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Incretin-based Therapy

and DPP-4 Inhibitors

ผศ.ดร.นพ.วีระเดช พิศประเสริฐ สาขาวิชาโภชนวิทยาคลินิก ภาควิชาอายุรศาสตร์

คณะแพทยศาสตร์ มหาวิทยาลัยขอนแก่น

Scope

History

Mechanism of action

Pharmacological profile of insulin enhancer

History • 1902 : mechanism of pancreatic secretion

– nature of signal of pancreas chemical stimulus

– extracts from intestinal wall after stimulated by acid = “secretin”

• 1906 : 1st attempt at “extracts of intestinal mucosa” therapies for treating diabetes

• 1921 : different results of extracts of duodenal mucosa on fasting blood glucose and/or on hyperglycemia

Pharmacol Rev. 2008 December ; 60(4): 470–512

History • 1932 : “incretin” = an extract from upper gut

mucosa that produces hypoglycemia but does not induce exocrine secretion

• 1964 : “incretin effect”

Pharmacol Rev. 2008 December ; 60(4): 470–512

J Clin Endocrinol Metab. 1986; 63: 492–498

Oral Glucose Tolerance Test and Matched IV Infusion

Pla

sm

a G

luc

os

e (

mg

/dL

)

0

50

100

150

200

–30 0 30 60 90 120 150 180 210

Time (min)

Pla

sm

a In

su

lin

(p

mo

l/L

)

0

100

200

300

400

–30 0 30 60 90 120 150 180 210

Time (min)

Incretin Effect Different Responses to Oral vs IV Glucose

Oral IV

50 g Glucose

N=6

Incretins

Y A

E G

T F

I S

D Y

S I

A M

D K

I H

Q Q

D F V N W L L A

Q K G K K N D W K

H N Q T I

GIP: Glucose-dependent Insulinotropic Peptide

H A

E G T

F T

S D V

S S

Y L

E G Q

A A

K E F I A

W L V K G R

G

GLP-1: Glucagon-like Peptide-1

Amino acids shown in orange are homologous with the structure of glucagon.

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L-cell

(ileum)

Proglucagon

GLP-1 [7–37]

GLP-1 [7–36 NH2]

K-cell

(jejunum)

ProGIP

GIP [1–42]

GLP-1 and GIP are Synthesized and Secreted from the Gut in Response to Food Intake Function of GLP-1 & GIP

Comaparison Between GLP-1 and GIP

GLP-1 GIP Stimulate insulin release from β-cell

Stimulate insulin release from β-cell

Significant effects on β-cell growth and survival

Potential effects on β-cell growth and survival

Potent inhibition of gastric emptying

Modest effects on gastric emptying

Potent inhibition of glucagon secretion

No significant inhibition of glucagon secretion

Reduction of food intake and body weight

No significant effects on satiety or body weight

Incretin Effect in Healthy Participants and in Patients with Type 2 DM

J Am Pharm Assoc. 2009;49(suppl 1):S16–S29

−15 −10 0 5 10 15 20 30 45 60 75 90 105 120 150

0

2000

4000

6000

8000

C-P

ep

tid

e (

pm

ol/

L)

Time (min)

Diabetologia. 2002; 45: 1111–1119

Different Insulinotropic Effects of GLP-1 and GIP in Patients with T2DM

GLP-1

GIP

Saline

Hyperglycemic Clamp

Saline or GIP or GLP-1

GLP-1 Restores Insulin and Glucagon Responses in a Glucose-sensitive Manner in Patients with T2DM

0

50

100

150

200

250

300

* *

* *

* * *

–30 0 30 60 90 120 150 180 210 240

Time (min)

GLP-1 infusion

Glucose (mg/dL) N=10

0.0

0.5

1.0

1.5

2.0

2.5

3.0

* * *

* * *

* *

–30 0 30 60 90 120 150 180 210 240

Time (min)

GLP-1 infusion

C-peptide (nmol/L)

–30 0 30 60 90 120 150 180 210 240

Time (min)

0

5

10

15

20

25

30

* * * *

GLP-1 infusion

Glucagon (pmol/L)

GLP-1†

Placebo Diabetologia. 1993; 36: 741–744

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Physiology of GLP-1 Secretion and Action on GLP-1 Receptors

