Exploring New Pathways in the Management of Diabetes through … · D’Alessio DA, et al. J Clin...

Exploring New Pathways

in the Management of Diabetes

through DPP-4 Inhibitors

Young Min Cho, MD, PhD

Department of Internal Medicine

Seoul National University College of Medicine

Le MariageWine & Cheese

Le Mariage홍어 + 돼지고기 + 김치

Le Mariage

?

Vildagliptin (Galvus®)

A highly specific substrate of the enzyme DPP-4

Substrate-like

enzyme blocker

+

DPP-4

K-1

K1

Substrate-like

enzyme blocker:

DPP-4 complex

K2

Slow

(~ 1 h)

DPP-4Inactive

substrate-like

enzyme blocker

+Slow dissociation

0

25

50

75

100

125

-2 0 2 4 6 8 10 12 14 16 18 20 22 24Time (h)

Vildagliptin Dose-dependency of DPP-4 Inhibition in

Patients with T2DMDPP-4 activity (% baseline)

Placebo (n=16)

Vilda 10 mg (n=16)

Vilda 25 mg (n=16)

Vilda 50 mg (n=16)

Vilda 100 mg (n=15)

Vilda 200 mg (n=16)

Vilda 400 mg (n=16)

DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitus; vilda=vildagliptin.

He YL, et al. J Clin Pharmacol. 2007; 47: 633–641.

Vildagliptin 100 mg once daily was used in this study. Galvus (vildagliptin) is approved for 50 mg once or twice daily in

combination with metformin or a TZD, and Galvus (vildagliptin) 50 mg once daily in combination with a sulfonylurea.

HbA1c=hemoglobin A1c; met=metformin;

PBO=placebo; vilda=vildagliptin

*P <0.001. Primary intention-to-treat population.

Bosi E, et al. Diabetes Care 2007; 30: 890-895.

Vildagliptin Add-on to Metformin:

Reduction in HbA1c over 24 Weeks

7.2

7.4

7.6

7.8

8.0

8.2

8.4

8.6

−4 0 4 8 12 16 20 24

Time (weeks of treatment)

Mean HbA1c (%)

PBO + met (n=130)

Vilda 50 mg twice daily + met (n=143)

Vilda 50 mg once daily + met (n=143)

Add-on treatment to metformin (2.1 g mean daily)

−0.7% vs PBO

−1.1% vs PBO

*

*

HbA1c=hemoglobin A1c; PBO=placebo; SU=sulfonylurea; vilda=vildagliptin.

*P <0.001 vs PBO. Primary intention-to-treat population.

Garber A, et al. Diabetes Obes Metab. 2007; 10: 1047–1056.

Vildagliptin: Reduction in HbA1c over 24 Weeks

Time (Weeks)

7.6

7.8

8.0

8.2

8.4

8.6

8.8

9.0

−4 0 4 8 12 16 20 24

Mean HbA1c (%)

PBO + glimepiride (n=144)

Vilda 50 mg once daily + glimepiride (n=132)

Vilda 50 mg twice daily + glimepiride (n=132)

−0.6% vs PBO

−0.7% vs PBO

*

*

Duration: 24 weeks

Add-on to SU:

vilda vs PBO

Add-on Treatment to an SU (Glimepiride 4 mg Once Daily)

Le Mariage

GLP-1

secretagogues

Concentration of active liraglutide is higher than

GLP-1 concentration with a DPP-4 inhibitor

*GLP-1 levels for liraglutide calculated as 1.5% free liraglutide

Adapted from: Degn et al. Diabetes 2004;53:1187–94; Mari et al. J Clin Endocrinol Metab 2005;90:4888–94

GLP-1 Levels at 1 Month After Roux-en-Y Gastric Bypass

Surgery in Obese Patients With Type 2 Diabetes

Diabetes Care 30:1709–1716, 2007

ORAL GLUCAGON-LIKE PEPTIDE-1 (GLP-1) RECEPTOR

AGONISTS FOR THE TREATMENT OF TYPE 2 DIABETES

• In vitro activity of TTP GLP-1R agonist on GLP-1R: EC50 = 4–27nM

• Specific to human GLP-1R among members of the GLP-1R family

• A single p.o. administration reduced glucose excursions after an OGTT in normal mice– ↓ food intake, ↓ body weight, ↓ fat, ↑ c-fos in PVN and ARC

• ↑insulin secretion in response to glucose in vitro (human islets) and in vivo (mice and minipigs)

• Phase Ib/IIa with TPP054 compound – Oral bioavailability = 50%

– A 14 day treatment decreased both fasting and postprandial glucose levels.

