin and the sulfonylurea glipizide with metformin reduced HbA1c levels in all subgroups.1
The greatest effect was observed in patients with baseline HbA1c ≥9%.1
Purpose:
To review the head-to-head data vs glipizide by baseline HbA1c.
Take-away:
As can be expected, both sitagliptin and glipizide provided increased HbA1c reductions in the highest baseline groups.
Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205 with permission from Blackwell Publishing Ltd., Boston, MA.
aSpecifically glipizide ≤20 mg/day.
bSitagliptin 100 mg/day with metformin (≥1500 mg/day); Per-protocol population. Add-on sitagliptin with metformin vs sulfonylurea
with metformin study.
1/Nauck p.198 C2 P1 L1-3 p.199 C1 Pcont L1-6
p.201 Figure 2B 28
Reference
1. Nauck MA, Meininger G, Sheng D, et al; for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205. 28

37. Least squares mean change over timec Patients With ≥1 Episode, %
Sitagliptin With Metformin Provided Weight Reduction (vs Weight Gain) and a Much Lower Incidence of Hypoglycaemia
 between groups = –2.5 kg
Least squares mean change over timec
Body Weight, kg ± SE
Sulfonylureaa plus metformin (n=416)
Sitagliptinb plus metformin (n=389) −3 −2 −1 1 2 3
Weeks 12 24 38 52
Hypoglycaemiac
P<0.001
32% 5% 10 20 30 40 50
Week 52
Patients With ≥1 Episode, %
Sulfonylureaa plus metformin (n=584)
Sitagliptinb plus metformin (n=588)
1/Nauck p.200 C1 P1 L1-4, C1 P2 L1-3, C2 Pcont L1-3
p.202 Figure 4
p.202 Table 3
p.196, C1 Pcont L7-9
Sitagliptin With Metformin Provided Weight Reduction (vs Weight Gain) and a Much Lower Incidence of Hypoglycaemia
The graph on the left shows the change in body weight observed during the study period of 52 weeks with sitagliptin 100 mg once daily with metformin and sulfonylurea (specifically glipizide) with metformin.1
Sitagliptin 100 mg once daily with metformin resulted in a significant decrease in body weight that was maintained through week 52 of the study (–1.5 kg), whereas sulfonylurea (specifically glipizide) with metformin resulted in a significant increase in body weight compared with baseline values (1.1 kg).1
The difference in body weight between the sitagliptin 100 mg once daily with metformin and the sulfonylurea (specifically glipizide) with metformin treatment groups was significant (–2.5 kg, P<0.001).1
The graph on the right shows that sitagliptin 100 mg once daily with metformin resulted in a significantly lower incidence of hypoglycaemic episodes than sulfonylurea (specifically glipizide) with metformin (5% vs 32%, respectively).1 The difference in hypoglycaemia between the sitagliptin 100 mg once daily with metformin and sulfonylurea (specifically glipizide) with metformin treatment groups was significant (27%, P<0.001).1
There was no meaningful difference between the groups with regard to the incidence of overall clinical adverse events assessed as serious or leading to discontinuation. Two serious adverse events were reported in the glipizide group and none in the sitagliptin group. The overall incidence of GI adverse events was similar for the treatment groups (20.4% for sitagliptin, 19.3% for glipizide).1
Purpose:
To review some key pre-specified adverse events of interest from the head-to-head study vs glipizide on a background of metformin.
Take-away:
Sitagliptin showed significant advantages over glipizide with respect to weight gain and hypoglycaemia.
aSpecifically glipizide ≤20 mg/day; bSitagliptin (100 mg/day) with metformin (≥1500 mg/day); cAll-patients-as-treated population.
Least squares mean between-group difference at week 52 (95% CI): change in body weight = –2.5 kg [–3.1, –2.0] (P<0.001); Least squares mean change from baseline at week 52: glipizide: +1.1 kg; sitagliptin: –1.5 kg (P<0.001).
Add-on sitagliptin with metformin vs sulfonylurea
with metformin study.
Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205 with permission from Blackwell Publishing Ltd., Boston, MA.
1/Nauck p.200, C1 P1 L1-4;
C1 P2 L1-3;
C2 Pcont L1-3;
p. 202, C2 P2 L1-11 Figure 4
p.199 C2 P1 L1-4,
L9-13, L27-30 29
Reference
1. Nauck MA, Meininger G, Sheng D, et al; for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205. 29