Lancet 2006; 368: 1696–705

Stomach

gastric emptying decelerated acid secretion ↓ Endocrine pancreas:

Secretion

β cells: insulin secretion ↑

α cells: glucagon secretion ↓

δ cells: somatostatin secretion ↑

Biosynthesis

(Pro-) insulin↑

β-cell mass

growth, regeneration, neogenesis ↑ apoptosis ↓

Physiology of GLP-1 Secretion and Action on GLP-1 Receptors

Lancet 2006; 368: 1696–705

Insulin-like effects:

- glucose uptake ↑

- glycogen synthesis ↑ (? Indirect actions)

Adipose tissue

Liver

Muscle

Physiology of GLP-1 Secretion and Action on GLP-1 Receptors

Lancet 2006; 368: 1696–705

Brain/nervous system:

Hypothalamus

appetite ↓, satiety ↑

food intake ↓, water intake ↓

Nucleus tractus solitarii

GLP–1 production

Access

CNS: circumventricular organs

(circulating GLP-1)

Autonomic nervous system

Afferent vagus (GLP-1 from GI tract) “Hepatoportal” region

Mechanisms of GLP-1-regulated Glucose Homeostasis

Sites of action Effect of GLP-1

Pancreatic β cell Enhance insulin secretion May play important role in islet neogenesis and proliferation of β cells ↓ apoptosis in β cells in vitro ↑ markers of β cell function

Pancreatic α cell ↓ glucagon secretion

Periphery ↑ glucose uptake

Stomach Delays gastric emptying ↓ food intake

CNS Induces satiety J Am Pharm Assoc. 2009;49(suppl 1):S16–S29

GLP-1 Mediated Actions

Current Opinion in Pharmacology 2006, 6:598–605

Physiology of GLP-1

Diabetes Care 2009; 32(suppl2): S223-S231

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Diabetes Care 2009; 32(suppl2): S223-S231

Incretin Mimetics

Diabetes Care 2009; 32(suppl2): S223-S231

DPP-IV Inhibitor / Incretin Enhancer

Inhibition of DPP-4 Increases Active GLP-1

GLP-1 inactive

(>80% of pool)

Active GLP-1

Meal

DPP-4

Intestinal GLP-1 release

GLP-1 t½=1–2 min

DPP-4

inhibitor Diabetes. 2000; 49 (Suppl 1): A39

Diabetes. 1995; 44: 1126–1131 22

DPP-4 Inhibition Increases Concentrations of Active Incretins

DPP-4=dipeptidyl peptidase-4; GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1. aIncretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels increase in response to a meal.

1. Kieffer TJ et al. Endocr Rev. 1999;20(6):876–913. 2. Drucker DJ. Diabetes Care. 2003;26(10):2929–2940. 3. Holst JJ. Diabetes Metab Res Rev.

2002;18(6):430–441.

Hepatic glucose production Peripheral glucose uptake

Blood glucose in fasting and

postprandial states

Glucose-dependent

Glucagon from α cells Glucose-dependent

Insulin from β cells

Release of active incretins by the intestinea

By increasing and prolonging

active incretin levels, DPP-4

inhibitors increase insulin

release and decrease

glucagon levels in the

circulation in a glucose-

dependent manner.

DPP-4

enzyme Inactive

GLP-1 and GIP X DPP-4

inhibitor

GLP-1 GIP

GLP-1 Analogues vs Control in Adults With Type 2 Diabetes

JAMA. 2007;298(2):194-206

DPP-4 Inhibitors vs Control in Adults With Type 2 Diabetes

JAMA. 2007;298(2):194-206

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A Comparison between Incretin Mimetics and DPP4 Inhibitors

Incretin Mimetics DPP4 Inhibitors

Nausea is often (44%) Nausea is rare (1.4%)

Gastric emptying delay GI effects are rare

Weight loss Weight neutral

Not recommended for Pt with Cr clearance < 30 ml/min

Dose adjustment for renal insufficiency

Twice-daily dose Once-daily dose

Administered by injection Orally administrated

HbA1c reduction 0.8-1% HbA1c reduction 0.6-0.85%

Adv Ther. 2008;25(7):627–643 27

DPP-4 Inhibitors: Pharmacologic Profiles

DPP-4 Inhibitors Differ in Molecular Structures and Pharmacologic Properties

28

Chemical

Class β-Phenethylamines1 Cyanopyrrolidines Aminopiperidine8 Xanthine

Generic Name

Sitagliptin2 Vildagliptin3–5 Saxagliptin3,6,7 Alogliptin9,10 Linagliptin11,12

Molecular

Structure

Bioavailability ~87% 85% >75 %4 N/A ~30%

Half-life 12.4 h ~2–3 h 2.5 h (parent)