– No nausea/vomiting

C. Valcarce et al. from Transtech Pharma, High Point, NC, USA

Abstracts of the 4th International Congress on Prediabetes and Metabolic Syndrome

Journal of Diabetes 2011;3(suppl 3): 16

MariageCombinations of GLP-1 secretagogues and DPP-4 inhibitors

Potential benefits

• Higher plasma GLP-1 levels

• Physiologic route of GLP-1

secretion

• Possible effects on food

intake, weight loss, and

gastric motility

DPP4

inhibitors

GLP-1

secretagogues

Measures enhancing GLP-1 secretion

Conventional oral anti-diabetes/anti-obesity drugs that increase GLP-1 secretion

• Metformin

• α-glucosidase inhibitors

• Colesevelam

• Dietary fibers

Agonists of G-protein coupled receptors on L-cells (GLP-1 secretagogues)

• Specific TGR 5 agonists: 6α-ethyl-23(S)-methyl-cholic acid (EMCA, INT-777)

• GPR119 agonists: AR231453 (Arena Pharm.)

Surgical procedure

• Roux-en Y gastric bypass

• Ileal interposition

Gene therapy

Cho YM, Merchant CE, Kieffer TJ: Pharmacology & Therapeutics 2011

Metformin differentially modulates

plasma levels of incretins in mice

Maida A et al. Diabetologia. 2011;54(2):339-49

Metformin at doses exhibiting GLP-1-increasing effects

exerted no effect on plasma DPP-4 activity in mice.

V, vehicle

A, AICAR 250 mg/kg

S, sitaglitpin 1 mg/kg


Metformin increases islet incretin receptor expression

in a PPARα dependent fashion in mice.


Metformin

(dimethylbiguanide)

PPARα

Beta cells

L cells

Hepatic glucose

production

GLP-1R & GIPR

GLP-1

K cells

No effect

Gastric emptying

GLP-1-mediated

?

Peripheral

glucose

disposal

Glucose

utilisation

in the gut

Cho YM & Kieffer TJ. Diabetologia 2010

Metformin: a GLP-1 enhancer and sensitizer

Co-administration of metformin/a DPP4 inhibitor increases

active GLP-1 greater than either drug alone in human subjects

Migoya EM. Clinical pharmacology & Therapeutics 2011

Healthy nondiabetic subjects (n = 16) received sitagliptin alone (100 mg once daily × 2 days),

metformin alone (500 mg twice daily on day 1 and 1,000 mg on day 2), coadministration treatment

(sitagliptin + metformin), or placebo in a blinded (double-dummy), randomized, crossover manner.

Effects of Vildagliptin and Vildagliptin plus Metformin on

Fasting GLP-1 Levels

0

2

4

6

8

10

12

14

*

Intact GLP-1 (pM)

Fasting Levels of Intact GLP-1 at

Baseline and at 3 Months

BL=baseline; GLP-1=glucagon-like peptide-1; met=metformin; PBO=placebo; vilda=vildagliptin.

*P <0.05 vildagliptin 3 months vs baseline; **P <0.05 vildagliptin add-on metformin significantly improved at 3 months vs baseline.†Contains patients on vildagliptin alone and those on vildagliptin plus metformin.

D’Alessio DA, et al. J Clin Endocrinol Metab. 2009; 94: 81-88.

