Differential Treatment Options With Modern Incretin-mediated Therapies

Moderator:John Wilding, MDProfessor of MedicineUniversity Hospital AintreeLiverpool, United Kingdom

Panelists: Tina Vilsbøll, MDHead of Diabetes ResearchGentofte HospitalUniversity of CopenhagenCopenhagen, Denmark

Panelists (cont.):Jean-Pierre Courrèges, MDHead of Internal MedicineDiabetology Vascular Diseases UnitCentre Hospitalier NarbonneNarbonne, France

Stephan Matthaei, MDProfessor of MedicineDiabetes Center QuakenbrückHannover, Germany

Incretin-based Therapies

DPP-4 inhibitors Protect native GLP-1 from

inactivation by DPP-4

GLP-1 receptor agonistsMimic native GLP-1

Sitagliptin

Vildagliptin

Saxagliptin

Exenatide(Exendin-based therapy)

Liraglutide(Human GLP-1 analogue)

Drucker DJ, Nauck MA. Lancet. 2006;368:1696-1705.

Physiological Effects of GLP-1

Gastric emptying1,2

Stomach

Insulin secretion1

Glucagon secretion1,2

Insulin biosynthesis1

Beta cell proliferation*1

Beta cell apoptosis*1

Preserved hypoglycemic counter-regulation3

*In animal models Muscle(indirect effect)

Glucose uptake1Food intake2

Brain

Pancreas

Glucose production1

Liver(indirect effect)

GLP-1 from intestinal L cells

1. Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157; 2. Drucker DJ. Diabetes Care. 2003;26:2929-2940; 3. Drucker DJ, Nauck MA. Lancet. 2006;368:1696-1705.Figure adapted from reference 1.

Glucose-dependent insulin secretion

Glucagon secretion

Somatostatin secretion

Ørskov C, et al. Endocrinology. 1988;123:2009-2013; Drucker J, et al. Proc Natl Acad Sci USA. 1987;84:3434-3438.

Pancreatic cells: -cell -cell -cell

GLP-1: Functional Pancreatic Effects

Hepatic glucose output

Insulin synthesis

GLP-1 Analogues and DPP-4 Inhibitors: Two Different Incretin-based Treatment Options

Girard J. Diabetes Metab. 2008;34:550-559; Gautier JF, et al. Diabetes Metab. 2005;31:233-242.

indirect action of DPP-IV inhibitors:

endogenous

DPP-4 inhibitorsGLP-1 analogues

direct action of GLP-1 analogues on targets:

exogenous

Insu

lin S

ecr

etio

n R

ate

(p

mo

l/kg

/min

)

Time (min)

1

0

0 60 120 180 240

4.3(77)

3.7(67)

3.0(54)

2.3(41)

Controlled plasma glucose plateau mmol/L (mg/dL)

Liraglutide (n = 11)

Placebo (n = 11)

Nauck M, et al. Diabetes. 2003;52(suppl 1):A128.

Glucose-dependent Effect: GLP-1 Analogues Do Not Induce Insulin Secretion at Low Glucose Levels

Data are mean ± SEM

Clinical Effects of DPP-4 Inhibitors vs GLP-1 Analogues

DPP-4 inhibitors GLP-1 receptor agonists

Administrationoral: 100 x 1or 50mg x 2

s/c Injection: 5/10ug x 2or 1.2/1.8mg x 1

Half-life 2.5 hrs or 12-14 hrs 2.4 hrs or 11-15 hrs

HbA1c vs placebo -0.7 to -1.0% -1.0 to -1.5%

Postprandial G + +++

Weight Neutral +++

Systolic blood pressure Neutral ++

Gastric flow 0 +++

Hypoglycemic risk 0 / + with SU 0 / + with SU

Tolerability excellent Nausea / GI side effects

GLP-1 Levels Are Pharmacological With a GLP-1 Analogue and Physiological With a DPP-4 Inhibitor

GLP-1 levels after 7 days of liraglutide6 µg/kg x 1/day (n = 13)

GLP-1 levels after 28 days of vildagliptin 100 mg x 2/day (n = 9)

Degn KB, et al. Diabetes. 2004;53:1187-1194; Mari A, et al. J Clin Endocrinol Metab. 2005;90:4888-4894.