3 h (metabolite) 12.4–21.4 h

Effective t1/2 ~12 h

Terminal t1/2 >100 h

Absorption

tmax (median) 1–4 h 1.7 h

2 h (4 h for active

metabolite) 1–2 h 1.5 h

DPP-4=dipeptidyl peptidase-4. aPharmacodynamic studies were performed in different assay systems and should not be compared.

1. Kim D et al. J Med Chem. 2005;48:141–151. 2. Data on file, MSD. 3. Matsuyama-Yokono A et al. Biochem Pharmacol. 2008;76:98–107. 4. Villhauer EB et al. J Med Chem. 2003;46:2774–2789. 5. EUSPC for Galvus. 6. Augeri DJ et al. J Med Chem. 2005;48:5025–5037. 7. EUSPC for Onglyza. 8. Feng J et al. J Med Chem. 2007;50:2297–2300. 9. Lee B et al. Eur J Pharmacol. 2008;589:306–14. 10. Christopher R et al. Clin Ther. 2008;30:513–527. 11. Thomas L et al. J Pharmacol Exp Ther. 2008;325:175–182. 12.

EUSPC for Trajenta.

F

F

F O

N

N H 2

N N N

C F 3 N N

O

H 3 C

O N

C N

N H 2

N

O

H H

N C H O

N H 2

H O

N H

O

N

N C N

N O

N

N

N

N N

O

NH2

Pharmacokinetic Properties of DPP-4 Inhibitors

29

Sitagliptin

(Merck)

Vildagliptin

(Novartis)

Saxagliptin

(BMS/AZ)

Alogliptin

(Takeda)

Linagliptin

(BI)

Oral

administration Once daily 2 times a day Once daily Once daily Once daily

Therapeutic

dose 100 mg/day 50 mg bid 5 mg/day

12.5 – 25

mg/day 5 mg/day

Elimination

Renal 87%

(79%

unchanged)

Renal 85%

(23%

unchanged)

Renal 75%

(24% as parent;

36% as active

metabolite)

Renal

(60%–71%

unchanged)

Feces 80%

(90%

unchanged)

Renal 5%

Dose

reduction with

renal

impairment

Yes

(25 – 50 mg) No

Yes

(2.5 mg) Probably yes Probably no

Diabetes, Obesity and Metabolism 2010; 12: 648 – 658.

Pharmacokinetic Properties of DPP-4 Inhibitors

30

Sitagliptin

(Merck)1

Vildagliptin

(Novartis)2

Saxagliptin

(BMS/AZ)3

Alogliptin

(Takeda)5

Linagliptin

(BI)6,7

Distribution 38% protein

bound

9.3% protein

bound

Low protein

binding N/A

Concentration-

dependent protein

binding:

1 nM: 99% (DPP-4)

≥30 nM: 75%–89%

Metabolism ~16% metabolized

low potential of drug

interactions with substrates

of CYP3A4, 2C8, and 2C9”

69% metabolized

mainly renal

(inactive metabolite)

Hepatic

(active metabolite)

CYP3A4/5

<8%

metabolized

~13%

metabolized

Hepatic

Insufficiency

No dose

adjustment

Not

recommended

Does adjustment in co-

administration w CYP-

enhancers/

suppressors;

no adjustment in HI

No dose

adjustment

No dose

adjustment

Drug-drug

interactions No No Yes No No

DPP-4=dipeptidyl peptidase-4. aPharmacokinetic studies were performed in different assay systems and should not be compared. 1. Data on file, MSD. 2. EUSPC for Galvus. 3. EUSPC for Onglyza. 4. EPAR for Onglyza. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001039/WC500044319.pdf. Accessed May 4, 2011. 5. Christopher R et al. Clin Ther. 2008;30:513–527. 6. EUSPC for Trajenta. 7. Blech S et al. Drug Metab Dispos.2010;38:667–678. 2. Kidney Blood Press Res 2012;36:65-84