GLP-1 analogs and DPP-4 inhibitors

Saturday 16 July, 2011

Keystone, Colorado

Matthew C. Riddle

Professor of Medicine

Oregon Health & Science University Oregon

Presenter Disclosure

I have received the following forms of support:

Research grants Amylin, GSK, Lilly, sanofi-aventis

Honoraria for consulting Amylin, Lilly, NovoNordisk, Roche, sanofi-aventis

Honoraria for speaking Lilly, sanofi-aventis

Hours after beginning a meal

1 2 3 4 5 60

Toft-Neilsen M-B et al. J Clin Endocrinol Metab 2001;86: 3717-3723

Cummings DE et al. Diabetes 2001;50: 1714-1719

Patterns of hormones which regulate

plasma glucose and food intake

AmylinInsulin

Ghrelin

GLP-1

Meal

Glucagon

It’s not just insulin !

Ways to enhance GLP-1 receptor stimulation

GLP-1 – chronic infusion

Oral DPP-4 inhibitors

Vildagliptin (Galvus)

Sitagliptin (Januvia)

Saxagliptin (Onglyza)

Linagliptin (Tradjenta)

Short-acting GLP-1 agonist

Exenatide (Byetta)

Long-acting GLP-1 agonists

Liraglutide (Victoza)

Exenatide Q weekly (Bydureon)

Intermediate-acting agonist

Lixisenatide (Lyxumia)

Effects of GLP-1 infusion

Larsen J et al. Diabetes Care 2001; 24: 1416-21

24-h GLP-1 sc infusion

16-h GLP-1 sc infusion

Day 7Day 0

100

150

200

250

300

350

400

06 08 10 12 14 16 18 20 22 00 02 04

400

100

150

200

250

300

350

06 08 10 12 14 16 18 20 22 00 02 04

mg/dl

Time of day

mg/dl

Effect gone in 4 hours

Glucose profiles in 40 patients with T2DM

Main effect on basal glycemia

6-week GLP-1 sc infusion by pump

GLP-1Salinemg/dL

450

360

270

180

90

0

0 1 2 3 4 5 6 7 8

450

360

270

180

90

0

0 1 2 3 4 5 6 7 8

Zander M et al. Lancet 2002; 359: 824-30

Week 6 -- on sc infusions

Glucose profiles in 20 patients with T2DM

Hours

Week 0 -- off OAD 3 wks

4-weeks vildagliptin orallyResponses to breakfast

5,0

8,0

11,0

14,0 Glucose mmol/L

0

25

50

75

-30 30 90 150 210

Minutes

Insulin pmol/L

50

75

100

125

-30 0 30 60 90 120

Placebo

Vilda 100mg

Glucagon pg/mL

0

5

10

15

20

25GLP-1 pmol/L

Ahrén B et al. J Clin Endocrinol Metab 2004;89:2078-84

Minutes

Effects of DP-4 Inhibitors

Sitagliptin is as effective as ½ dose metformin1091 patients randomized to PLBO, sitagliptin, or both

Goldstein BJ et al. Diabetes Care 2007;30: 1979-87

1.0

0

2.0

Placebo-adjusted reduction of A1c from 8.8% baseline (%)

Metformin

2000 mgMetformin

1000 mgSitagliptin

100 mg

-1.30%

-0.99% -0.83%

Effects of GLP-1 agents

Agonists DPP-4 inhibitors

Potentiate insulin secretion ++ +

Suppress glucagon ++ +

Reduce calorie intake ++ +

Slow gastric emptying + or ++ -

Tachphylaxis to GLP-1 effects

Reduced effect with ongoing Rx

Potentiate insulin secretion No

Suppress glucagon No

Reduce calorie intake No

Slow gastric emptying Yes

Tachyphylaxis to GLP-1 effects

9 healthy subjects

8.5 hour GLP-1 or placebo infusions

Meal tests as 0 and 4 hours

Responses to meals vs placebo

0 hours 4 hours

Glucose No increase Blunted

Gastric emptying Markedly slowed Less slowed

Insulin Much reduced Less reduced

Nauck MA et al. Diabetes 2011;60: (on-line 24 March)