Time (h)

30

60

90

120

8 1612 20 24

0

GLP

-1 (

pm

ol/

L)

Time (h)

30

60

90

120

8 1612 20 240

GLP

-1 (

pm

ol/

L)

Liraglutide dose

Vildagliptin dose

x 1/day

-1.2 -1.5 -0.9

-2.0

-1.5

-1.0

-0.5

0.0

Ch

an

ge

in H

bA

1c(%

)

Liraglutide 1.2 mg OD Liraglutide 1.8 mg OD Sitagliptin 100 mg OD

GLP-1 vs DPP-4 Study:HbA1c Change From Baseline

***

***

*** P < .0001

Mean (1.96 SE); Data are from the full analysis set LOCF (last observation carried forward)

Pratley RE, et al. Lancet. 2010;375:1447-1456; Data on file: 1860/26Feb10/HbA1c.

P < .0013

Baseline 8.4% 8.4% 8.5%

n = 211 214 210

Efficacy and Safety of Incretin-Based Therapies: Clinical Trial Data

White J, J Am Pharm Assoc. 2009; 49 (suppl 1): S30 – S40

Postprandial Plasma Glucagon Concentration During Meal Ingestion:At Baseline and After Treatment With Exenatide or Sitagliptin

DeFronzo RA, et al. Curr Med Res Opin. 2008;24:2943-2952.

Postprandial Plasma Glucose Concentration During Standard Meal:At Baseline and After Treatment With Exenatide or Sitagliptin

DeFronzo RA, et al. Curr Med Res Opin. 2008;24:2943-2952.

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

Liraglutide 1.2 mg Liraglutide 1.8 mg Glimepiride Placebo

GLP-1 vs Glimepiride, Add-on to Metformin (LEAD-2):

Hypoglycemia With GLP-1 Is Similar to Placebo

Novo Nordisk A/S, data on file. LEAD-2_Minor_hypoglyc_data; Nauck MA, et al. Diabetes Care.2009;32:84–90.

Eve

nts

pe

r P

atie

nt

Year *

*P < .001 vs liraglutide 1.2 and 1.8 mgHypoglycemia defined as BG < 3.1 mmol/L

‡‡

n = 240 n = 242 n = 242 n = 121

‡difference between liraglutide and placebo not recorded

4 mg

Effect of Exenatide Compared to Premixed Insulin on Body Weight

Nauck MA, et al. Diabetologia. 2007, 50, 259-267.

5.4 kg

Insulin

Exenatide

GLP-1 Analogue vs DPP-4 Inhibitor:Weight Loss After 6 Months

Liraglutide 1.8 mg Sitagliptin 100 mgLiraglutide 1.2 mg

P < .0001

Liraglutide group (1.2 mg or 1.8 mg) vs sitagliptin group

- 1.0

- 2.9

- 3.4

Ch

ange

in W

eig

ht

(kg)

Pratley RE, et al. Lancet. 2010;375:1447–1456.

GLP-1 Analogue vs DPP-4 Inhibitor:Weight Loss Over 6-Month Period

Pratley RE, et al. Lancet. 2010;375:1447-1456.

day day day

Summary of Randomized Controlled Trials With GLP-1 Analogues: Liraglutide

Drab S. Pharmacotherapy. 2010;30(6):609-624.

-2.3

0.4

-2.8

P = .0467

P = .0128

-2.8-2.6

-0.9

-6.7

-4.0

0.5

P = .0001

Met add-on1

n = 236 241 239

SU add-on2

n = 244 231 229

Met + TZD add-on3

n = 176 178 173

Met + SU add-on4

n = 227 228

Met = metformin; ns = not significant; SU = sulphonylurea; TZD = thiazolidinedione (glitazone)

1. Nauck MA, et al. Diabetes Care. 2009;32:84-90.2. Marre MA, et al. Diabet Med. 2009;26(3):268-278.3. Zinman B, et al. Diabetes Care. 2009;32:1224-1230 (LEAD-4).4. Russell-Jones D, et al. Diabetologia. 2009;52(10):2046-2055.

