Role of incretins inthe treatment of type 2 diabetes

Jens Juul HolstDepartment of Medical PhysiologyPanum InstituteUniversity of CopenhagenDenmark

Diabetes & ObesitySpanish Society of Internal MedicinePalma de Mallorca, February 2007

Incretin function in type 2 diabetes

• Secretion of GLP-1 impaired• Beta-cell sensitivity to GLP-1 decreased• Secretion of GIP slightly impaired• Effect of GIP abolished or grossly impaired

• If the impaired incretin responsecontributes significantly to the defectiveinsulin secretion in type 2 diabetes, willrestoration of incretin action improve metabolism?

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1212

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00:0000:00 04:0004:00 08:0008:00 12:0012:00 16:0016:00

SnackSnackLunchLunchBreakfastBreakfast

Diabetic Diabetic -- salinesaline

NonNon--diabeticdiabetic

Glu

cose

Glu

cose

(mm

ol/

L)(m

mol/

L)

Time of day Time of day Rachman et al., Diabetologia 1997

Proof of hypothesis: Glucose tolerance canbe restored by iv GLP-1 in T2DM

Diabetic Diabetic -- GLPGLP--11(1.2 (1.2 pmolpmol/kg/min)/kg/min)

Actions of GLP-1

• Insulin secretion:– Potentiates glucose-induced insulin secretion– Enhances all steps of insulin biosynthesis– Upregulates insulin gene expression– Upregulates expression of genes essential for beta-cell function

(glucokinase, Glut 2, etc.)– Mitotic for beta-cells– Promotes differentiation of duct progenitor cells– Inhibits apoptosis

• Inhibits glucagon secretion• Inhibits gastrointestinal secretion and motility• Inhibits appetite and food intake• Expedient cardiovascular effects

Native GLP-1 is rapidly degraded by DPP-IV

DPP-IV

7

37

9

T½ = 1–2 min (i.v.)MCR = 5–10 l/min

Vilsboll et al. J Clin Endocrinol Metab 2003

How can we exploit the therapeutical potential of GLP-1?

• Continuous administration of GLP-1

Effects of six weeks’ continuous subcutaneousinfusion of GLP-1 in patients with type 2diabetes

Zander et al, Lancet 2002

Main findings: Zander et al. Lancet 2002

• Continuous subcutanous infusion of GLP-1 for 6 weeks in type 2 diabetes patients:– Reduced fasting and mean plasma glucose by

4.3 and 5.5 mmol/l, respectively– Reduced HbA1c by 1.3% and normalised

fructosamine– Resulted in a weight loss of 2 kg, presumably

because of significantly reduced appetite– Improved insulin sensitivity and enhanced

beta-cell secretion– Had no significant side effects

ResultsWeek 0

Beta-cell function (C-peptide levels) Week 14000Week 6

2000

3000

pmol

/l

Saline NS1000

00 10 20 30 40 50 60 70 80 90

0

1000

2000

3000

4000

5000

6000

7000

0 10 20 30 40 50 60 70 80 90

pmol

/l

Incremental AUC:(0–90 min): p = 0.001

∆ values: p = 0.0002

GLP-1

Time (min)

How can we exploit the therapeuticalpotential of GLP-1?

• Continuous administration of GLP-1• Resistant analogues of GLP-1 (receptor activators, incretin mimetics)

GLP-1 receptor agonists

• Exendin 4, from saliva of the GilaMonster, 53%homologous withGLP-1 and fullagonist on the GLP-1 receptor

• Insensitive to DPP-IV

Gila Monster

0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.50

100

200

300

400

500

600

700

800 0.1 µg/kg0.2 µg/kg0.3 µg/kg0.4 µg/kg

Pla

sma

AC

2993

(pg/

mL)

Kinetics of s.c. AC2993 in type 2 diabetes patients

Time (hours after dose)Kolterman et al 2005

Placebo-ControlledTrials

Exenatide reduces HbA1c after 2 years

Add-on to existing OHA

Exenatide 10µg bid

Duration of treatment (years)

Open-Label UncontrolledExtension studies

∆A

1C (%

)

-1.2 ± 0.1%

0.0

-0.5

-1.5

-1.0

0.0 0.5 1.0 1.5 2.0

Baseline A1c8.2%

2 yr data for 82-wk cohort N = 146 Mean ± SE

Ratner et al, ADA 2005

Exenatide reduces body weight after 2 years

Add-on to existing OHA

Exenatide 10µg bid

-15.0

-12.5

-10.0

-7.5

-5.0

-2.5

0.0

2.5I II III IV

+1.9 kg

-2.5 kg

-5.9 kg

-12.2 kg

Meanbaseline weight: 104 kg 100 kg 97 kg 98 kg

Ch

ang

e in

bo

dy

wei

ght (

kg)

0 10 20 30 40 50 60 70 80 90 100 110-7

-6

-5

-4

-3

-2

-1

0

1

Time (wk)

Placebo-ControlledTrials

Open-Label UncontrolledExtension Studies

Baseline Weight100 kg

-4.7 ± 0.3 kg

∆ B

ody

Wei

ght (

kg)

N = 283; Mean (SE).