Vilda group† Placebo

BL BL3 months 3 months

n = 20 20 19 19

20

Intact GLP-1 (pM)

**

0

2

4

6

8

10

12

14

Vilda only

Fasting Levels of Intact GLP-1 in

Vildagliptin Subgroups at 3 Months

Vilda + met

7 13

Inhibition of apical sodium-

dependent bile acid transporter

(ASBT, SLC10A2)

Increased concentration of bile

acids in the intestine

Stimulation of GLP-1 secretion

from L cells via the G-protein-

coupled receptor TGR5

Reviewed in Cho YM & Kieffer TJ. Diabetologia 2010

GLP-1 secretion? DPP-4 inhibition?

Mechanism of increased GLP-1 levels with metformin treatment

• DPP-4 activity in the

circulation has been reported

to be reduced in rodents or

humans treated with

metformin.

• Metformin does not directly

inhibit DPP-4 activity in vitro

• Metformin at doses exhibiting

GLP-1-increasing effects

exerted no effect on plasma

DPP-4 activity in mice.

• Metformin increased plasma

GLP-1 levels in rats genetically

lacking DPP-4.

ASBT inhibition

TGR5 activation

Metformin and incretins converge to

regulate hepatic glucose production

GLP-1

αβ−

−

+

Hepatic

glucose

production

−

+

−

Metformin

Extrapancreatic

glucose-lowering

mechanisms

Glucagon

Insulin

Pancreas

23

Meal

*

*

*

*

*

** * *

**

*

Vildagliptin 100 mg (n=16)

Placebo (n=16)

Acute Effects of Vildagliptin on GLP-1 Levels in

Patients with T2DM

GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus.

*P <0.05.

Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249–1255.



0.0

4.0

8.0

12.0

16.0

17:00 20:00 23:00 02:00 05:00 08:00

Time

Active GLP-1 (pmol/L)

*

24

Acute Effects of Vildagliptin on Glucagon Levels in

Patients with T2DM

Meal

*

* **

*

*

*

*

*P <0.05 vs placebo.




−60

−50

−40

−30

−20

−10

0

10

20

17:00Time

Delta Glucagon (ng/L)

20:00 23:00 02:00 05:00 08:00

Placebo (n=16)


*

25

Acute Effects of Vildagliptin on Insulin Secretion Rates

in Patients with T2DM

AUC=area under the curve; ISR=insulin secretion rate.

*P <0.05.




ISR (AUC) / glucose (AUC)

100 (pmol•kg-1•min-1)/(mg/dL)

0

2

4

6

8

18:00

* *

***

** * * * * * * * * * * * * * *

Time

20:00 23:00 02:00 05:00 08:00

Placebo (n=16)


**

Meal

26

Acute Effects of Vildagliptin on Endogenous Glucose

Production in Patients with T2DM

EGP=endogenous glucose production.

*P <0.05 vs placebo.




0

−0.3

−0.6

−0.9

−1.2

−1.5

Delta EGP (mg/kg/min)

17:00 20:00 23:00 02:00 05:00 08:00

Time

**********

*

*

**************** Placebo (n=16)


Meal

MOA of combination of metformin and a DPP-4

inhibitor on improved glucose homeostasis

• Increase hepatic insulin sensitivity (M>D)

• Insulinotropic action (D)

• Enhance GLP-1 levels in a synergistic manner (M+D)

• Enhance GLP-1 sensitivity in beta cells by increasing

GLP-1 receptor expression (M)

M, metformin; D, DPP-4 inhibitors

28

Vildagliptin Add-on to Metformin: Study

Design and Objective

Objective: to demonstrate superior HbA1c reduction with vildagliptin

+ metformin vs metformin monotherapy

Target population: T2DM on maximal dose of metformin;

HbA1c 7.5–11%

HbA1c=hemoglobin A1c; T2DM=type 2 diabetes mellitus

*Patient number refers to primary intention-to-treat population.


n=130: Placebo + metformin

n=143: Vildagliptin 50 mg twice daily + metformin

n=143: Vildagliptin 50 mg once daily + metformin

24 weeks

Metformin>1500 mg

(monotherapy, stable dose)

4 weeks

N=416*

29

HbA1c=hemoglobin A1c; met=metformin;


*P <0.001. Primary intention-to-treat population.