Ch

ange

in S

BP

Fro

m B

ase

line

(m

mH

g)Effect of Liraglutide on Systolic Blood Pressure

-5.6-6

-5

-4

-3

-2

-1

0

1

P = ns

P = ns

-1.1

Rosiglitazone††Liraglutide 1.8 mg

Liraglutide 1.2 mg

Glimepiride† Placebo

Glargine †††

P < .0001

P < .0001

† Glimepiride dose: LEAD-1; 2-4 mg/day, LEAD-2 and LEAD-5; 4 mg/day †† Rosiglitazone dose: LEAD-1; 4 mg/day, LEAD-4; 8 mg/day

††† Glargine dose: Individually titrated to reach FPG of ≤ 5.5 mmol/L

Liraglutide Improves Cardiovascular Biomarkers: BNP, PAI-1, and hsCRP

Liraglutide vs Exenatide (LEAD-6):HbA1c Reduction (26 weeks and extension)

-1.4

-1.2

-1.0

-0.8

-0.6

-0.4

-0.2

0.0

P < .0001

Baseline 8.2%

n = 227

Baseline 8.1%

n = 236

Ch

ange

in H

bA

1c

(%)

3.Data on File LEAD 6-13, Novo Nordisk.

Mean (2SE)

Liraglutide 1.8 mg OD

-1.12

-0.89

Liraglutide 1.8 mg OD Liraglutide 1.8 mg

P < .0001P = NS

1.Buse J, et al. Lancet. 2009;374(9683):39-47.2.Buse J, et al. Diabetes Care. 2010;33:1300-1303.

Exenatide 10 μg BID

Liraglutide vs Exenatide (LEAD-6):Both GLP-1 Treatments Lower Body Weight

Mean (2 SE)Estimated treatment difference in changes for full population at week 26 NS

Adapted from data on file, Novo Nordisk.

86

90

94

98

0 4 8 12 16 20 24 28 32 36 40

Bo

dy

wei

ght

(kg)

0Liraglutide

Exenatide

Time (weeks)

Exenatide group switched to liraglutide (week 26)

Liraglutideliraglutide

Exenatideliraglutide

*Statistical significance of difference not reported

*

0

2

4

6

8

10

12

14

0 4 8 12 16 20 24

Su

bje

cts

(%

)

Time (weeks)

Liraglutide 1.8 mg Liraglutide 1.2 mg Glimepiride Placebo

GLP-1 vs Glimepiride (Add-on to Metformin, LEAD-2): Nausea Prevalence Declining Over 6-Month Period

26

Proportion of subjects with nausea by week and treatment – safety population

Data on file (LEAD2/01), Novo Nordisk.

GLP-1 Analogue vs DPP-4 Inhibitor:Nausea Incidence Declining Over 6-Month Period

Pratley RE, et al. Lancet. 2010;375:1447-1456.

day day day

Liraglutide vs Exenatide (LEAD-6): Nausea With Liraglutide Appears More Transient Than With Exenatide

Pro

po

rtio

n o

f Su

bje

cts

(%)

Time (weeks)

0 2 4 6 8 10 12 14 16 18 20 22 24 26

10

8

6

4

2

0

12

14

18

20

16

Exenatide 10 μg BID

*** P < .0001 for treatment differences (estimated treatment rate ratio for liraglutide vs exenatide, 0.448)

***

Data are number (%) of patients exposed to treatment (safety population)

Liraglutide 1.8 mg OD

Buse J, et al. Lancet. 2009;374:39–47 (LEAD-6).

Liraglutide 1.8 mg OD

* Time of day = 07:00–09:00

** Time of day = 17:00–19:00

Exenatide 10 µg BID

Arrows show the timing of injections

18

16

14

12

10

8

6

4

2

0

140

120

100

80

60

40

20

0

Time Since First Dose of the Day (h)n = 14

0 2 4 6 8 10* **

12 14 16 18 20 22 24

Tota

l Lir

aglu

tid

e C

on

cen

trat

ion

(n

mo

l/L)

Exe

nat

ide

Co

nce

ntr

atio

n (

pm

ol/

L)

Rosenstock J, et al. Diabetes. 2009;58(suppl 1):A150.