Henry et al. ADA 2006: 485-P

Survival during 2-year carcinogenicity studyMale mice Female mice

65

Hiles et al. ADA 2004

Num

ber s

urvi

ving

15

4555

0

3525

65

15

4555

3525

15

4555

3525

15

4555

3525

20 40 60 80 100 0 20 40 60 80 100

0 20 40 60 80 100 0 20 40 60 80 100Week Week

Male rats Female rats

Last dose:week 98

Last dose:week 96

Control 118 µg/kg/day70 µg/kg/day250 µg/kg/dayControl 2

Exenatide has been on the marketin the US since June 1 2005 under thename ”Byetta” and launch in Europeis expected in May 2007

Liraglutide is a long-acting GLP-1 derivative

Improved pharmacokinetics by:• Self association• Albumin binding

• Slow absorption from subcutis• Metabolic stability• Long plasma half-life • Stability against DPP-IV

Multiple-dose pharmacokinetics: a fast and flat plateau

Pla

sma

lirag

lutide

(pm

ol/

l)

Time (hours)0 48 288144 192 24096

6000

4000

2000

0

8000 • Multiple dose kinetics mirrors single dose

• Steady-state reached after 3 doses

Single subject profile

Based on modelling of individual data. Study published in: Agersø et al. Diabetologia 2002;45:195–202.

Study 1189

Liraglutide, Phase 2b-studies (June 2006):

•165 patients with type 2 diabetes previously treated with OAA,HbA1c 8.5 %

•Double-blind, placebo-controlled, randomised trial•Liraglutide was given for 14 weeks in monotherapy

•HbA1c decreased 1.5-2 %, 45 % had < 7% (vs < 8 % in Placebo)•Fasting BG reduced by > 3 mmol/L•Body weight decreased by 3 kg from 90 kg.

•Nausea in 5-10 % initially, decreasing markedly with time.•No hypoglycaemia

• Vilsboll et al: ADA 2006

Liraglutide, japanese study (August 2006):

•200 subjects previously treated withdiet/exercise and/or single oral agentwere given liraglutide once daily•HbA1c down 2.0 % after 15 weeks•75 % below 7 %•No hypoglycemia

How can we exploit the therapeuticalpotential of GLP-1?

• Continuous administration of GLP-1• Inhibition of GLP-1 degradation• Resistant analogues of GLP

(receptor activators, incretin mimetics)

Survival of s.c. GLP-1 in type 2 diabetes

0 30 60 90 120 150 180 210 240

Time (min)

0

100

200

300

400

GLP

-1 (p

mol

/l)

**

** ** ** ** ** *

Intact GLP-1 + metabolite

Intact GLP-1

Deacon et al. 1995

!DPP IV in complex w valine-pyrrolidideith

Valine-pyrrolidide

Rasmussen et al; Nature, 2003

Valine-Pyrrolidide Inhibits Plasma DPP IV Activity in Anaesthetised Pigs

0 30 70 110 150Time (min)

0

20

40

60

80

100

DPP

IV a

ctiv

ity (%

of b

asa l

)

N

O

NH2

Valine Pyrrolidide

N

O

NH2

Valine Pyrrolidide

Deacon et al., Diabetes 47:764-769, 1998

DPP-IV inhibition prevents N-terminal degradation of GLP-1 in anaesthetised pigs

Deacon et al. Diabetes 1998;47:764–9

0 20 40 60 80 100 120 140 160 180 200 220

GLP-1 infusion

Glucose

GLP-1 infusion

Glucose

Val-pyd500

GLP

-1 (p

mol

/l)

400

300

200

100

0

Time (min)

Intact GLP-1Total GLP-1

DPP-IV inhibition enhances GLP-1 induced insulin secretin in pigs

0 10 20 30 40 50 60 70 80 90–10–20–300

100

200

300

400

500

600

Insu

lin (p

mol

/l)

GLP-1 infusion

Glucose

Val-pyr

Time (min)+ Val-pyr - Val-pyr

More than 30 companies start to develop DPP-IV inhibitors

Leading compounds:

Novartis: LAF 237 (Vildagliptin, Galvus)

Merck: MK-0431 (Sitagliptin, Januvia)

Diabetes Care 2004

–4 0 4 8 12 16 20 24 28 32 36 40 44 48 526.8

7.2

7.6

8.0

8.4

LAF/MET(core, ITT, n = 56)

PBO/MET(core, ITT, n = 51)

LAF/MET(extension, ITT, n = 42)

PBO/MET(extension, ITT, n = 29)