38. Summary: Sitagliptin or Glipizide as Add-on Combination With Metformin
Efficacy profile
Comparable efficacy in lowering HbA1c
Both provided greater HbA1c reductions in patients with the highest baseline HbA1c
Safety profile
Both were generally well tolerated
Adverse event profiles (ie, serious and GI-related adverse events, those leading to discontinuation) were similar, with the exception of hypoglycaemia
Significantly lower incidence of hypoglycaemic episodes associated with sitagliptin with metformin
Body weight significantly decreased for sitagliptin with metformin, but increased for glipizide with metformin
Summary: Sitagliptin or Glipizide as Add-on Combination With Metformin
Efficacy profile1
Sitagliptin with metformin vs glipizide with metformin
Comparable (non-inferior) efficacy for patients who had inadequate glycaemic control
Similar in lowering HbA1c
Both provided increased HbA1c reductions in patients with the highest baseline HbA1c
Safety profile1: administration of sitagliptin with metformin versus glipizide with metformin
Both treatments were generally well tolerated
Adverse event profiles (specifically serious adverse events, GI-related adverse events, and those leading to discontinuation) were similar between treatment groups, with the exception of hypoglycaemia
Sitagliptin with metformin induced a significantly lower incidence of hypoglycaemic episodes than sulfonylurea (specifically glipizide) with metformin
Body weight significantly decreased for sitagliptin with metformin, but increased for glipizide with metformin
Purpose:
To review the clinical efficacy and safety of sitagliptin or glipizide as add-on combination with metformin.
Take-away:
Sitagliptin and glipizide had comparable efficacy and tolerability as add-on combination with metformin. Sitagliptin had significant advantages over glipizide with respect to weight gain and hypoglycaemia.
1/Nauck p.197, C2, P3, L1-9, L14-18
p.198, C1, Pcont, L1-7
p.198 C2 P1 L1-3 p.199 C1 Pcont L1-6
p.201 Figures 2A and 2B 30
1/Nauck p.200, C1 P1 L1-4;
C1 P2 L1-3;
C2 Pcont L1-3;
p. 202, C2 P2 L1-11 Figure 4
p.201 Table 3
p.199 C2 P1 L1-4,
L9-13, L27-30
Nauck MA et al. Diabetes Obes Metab. 2007;9:194–205.
Reference
1. Nauck MA, Meininger G, Sheng D, et al; for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205. 30

39. Summary: Initial Combination Therapy With Sitagliptin Plus Metformin Through 54 Weeks
Efficacy profile
Marked reductions in HbA1c for up to 54 weeks
Continued and substantial reductions in FPG and 2-hour PPG concentrations
Improved measures of β-cell function (HOMA-β; proinsulin-to-insulin ratio)
Provided greater HbA1c reductions in patients with the highest baseline HbA1c
Safety profile
Generally well tolerated
Discontinuation due to adverse events was low across treatment groups
Adverse event profile similar to that observed with metformin monotherapy, including gastrointestinal adverse events
Weight loss similar to that observed with metformin monotherapy
Low incidences of hypoglycaemia
1/Goldstein
p.1983
C3 P1 L1-6, L20-24
C3 P2 L1-5
C2 P1 L1-6;
C3 Pcont L1-8
p.1985, C2 P1 L7-12
Summary: Initial Combination Therapy With Sitagliptin Plus Metformin Through 54 Weeks
Efficacy profile1-3: Co-administration of sitagliptin and metformin as initial therapy
Provided marked reductions in HbA1c for up to 54 weeks
Provided continued and substantial reductions in FPG and 2-hour PPG concentrations
Improved measures of β-cell function (HOMA-β; proinsulin-to-insulin ratio)
Provided greater HbA1c reductions in patients with the highest baseline HbA1c
Safety profile1-3: Co-administration of sitagliptin and metformin as initial therapy
Was generally well tolerated
Produced a low incidence of discontinuation due to adverse events
Had adverse event profile similar to that observed with metformin monotherapy, including gastrointestinal adverse events
Resulted in weight loss numerically similar to that observed with metformin monotherapy
Resulted in low incidences of hypoglycaemia
Purpose:
To review the clinical efficacy and safety of initial combination therapy with sitagliptin plus metformin.
Take-away:
Co-administration of sitagliptin and metformin as initial therapy provided glycaemic control for up to 54 weeks and had a comparable safety profile to that observed with metformin monotherapy.
2/CSR 0431_P036_09_Efficacy
Section pg.18 P1 L4-9, p.21 Table
Section p.24 P1 L1-4, p.25 Table
Section p.45
P1 L1-6, Table 11-18, p.46 Table
Section p.54 Figure 11-19, p.55 Table 11-24
Section p.8 P1 L1-10, p.13 P1 L1-6
Goldstein BJ et al. Diabetes Care. 2007;30:1979–1987; Williams-Herman D et al. Poster presentation at ADA 67th Annual Scientific
Sessions in Chicago, Illinois, USA, 22–26 June Late Breaker (04-LB). 38
3/ADA Poster
Williams-Herman D et al ADA 04-LB
Figures 1,2,4,5,6
Table 4
Table 5
Summary
References
1. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE; for the Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30:1979–1987.
2. Data on file, MSD.
3. Williams-Herman D, Johnson J, Lunceford J. Initial combination therapy with sitagliptin and metformin provides effective and durable glycemic control over 1 year in patients with type 2 diabetes: a pivotal phase III clinical trial. Poster presentation at ADA 67th Annual Scientific Sessions in Chicago, Illinois, USA, 22–26 June Late Breaker (04-LB). 38