Plasma glucose

mg/dL

Time of day/Hours

180

260

220

140

100

0800 1200 1600 2000 2400 0400 0800

180

140

220

100

0 4 8 12 2416 20

Degn KB et al. Diabetes 2004;53: 1187-94Ahrén B et al. J Clin Endocrinol Metab 2004;89:2078-84

Liraglutide vs placebo

Vildagliptin vs placebo

Ways to enhance GLP-1 receptor stimulation

GLP-1 – chronic infusion

Oral DPP-4 inhibitors

Vildagliptin (Galvus)

Sitagliptin (Januvia)

Saxagliptin (Onglyza)

Linagliptin (Tradjenta)

Short-acting GLP-1 agonist

Exenatide (Byetta)

Long-acting GLP-1 agonists

Liraglutide (Victoza)

Exenatide Q weekly (Bydureon)

Intermediate-acting agonist

Lixisenatide (Lyxumia)

Single-dose lixisenatide:

Effect on postprandial glucose Drug naïve T2DM patients, standard meal 1 hour after injection

Christensen M et al, IDrugs 2009 12(8):503-513

Blood

glucose

(mg/dL)

Hours after injection

0

100

200

300

400

Injection Meal

0 1 2 3 4 50

100

200

300

400

1 µg (n=4) 3 µg (n=4)

10 µg (n=4) 20 µg (n=4) 40 µg (n=4)

Placebo (n=10)

Not approved by FDA

28-day treatment with lixisenatide:

Effect on fasting and postprandial glucoseT2DM patients on metformin and/or SU, subgroup treated with

up to 20 mcg taken in AM

Baseline

28 days of treatment

Breakfast Lunch Dinner

Hours after morning injection

Blood

glucose

(mg/dL)

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

300

250

200

150

100

50

Distiller LA, Ruus R. Diabetologia 2008; 51 (Suppl1): A155

Strong effect on postprandial increment after breakfast,

less after lunch and none after dinner

Lixi injection

-1.0

-0.2

-0.5†

-0.5

**

-0.7

* -0.8

*

0n = 107 n = 55 n = 50 n = 53 n = 51

LS mean

change

of A1c (%)

-0.1

-0.2

-0.3

-0.4

-0.7

-0.8

-0.9

-0.5

-0.6

Placebo 20 µg 30 µg10 µg5 µg

Lixisenatide QD

*p < 0.0001, **p < 0.005, †p < 0.05 vs. placebo

-3.9

*

n = 51 n = 53 n = 52 n = 53

-2.1 -2.2-2.6

20 µg 30 µg10 µg5 µg

-0.9

*

-0.7

*-0.8

*

-0.8

*

n = 51 n = 54 n = 52 n = 53

20 µg 30 µg10 µg5 µg

Lixisenatide BID

Lixisenatide BID

7.5%

-4.5

n = 108 n = 54 n = 50 n = 52 n = 51

LS mean

change

of weight (kg) -2.0-2.4

-3.0† -3.5

*

-1.9

0

-0.5

-2.0

-1.0

-1.5

Placebo 20 µg 30 µg10 µg5 µgLixisenatide QD

88 kg

-2.5

-3.0

-3.5

-4.0

Ratner R et al. Diab Med 2010; 27:1024-32

Lixisenatide dose-ranging studyReduction of A1c and weight

A family of GLP-1 agonists

with different durations of action?

Danne T et al. Diabetes Care. 2003;26:3087-3092. Hirsch IB. Medscape Gen Med. 2005;7:49. Available at:

http://www.medscape.com/viewarticle/515847. Rave K et al. Diabetes Care. 2005;28:1077-1082.

0 1 2 53 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Insu

lin

acti

on

Hours

Lixisenatide 8–16 h ?

Exenatide 4-8 hr ?

Native GLP-1 <1 hr ?

Liraglutide >24 h

Exenatide QW > 1 wk

A family of GLP-1 agonists

with different durations of action?

Danne T et al. Diabetes Care. 2003;26:3087-3092. Hirsch IB. Medscape Gen Med. 2005;7:49. Available at:

http://www.medscape.com/viewarticle/515847. Rave K et al. Diabetes Care. 2005;28:1077-1082.

0 1 2 53 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Insu

lin

acti

on

Hours

Lixisenatide 8–16 h ?

Exenatide 4-8 hr ?