Time (weeks)MET, metformin; PBO, placebo

Ahrén et al. LAF 237 for 12 and 52 weeks

HbA

1c(%

)

Meal-related beta-cell function and insulin sensitivity by LAF 237 (vildagliptin) in metformin-treated patients with type 2 diabetes

0.050

0.045

0.040

0.035

0.030

0.0250 12 24 52

300

Insu

lin s

ensi

tivity

275

250

225

200

14

12

10

8

60 12 24 52 0 12 24 52

Ada

ptat

ion

inde

x

Time (weeks) Time (weeks) Time (weeks)

* * * * * * * **

Insu

lin s

ecre

tion

LAF 237 + Metformin Metformin alone

Ahrén et al. Diabetes Care 2005;28:1936–40

Vildagliptin (Galvus) enhances endogenousGLP-1 and suppresses glucagon levels

throughout the night

Balas et al. ADA 2006, 122-OR

Vildagliptin (Galvus) suppresses endogenousglucose production throughout the night

Balas et al. ADA 2006, 122-OR

33Protocol 024

Sitagliptin Showed Similar Glycemic Efficacy to Glipizide When Added to Metformin

Week0 6 12 18 24 30 38 46 52

A1C

(%)

6.0

6.4

6.8

7.2

7.6

8.0

Mean change from baseline (for both groups)*: -0.67%

Sitagliptin 100 mg + Metformin (n=382) Glipizide + Metformin (n=411)

* Per-protocol analysis; -0.51% and -0.56% for sitagliptin and glipizide in LOCF analysis.

34Protocol 024

Progressively Greater Reductions in A1C as Baseline A1C Rises

Per Protocol Population

Study inclusion criteria 6.5-10%.

∆ A

1C (%

)

-2.4

-2.0

-1.6

-1.2

-0.8

-0.4

0.0

Baseline A1C Category<7% 7 - <8% 8 - <9% ≥9%

Sitagliptin 100 mg qd Glipizide

-1.68 -1.76

-1.13 -1.11

-.53 -.59

-.27 -.13

35Protocol 024

Sitagliptin Once Daily Showed Decreased Body Weight Compared to Glipizide (52 Weeks)

∆ between groups = –2.5 kg (p<0.001)

86

88

90

92

94

0 12 24 38 52Time (weeks)

Bod

y W

eigh

t (kg

)

Sitagliptin 100 mg + Metformin (n=382)Glipizide + metformin (n=411)

Hypoglycaemia: Sitagl. 4.9 %, Glipizide 32 %

36 Protocol 036

Sitagliptin + Metformin Factorial Study Design

N = 1091 Randomized

Mean baseline A1C = 8.8%

ScreeningPeriod

Single-blindPlacebo Double-blind Treatment Period

Diet/exercise Run-in Period

Eligible if A1C 7.5 to 11%

If on an OHA, D/C’ed

Week- 2 Day 1

Sitagliptin 50/Met 1000 BID

Placebo

Sitagliptin 100 mg qd

Metformin 500 BID

Metformin 1000 BID

Sitagliptin 50/Met 500 BID

Week 24

Duration up to 12 weeks based on prior therapy

Open Label Cohort Sitagliptin 50/Met 1000 BID

RANDOMIZATION

37 Protocol 036

Initial Combination of Sitagliptin and MetforminProduced a Marked Improvement in A1C

A1C

(%)

Sita 50 mg b.i.d+ Met 1000 mg b.i.d.

Sita 50 mg b.i.d+ Met 500 mg b.i.d.

Met 1000 mg b.i.d.

Met 500 mg b.i.d.

Sita 100 mg q.d.

Placebo

0 6 12 18 246.5

7.0

7.5

8.0

8.5

9.0

9.5

Week

Clinical experience with DPP-IV inhibitors:

• There is experience from up to 104 weeks treatment inthousands of patients

• The inhibitors are comparable to existing OADs in monotherapy

• They show additional efficacy when used in combination bothwith SU, glitazones, metformin and insulin.

• Their effect on HbA1C is maintained for 104 weeks

• Effect on HbA1c depends on starting level (up to 3 %)

DPP-IV inhibition:

•Inhibitors (Januvia) for once daily oral administrationare already on the market in the US and in Mexico

•Recommended for Approval in Europe, Jan. 2007

•So far no class related adverse effects

•Effective in experimental and clinical diabetes

•Potential for diabetes prevention

•Neutral with respect to body weight

Conclusions

• GLP-1 based therapy of type 2 diabetes mellitus canbe expected to:

– reduce hyperglycaemia andHbA1C levels– Reduce appetite and lower body weight

(agonists) or be weight neutral (inhibitors)– Improve blood lipids– Improve insulin sensitivity– Enhance beta-cell secretion– Be efficacious without side effects

• Will the therapy prevent progression of disease?