40. Summary: A Case for Earlier Use of Combination Therapy in the Management of Type 2 Diabetes
Sitagliptin and metformin have complementary mechanisms of action that address all 3 core defects of type 2 diabetes
Improves HbA1c, fasting plasma glucose and post-prandial glucose
As initial therapy, compared with metformin monotherapy, co-administration of sitagliptin with metformin provides improved efficacy without increased incidence of weight gain or hypoglycaemia
Provides an additive effect on the reduction of HbA1c
Improves the markers of β-cell function
Has similar adverse event profile to metformin monotherapy
Combination of therapy of sitagliptin as an add-on to sulfonylurea or as an add-on to sulfonylurea plus metformin resulted in a reduction in HbA1c and was generally well-tolerated
Summary: A Case for Earlier Use of Combination Therapy in the Management of Type 2 Diabetes (continued)
Sitagliptin, a first-in-class oral DPP-4 inhibitor1,2:
Improves HbA1c, FPG and PPG
Is generally weight neutral, has a low risk of hypoglycaemia and is generally well tolerated
Sitagliptin and metformin have complementary mechanisms of action that address all 3 core defects of type 2 diabetes.1,3
As initial therapy compared with metformin monotherapy, co-administration of sitagliptin with metformin provides improved efficacy without increased incidence of weight gain and hypoglycaemia3:
Provides an additive effect on the reduction of HbA1c and the percentage of patients getting to glycaemic goal
Improves the markers of β-cell function
Has similar adverse event profile to metformin monotherapy
Combination of therapy of sitagliptin as an add-on to sulfonylurea or as an add-on to sulfonylurea plus metformin resulted in a reduction in HbA1c and was generally well-tolerated.2,4
Purpose:
To summarise the content of the presentation, including the mechanism of action and the clinical data overview of combination therapy with sitagliptin and metformin (as add-on or initial therapy) and combination therapy of sitagliptin and sulfonylurea (as add-on to sulfonylurea alone or sulfonylurea plus metformin).
2/Nauck: p.197 C2 P3 L1-9 L14-18; p.198 C1 P1 L1-7, C2 P2 L1-3; p.201 Figures 2A and 2B.
3/Goldstein: p.1982 Table 1, p.1984 Table 2; p.1983 C3 P1 L1-6, C3 P2 L1-9, C2 P1 L1-6, C3 Pcont L1-8; p.1986 C1 P2 L1-8, L8-17
1/WPC-JMT-T
p.20 Section XXa, P1 L1-3, P2 L1-16.
p.21 Pcont L7-9
Nauck MA et al. Diabetes Obes Metab. 2007;9:194–205;; Goldstein BJ et al. Diabetes Care. 2007;30:1979–1987; Hermansen K et al. Diabetes Obes Metab. 2007;9:733–745. 42
4/Hermansen: p.737 C2 P2 L1-4; p.739 Table 2, C1 P4 L1-3; p.742 Table 4
References
1. Data on file, MSD.
2. Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205.
3. Goldstein BJ, Feinglos MN, Lunceford JK, et al; for the Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care. 2007;30:1979–1987.
4. Hermansen K, Kipnes M, Luo E, et al; for the Sitagliptin Study 035 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007;9:733–745. 42

41. Clinical data overview of combination therapy of sitagliptin and sulfonylurea (as add-on to sulfonylurea alone or sulfonylurea plus metformin)
Contents
The next section will focus on the clinical overview of combination therapy with sitagliptin and metformin (as add-on or initial therapy) and combination therapy of sitagliptin and sulfonylurea (as add-on to sulfonylurea alone or sulfonylurea plus metformin).
Purpose:
To review with the audience the clinical data of combination therapy with sitagliptin and metformin (as add-on or initial therapy) and combination therapy of sitagliptin and sulfonylurea (as add-on to sulfonylurea alone or sulfonylurea plus metformin) 26 26