Reduction in HbA1c over 24 Weeks

7.2

7.4

7.6

7.8

8.0

8.2

8.4

8.6

−4 0 4 8 12 16 20 24


Mean HbA1c (%)

PBO + met (n=130)




−0.7% vs PBO

−1.1% vs PBO

*

*

30


Reduction in FPG over 24 Weeks


Mean FPG (mmol/L)

−4 0 4 8 12 16 20 24

8

9

10

11Vilda 50 mg once daily + met (n=143)


PBO + met (n=130)

−0.8 vs PBO

−1.7 vs PBO

*

**

FPG=fasting plasma glucose; met=metformin;


*P=0.003 vs PBO; **P <0.001 vs PBO. Primary intention-to-treat population.



31

Vildagliptin: Efficacious in Elderly and Obese

Patients and those with Poorly Controlled T2DM

BL=baseline; BMI=body mass index; HbA1c=hemoglobin A1c;

met=metformin; PBO=placebo; T2DM=type 2 diabetes mellitus; vilda=vildagliptin

Primary intention-to-treat population.

Data on file, Novartis Pharmaceuticals, LAF237A2303.

>65 years

Mean BL ~8.3%


BL BMI >30 kg/m2

Mean BL ~8.3%

-1.3

-0.8

-1.3

-0.2

0.2

0.0

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

0.2

0.4

Vilda 50 mg twice daily + met

PBO + met

Change from BL in HbA1c(%)

n= 20 22 103 86 29 29

BL HbA1c

>9%

32

Vildagliptin: Enhances β-cell Function and Improves PPG

when Metformin Alone is not Sufficient

AUC=area under the curve; ISR=insulin secretion rate;

met=metformin; PBO=placebo; PPG=postprandial glucose; vilda=vildagliptin

*P ≤0.001 vs PBO.


Data on file, Novartis Pharmaceuticals, LAF237A2303.


PBO + met (n=54)

β-cell function

Adjusted mean change in

ISR AUC / glucose AUC * *

6.97.3

1.6

0.0

2.0

4.0

6.0

8.0

10.0

2-h PPG

Adjusted mean change in

2-h PPG (mmol/L)

*

*

-1.9

-2.3

-0.1

-3.0

-2.0

-1.0

0.0


33

Vildagliptin Add-on to Metformin: Significantly

Lowers HbA1c over 52 Weeks

6.8

7.2

7.6

8.0

8.4

−4 0 4 8 12 16 20 24 28 32 36 40 44 48 52

Week

Vilda 50 mg daily + met (extension, ITT n=42)

PBO + met (extension, ITT n=29)

Vilda 50 mg daily + met (core, ITT n=56)

PBO + met (core, ITT n=51)

HbA1c (%)

P <0.0001

P <0.0001

∆ –1.1 ± 0.2%

n refers to ITT population.

HbA1c=hemoglobin A1c; ITT=intention-to-treat; met=metformin; PBO=placebo; vilda=vildagliptin

Adapted from Ahrén B, et al. Diabetes Care 2004; 27: 2874-2880.

34

Vildagliptin Effective Across Hyperglycemia Spectrum

Pooled Analysis in Add-on to Metformin

-0.6

-0.9

-1.6

-1.1

-2.0

-1.5

-1.0

-0.5

0.0

BL HbA1c

<8%

n= 186 148 68 34

BL=baseline; HbA1c=hemoglobin A1c; vilda=vildagliptin

*P <0.001 from BL. Pooled analysis from studies 2303, 2354, intention-to-treat / primary intention-to-treat population.

Data on file, Novartis Pharmaceuticals.