Liraglutide >24 h

Action profiles of insulin formulations

Danne T et al. Diabetes Care. 2003;26:3087-3092. Hirsch IB. Medscape Gen Med. 2005;7:49. Available at:

http://www.medscape.com/viewarticle/515847. Rave K et al. Diabetes Care. 2005;28:1077-1082.

0 1 2 53 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

Insu

lin

acti

on

Hours

NPH 12–16 h

Regular 6–8 h

Aspart, glulisine, lispro 4–5 h

Detemir 6-18 h

Glargine ~24 h

Blevins T et al. JCEM 2011;96:1301-1310

Effects of Exenatide BID vs Exenatide QW 252 T2DM patients on one or more OAD

24 weeks randomized open-label treatment

Δ A1c %

Δ FPG

mg/dL

Δ weight

kg

- 0.7% A1cP<0.0001

QW vs BID

- 23 mg/dLp<0.001

- 0.9 kg(NS)

Drucker DJ et al. Lancet 2008;372: 1240-50

Effects of Exenatide BID vs Exenatide QW 295 T2DM patients on diet ± OAD

30 weeks randomized open-label treatment

SMBG

profile

Δ FPG

mmol/L

Δ glucagon

ng/L

- 0.33% A1cP=0.0023

QW vs BID

Mainly

basal vs PP

effect

Same wt

reduction(3.7 vs 3.6 kg)

Buse J et al. Lancet 2009;374:39-47

Effects of Liraglutide vs Exenatide BID464 T2DM patients on 1-2 OAD

26 weeks randomized open-label treatment

- 0.33% A1cP=0.001

Lira vs Ex BID

More

basal vs PP

effect

Same wt

reduction(3.2 vs 2.9 kg)

Δ A1c %

% to A1c

targets<7.0% <6.5%

SMBG

profile

FPG

mmol/L

Weight

kg

A1c %

Effects of Exenatide BID vs Glargine551 T2DM patients on metformin + sulfonylurea

26 weeks Rx with titrated glargine or exenatide 10 mcgBID

A1c and weight: changes from baseline

A1c %

Δ Wt kg

Exenatide

Glargine

Heine RJ et al. Ann Intern Med 2005;143:559-569

Heine RJ et al. Ann Intern Med 2005;143:559-569

Effects of Exenatide vs Glargine551 T2DM patients on metformin + sulfonylurea

26 weeks Rx with titrated glargine or exenatide 10 mcgBID

SMBG and BG after test meal: changes from baseline

Exenatide Glargine

SMBG

Meal test

Buse JB et al. Ann Intern Med 2011;154:103-112

*p<0.05, ** p<0.01

Exenatide

30 weeks

Placebo

30 weeks

7-point glucose profilesLS Means ± SE

Exenatide BID added to titrated glargine ± OAD

A1c ~6.7%, weight difference 2.7 kg

Not approved by FDA

Riddle MC et al. ADA Annual Scientific Sessions 2010, Late-breaking abstract , Poster 18-LB

6

7

8

A1c %

9

Met + glargine

+ exenatide

n=16

Met + glargine

+ placebo

n=17

8/17 randomized

47% <6.5% A1c

2/17 randomized

12% <6.5% A1cp=0.03

A1c

6.5%

Distribution of A1c after 24 weeks

Titrated glargine added to exenatide+metformin

Not approved by FDA

A1c lowering power of GLP-1 agentsPlacebo-adjusted reductions (A1c%)

DPP-inhibitors Added to Met Added to Met+SU

Sitagliptin 0.7 vs baseline

Saxagliptin 0.6 0.9

Linagliptin 0.7

GLP-1 receptor agonists

Exenatide 0.9 1.0

Lixisenatide

Liraglutide 1.8 mg 1.1 1.1

Exenatide QW 1.5 vs baseline

Preliminary safety concerns with GLP-1 agents“Pancreatitis, pancreatic and thyroid cancer

with glucagon-like peptide-1 based therapies”

Elashoff M et al. Gastroenterology 2011;141: 150-6

Springer J & Stammschulte U. Gastroenterology 2011;141:20-3

Review of FDA adverse event reporting system database 2004-2009

Odds Rations from case-control analysis of pancreatitis and cancers.