Plasma Levels of Liraglutide Compared With Exenatide

Risk of Pancreatitis With GLP-1 Analogues

• Case reports have suggested a link

• ~30 cases with exenatide

• ~7 cases with liraglutide

• Biologically plausible pathways and some animal models suggest increased inflammation

• Postmarketing surveillance suggests higher rate of pancreatitis in diabetes (~3-fold increase) due to

• obesity, high TGs, gallstones

• No increased incidence with GLP-1 analogues

• Exenatide: ~170 cases per 100,000 pt years

• Insulin: ~200 cases per 100,000 pt years

• Placebo (background): ~300 cases per 100,000 pt years

• Needs ongoing surveillance and research

Peptide Structure of GLP-1 Analogues

Exenatide (from Gila monster) 53% homology

Liraglutide ~97% homology to native GLP-1

Drab S. Pharmacotherapy. 2010;30(6):609-624; Knudsen LB. J Med Chem. 2004;47:4128-4134.

GLP-1 AnaloguesExenatide• Discovered in Gila monster venom

• ~50-70% homology to GLP-1

• Resistant to DPP-4 degradation

• Twice-daily s.c. injection (pre meal)

• Lowers HbA1c by ~1%

• Antibodies in 55% to 70% (LAR) of patients

Liraglutide• Modified GLP-1 (single amino-acid change +

addition of fatty acid)

• Binds to albumin, thus resistant to degradation by DPP-4

• Once-daily s.c. injection (any time)

• HbA1c reduction by ~1.2%

• Antibodies in ~8% of patients

DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.Juhl CB, et al. Diabetes. 2002;51:424-429.

Evidence for CV Risk Reduction With GLP-1 Analogues

• CV risk marker reduction • TG/lipids

• PAI-1

• CRP

• BNP

• Sustained blood pressure and weight reduction

• Pooled data from clinical trials• Fewer CV events in liraglutide groups vs control but low numbers (trials not

powered for CV outcome)

• Retrospective US data analysis• CV event rate ~20% lower in exenatide group (~40,000 pts) vs controls

(~400,000 pts)

Need for hard CV outcome trials

Ongoing CV Outcome Trials With GLP-1 Analogues

• LEADER trial with liraglutide• ~9000 patients with type 2 diabetes

• MACE endpoints (CV death, myocardial infarction, stroke)

• Start September 2010, 42-60 months follow-up first results ~2016

• EXSCEL trial with exenatide LAR (once-weekly injection)• ~9500 patients with type 2 diabetes

• Composite endpoint of primary CV events

• Start June 2010, average 5.5 yrs follow-up results ~2017

ClinicalTrials.gov, Sept 2010.

Decline in Beta Cell Function Is Already Advanced at Time of Diagnosis

Adapted from Lebovitz H. Diabetes Reviews. 1999;7:139-153.

0

20

40

100

-4 6-10 -8 -6 -2 0 2 4

80

60

-12 8

T2D diagnosis

Time From Diagnosis (years)

Bet

a C

ell

Fun

ctio

n (

%, H

OM

A)

Effect of GLP-1 Analogue on Beta Cell Function (after 26 weeks treatment, add-on to SU)

Marre M, et al. Diabet Med. 2009;26:268-278.

Solid color = baseline (%) Graded color = change at week 26 (%)

HO

MA

(%

)

P < .05

P < .05*

**

* Difference between liragutide 1.2 mg vs placebo P = .011** No significant difference between liraglutide 1.8 mg and placebo

n = 206 n = 210 n = 210 n = 100

Potential New Indications for GLP-1 Analogues

• Obesity• Reduce weight

• Preserve beta cell function?

• Stop progression from prediabetes to type 2 diabetes?

• Large clinical trials planned

• Type 1 diabetes• Some small studies with positive results

• Larger trials needed

Await results from larger clinical studies

GLP-1 therapy is not a cure for either type 1 or type 2 diabetes

Role of Incretins in the Management of Type 2 Diabetes

• DPP-4 inhibitors and GLP-1 analogues• Oral vs injectable

• Weight neutral vs weight loss

• Modest vs pronounced HbA1c reduction

• GLP-1 analogues• Low risk of hypoglycemia

• Reduction of blood pressure and body weight

• Incidence of nausea declining over time

• No increased incidence of pancreatitis in type 2 diabetes

• Improvement of CV risk markers

• CV outcome studies ongoing

• Potential prospects in obesity and type 1 diabetes