42. Summary: Sitagliptin Add-on to Glimepiride With or Without Metformin Study
Efficacy profile
Provided sustained reduction in HbA1c for 24 weeks
Safety profile
Was generally well tolerated
No differences were observed in the incidence of clinical adverse events, serious adverse events, or adverse events leading to treatment discontinuation between groups
Provided modest increase in mean body weight in the overall cohort
Weight gain observed when added to glimepiride alone
Small numerical increase when added to the combination of glimepiride and metformin
As expected, the incidence of hypoglycaemia increased when glimepiride,
a sulfonylurea, was co-administered with sitagliptin
1/Hermansen p.737 C2 P1 L8-14
p.739 Table 2, C1 P4 L1-3
p.740 Pcont L2-6
p.740 Figure 2B
p.742 C2 P1 L1-3 L10-16
p.743 C1 Pcont L1-3, C2 P2 L1-2, L15-19
Summary: Sitagliptin Add-on to Glimepiride With or Without Metformin Study
Sitagliptin 100 mg in combination with glimepiride, with or without metformin, provided1:
Sustained reduction in HbA1c
Sitagliptin 100 mg in combination with glimepiride, with or without metformin1:
Was generally well tolerated
No meaningful differences between the groups were observed regarding the incidence of clinical adverse events, serious adverse events, or adverse events leading to treatment discontinuation
Modest increase in mean body weight in the overall cohort
Weight gain observed when added to glimepiride alone
Small numerical increase when added to the combination of glimepiride and metformin
As is generally observed when other anti-hyperglycaemic agents are used in combination with a sulfonylurea, the incidence of hypoglycaemia increased when glimepiride, a sulfonylurea, was co-administered with sitagliptin.1
Purpose:
To review the clinical efficacy and safety of sitagliptin add-on to glimepiride with or without metformin.
Take-away:
Sitagliptin in combination with glimepiride, with or without metformin provided sustained reduction in HbA1c and was generally well tolerated.
1/Hermansen p.737 C2 P1 L8-14
p.739 Table 2, C1 P4 L1-3
p.740 Pcont L2-6
p.740 Figure 2B
p.742 C2 P1 L1-3 L10-16
p.743 C1 Pcont L1-3, C2 P2 L1-2, L15-19 40
Hermansen K et al. Diabetes Obes Metab. 2007;9:733–745.
Reference
1. Hermansen K, Kipnes M, Luo E, et al; for the Sitagliptin Study 035 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007;9:733–745. 40

43. Read PA et al, Circ Cardiovasc Imaging published online Jan 14, 2010;
DPP-4 Inhibition by Sitagliptin Improves the Myocardial Response to Dobutamine Stress and Mitigates Stunning in a Pilot Study of Patients with Coronary Artery Disease
Read PA et al, Circ Cardiovasc Imaging published online Jan 14, 2010; 43

44. Echocardiographic Analysis
Regional wall LV motion (septal, lateral, anterior, inferior, anteroseptal and posterior )
Global LV function – mitral annular systolic velocity – 6 sites
Peak systolic tissue velocity (Vs)
Strain and strain rate
A diameter of >50% stenosis on CA was considered hemodynamically significant
Echocardiographic Analysis 44

45. Global LV function assessed by LV ejection fraction (mean ± SEM) at baseline, peal stress and 30 minute recovery.
72.6 ± 7.2%
63.9 ± 7.9%
P A Read et al. Circ Cardiovasc Imaging 2010; DOI: /CIRCIMAGING 45

46. In patients with CAD, metabolic manipulation with DPP4-inhibition to prevent degradation of GLP-1 can protect the heart from ischemic LV dysfunction during dobutamine stress and mitigate post- ischemic stunning.
Global and regional wall LV performance was greater following sitaglipitin at peak stress and at 30 minutes into recovery compared to control .
Conclusions 46

47. The rise in plasma insulin was also reduced by sitagliptin which suggests that the beneficial effect on the heart was due to GLP-1 and not to insulin.
At peak stress, sitagliptin improved both global function assessed by ejection fraction and mitral annular Vs, and regional wall function assessed by Vs, strain and strain rate.
This was primarily driven by increasing the performance of the ischemic segments.
Conclusions 47

48. Conclusions
In the recovery period, there was evidence of post- ischemic stunning in the control scans with reduced global and regional wall function compared to baseline.
However, sitagliptin protected the heart from ischemia and mitigated this effect. 48

49. Conclusions
The inhibition of DPP-4 augmented plasma levels of GLP-1 (7-36) which improved global and regional wall LV function during dobutamine stress and mitigated post-ischemic stunning in the recovery period.
This was predominantly driven by a cardioprotective effect on ischemic segments and was independent of insulin. 49

50. Conclusion Incretin Based therapy in diabetes
can be used as monotherapy or in combination therapy with other hypoglycemic agents
Safe, effective, provides long term glucose control
Benefits beyond glucose control
weight neutral or weight loss
probable CV benefits and beta cell mass enhancement

51. Thank you