Vilda 50 mg twice dailyChange from BL in HbA1c(%)

8< HbA1c

<9%

9< HbA1c

<10%

HbA1c

>10%

*

*

*

*

35

Initial Combination of Vildagliptin and Metformin:

Study Design and Objectives

Primary objective: to demonstrate efficacy of single-pill combination therapy of

vildagliptin and metformin compared with individual monotherapy in drug-naïve patients

with T2DM in a multicenter, randomized, double-blind, active-controlled study

Target population: drug-naïve patients with T2DM (HbA1c 7.5–11%)

*Randomized population. HbA1c=hemoglobin A1c; met=metformin; T2DM=type 2 diabetes mellitus; vilda=vildagliptin.

Bosi E, et al Diabetes Obes Metab. 2009; 11: 506–515.

Met 500 mg qd Met 500 mg bidMet 1000 mg AM

Met 500 mg PMMetformin 1000 mg bid

Vilda 50 mg qd

Vildagliptin 50 mg bidn=300

n=294

Vilda / met 50/500 mg qd

Low dose: vilda / met 50/500 mg bidn=290

50/1000 mg AM

50/500 mg PMHigh dose: vilda / met 50/1000 mg bidn=295

50/500 mg bid

Screening Titration Maintenance

N=1179*

2 weeks 2 weeks 2 weeks 2 weeks 18 weeks

24 weeks

Vilda/met 50/500 qd

36

Initial Combination of Vildagliptin + Metformin Provides

Significantly more HbA1c Reductions than the MonotherapiesMean Change in HbA1c (%)

Intention-to-treat population.

HbA1c=hemoglobin A1c; HD=high dose; LD=low dose; met=metformin; vilda=vildagliptin.

Bosi E, et al. Diabetes Obes Metab. 2009; 11: 506–515.

n = 287 277

Change from Baseline to End Point

Mean Baseline HbA1c ~8.6%

285 285

P <0.001

P=0.004

P <0.001

P <0.001

Vilda + HD met (50/1000 mg bid)

Vilda + LD met (50/500 mg bid)

Met 1000 mg bid

Vilda 50 mg bid

Duration: 24 weeks

Vilda + met vs mono

37

Safety and tolerability

Bosi E, et al. Diabetes Obes Metab. 2009; 11: 506–515

38

Initial Combination of Vildagliptin + Metformin:

Change in Body Weight

276 258271 275n =

Mean Change in Body Weight (kg)


Mean Baseline Body Weight ~88.3 kg

Duration: 24 weeks

Vilda + met vs mono



Met 1000 mg bid

Vilda 50 mg bid


HD=high dose; LD=low dose; met=metformin; vilda=vildagliptin.

Bosi E, et al. Diabetes Obes Metab. 2009; 11: 506–515.

not significant

Measures enhancing GLP-1 secretion

Conventional oral anti-diabetes/anti-obesity drugs that increase GLP-1 secretion

• Metformin

• α-glucosidase inhibitors

• Colesevelam

• Dietary fibers

Agonists of G-protein coupled receptors on L-cells (GLP-1 secretagogues)

• Specific TGR 5 agonists: 6α-ethyl-23(S)-methyl-cholic acid (EMCA, INT-777)

• GPR119 agonists: AR231453 (Arena Pharm.)

Surgical procedure

• Roux-en Y gastric bypass

• Ileal interposition

Gene therapy

Cho YM, Merchant CE, Kieffer TJ: Pharmacology & Therapeutics 2011

Modified from Cell Metabolism 2008;8:447-449

Exploiting New Pathways with DPP-4 Inhibitors

(=TGR5)

GLP-1

Secretagogues(L-cell-targeted drugs)

GLP-1

DPP4

DPP4

DPP4

DPP4

Exploring New Pathways

in the Management of Diabetes

through DPP-4 Inhibitors

Young Min Cho, MD, PhD

Department of Internal Medicine

Seoul National University College of Medicine

*p<0.05.1Ahrén B, et al. J Clin Endocrinol Metab 2004; 89: 2078-2084; 2Balas B, et al. J Clin Endocrinol Metab 2007; 92: 1249-1255; 3Matikainen N, et al. Diabetologia 2006; 49: 2049-2057; 4Rosenstock J, et al. Diabetes Care 2008; 31: 30-35;5Yasuda N, et al. Biochem Biophys Ref Commun 2002; 298: 779-784; 6Hinke S, et al. Biochem Biophys Ref Commun 2002; 291: 1302-1308;7Migoya E, et al. Presented at EASD 2007; abstract 0111; 8Dunning B, et al. Presented at EASD 2006; abstract 0174.