Exenatide 10.68

Pancreatic cancer

Thyroid cancer

Other cancers

Exenatide 2.95

Exenatide 4.73

Exenatide 1.08

Sitagliptin 6.74

Sitagliptin 2.72

Sitagliptin 1.48

Sitagliptin 0.80

Pancreatititis

Preliminary CV findings with a DPP-4 inhibitor“Linagliptin has simlar efficacy to glimepiride but improved cardiovascular safety over 2

years in patients with type 2 diabetes inadequately controlled by metformin”

1519 patients with T2DM treated with metformin

Randomized double-masked to linagliptin 5 mg or glimepiride up to 5 mg

Baseline A1c 7.7%

Glimepiride Linagliptin Difference

A1c reduction % -0.5 -0.4 Noninferior

Change of weight kg +1.3 -1.4 p=0.0001

CV death, MI, stroke, angina 1.7 % 3.4 % RR 0.50

p=0.04

Gallwitz B et al. ADA annual scientific sessions, June 2011, poster presentation 39-LB

Preliminary CV findings with GLP-1 agonistsCV benefit in animal model

Huber J et al. ADA annual scientific sessions, June 2011, Abstract # 968-P

Langendorff-perfused rat heart model (intact animal)

Infarction induced by 45 min LAD occlusion, 120 min reperfusion

Vehicle or GLP-1 agonist administered before/during reperfusion

Change of infarct size vs vehicle:

Native GLP-1 -32%

Liraglutide -29%

Lixisenatide -36%

Interpretation: direct (or indirect?) myocardial protection

Blonde L et al. Diab Obesity Metab 2006;8: 436-447

CV risk factors after exenatide treatmentT2DM patients treated with exenatide + SU/met

n=314 completing 30 wks randomized and 52 wks open label followup

Change from baseline to 82 weeks

A1c - 1.1 %

Weight - 4.4 kg

Triglycerides - 38.6 mg/dL

LDL-C - 1.6 mg/dL

HDL-C + 4.6 mg/dL

BP-syst - 1.3 mmHg

BP-diast - 2.7 mmHg

Long-term placebo-controlled outcome trials

of GLP-1 agentsTECOS Sitagliptin CV outcome study

2008-2014

14,000 patients with T2DM and known CVD

CAROLINA Cardiovascular outcome study of linagliptin versus glimepiride in

patients with type 2 diabetes

2010-2018

6000 patients with T2DM and high CV risk

LEADER Liraglutide effect and action in diabetes: evaluation of CV outcome

results - a long-term evaluation

2010-2016

8800 patients with T2DM and high CV risk

EXSCEL Exenatide study of CV event lowering: a trial to evaluate CV outcomes

after treatment with exenatide once-weekly in patients with T2DM

2010-2017

9500 patients with T2DM

ELIXA Evaluation of CV outcomes in patients with T2DM after acute coronary

syndrome during treatment with Lixisenatide

2010-2013

6000 patients with T2DM and acute coronary syndrome

Current costs of GLP-1 agents vs othersDrugstore.com quotations 7-8-11

Daily dose 90 day supply

Sitagliptin (Januvia) 100 mg $620

Saxagliptin (Onglyza) 5 mg $620

Glimepiride 4 mg $42 ($10 at Fred Meyer)

Glipizide extended 5 mg $36

Exenatide (Byetta) 10 mcg BID $825

Liraglutide (Victoza) 1.2 mg $860

NPH insulin (Humulin vial) 30 units $191

Glargine (Lantus vial) 30 units $332

Thanks for your attention !

Lixisenatide QD Lixisenatide BID

% with

nausea

0

5

10

15

20

25

30

35

40

Placebo 5 µg 5 µg10 µg 10 µg20 µg 20 µg 30 µg 30 µg

11.5

25.5

35.2

14.3

22.2

n=6 n=14 n=19 n=8 n=12

7.3

n=4

4.6

n=5

7.5

n=4 n=18

33.0

Ratner R et al. Diab Med 2010; 27:1024-32

Lixisenatide dose-ranging studyFrequency of nausea

A1c Patterns in UKPDS and ADOPT

UKPDS 34. Lancet 1998;352: 854-65 Kahn SE et al. N Engl J Med 2006;355:24 27-

43

9

8

7

6

0 2 4 6 8 10

Years

A1c

%

ADOPTUKPDS

Glyburide

Metformin ADOPTUKPDS

Chlorpropamide UKPDS

Rosiglitazone ADOPT