Synergy between Vildagliptin and Metformin

• Vildagliptin increases active GLP-1

levels by 2–4x through inhibition of

the DPP-4 enzyme1-4

• Metformin raises GLP-1 levels,

presumably through increasing

GLP-1 synthesis and not through

DPP-4 inhibition5-7

• Vildagliptin and metformin

synergize to maximise levels of

intact GLP-18 0

5

10

15

20

25

30

Vildagliptin

in drug-naïve

patients

(n=5)

Vildagliptin in

patients on

metformin

(n=12)

*

Effect of vildagliptin on

prandial active GLP-1 levels

in drug-naïve versus

metformin-treated patients

Active GLP-1 AUC0-2hr

(pmol/L)

0

20

40

60

80

100

120

-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Vildagliptin 50 mg twice daily

Sitagliptin 100 mg once daily

Relationship between Drug Exposure and GLP-1 Levels

with Vildagliptin and SitagliptinDrug Levels

Drug exposure1

DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1. *P <0.05 vs vildagliptin group.

Plasma levels during 24-h sampling comprising three standardized meals after 3 months of treatment in type 2 diabetic patients. 1He YL, et al. Clin Pharmacokinet. 2007; 46: 577–588; 1Herman GA, et al. Clin Pharmacol Ther. 2005; 78: 675–688; 2Marfella R, et al. J Diabetes Complications. 24: 79-83, 2010.

.

Intact GLP-1 (pmol/L)

Time (hours)

44

0 2 4 6 8 10 12 14 160

5

10

15

20

25

30

Breakfast Lunch Dinner

Vildagliptin 50 mg twice daily


Time (hours)

GLP-1 levels2

Comparison of Plasma GLP-1 Levels following

3 Months’ Treatment with Vildagliptin or Sitagliptin

GLP-1=glucagon-like peptide-1. *P <0.05 vs vildagliptin group,

Plasma levels during 24-h sampling comprising three standardized meals after 3 months of treatment in type 2 diabetic patients.

Marfella R, et al. J Diabetes Complications. 24: 79-83, 2010.

30

25

20

15

10

5

0

-20 0 15 30 6090 120 180 240 300 0 15 3060 90 120 180 240 300 0 15 3060 90 120 180 240 300 min


Intact GLP-1 (pmol/L)

Sitagliptin 100 mg

once daily + metformin (N=20)

Vildagliptin 50 mg

twice daily + metformin (N=18)

45

Comparison of Plasma Glucagon Levels following

3 Months’ Treatment with Vildagliptin or Sitagliptin


+ metformin (N=20)

Vildagliptin 50 mg

twice daily + metformin (N=18)

Marfella R, et al. J Diabetes Complications. 24: 79-83, 2010.

*P <0.05 vs vildagliptin group; Plasma levels during 24-h sampling comprising three

standardized meals after 3 months of treatment in type 2 diabetic patients.

90

80

70

60

50

40

30

20


Plasma Glucagon (mg/dL)

46

-20 0 15 30 6090 120 180 240 300 0 15 3060 90 120 180 240 300 0 15 3060 90 120 180 240 300 min

Initial Combination of Vildagliptin + Metformin:

Robust Change in FPGMean Change in FPG (mmol/L)

P <0.001

P=0.999

P <0.001

P <0.001



Met 1000 mg bid

Vilda 50 mg bid


Mean baseline FPG ~10.4 mmol/L

287 277285 285n =

Duration: 24 weeks

vilda + met vs mono


FPG=fasting plasma glucose; HD=high dose; LD=low dose; met=metformin; vilda=vildagliptin.

Bosi E, et al. Diabetes Obes Metab. 2009; 11: 506–515;

Data on file, Novartis Pharmaceuticals, LMF237A2302.

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