"Not all of us can do great things. But we can do small things with great love." — Mother Teresa

GLP-1 Receptor Agonists

Diabetes Prevalence: Projected Increase 2000-2030

Metabolic Syndrome

• 24% of U.S. adults

Diagnosis• 3 or more of the following

– Hypertension > 130/85– Waist > 40” men, >35” women– HDL < 40 for men, < 50 in women– Triglycerides > 150– Fasting glucose > 110

JAMA May 16, 2001JAMA May 16, 2001

JAMA Jan 16, 2002JAMA Jan 16, 2002

Prevalence of The Met Syn : US AdultsP

reva

len

ce

(%

)

0

5

10

15

20

25

30

35

40

45

20–29 30–39 40–49 50–59 60–69 70

Men

Women

Age (years)

Ford ES, et al. JAMA. 2002;287:356-359.

Prevalence Rates (%) of Insulin Resistance in Selected Metabolic Disorders

Bonora E, et al. Diabetes 1998;47:1643-Bonora E, et al. Diabetes 1998;47:1643-4949

Bonora E, et al. Diabetes 1998;47:1643-Bonora E, et al. Diabetes 1998;47:1643-4949

Coronary Heart Disease Mortality

0 2 4 6 8 10 12

0

5

10

15

20

RR (95% CI), 3.77 (1.74-8.17)

Follow-up, Y

Cu

mu

lati

ve H

azar

d (

%)

Yes

No

866

288

852

279

834

234

292

100

Met Syn: Survival Curves

No. at RiskMetabolic Syndrome

YesMetabolic Syndrome:

0 2 4 6 8 10 12

0

5

10

15

20

RR (95% CI), 3.55 (1.96-6.43)

Follow-up, Y

866

288

852

279

834

234

292

100

0 2 4 6 8 10 12

0

5

10

15

20

RR (95% CI), 2.43 (1.64-3.61)

Follow-up, Y

866

288

852

279

834

234

292

100

Cardiovascular Disease Mortality

All Cause Mortality

Lakka H-M, et al. JAMA. 2002;288:2709-2716.

No

-C

ell

Fu

nct

ion

(%

)*

PostprandialHyperglycemia

IGT†Type 2

DiabetesPhase I Type 2

DiabetesPhase II

Type 2 DiabetesPhase III

25

100

75

0

50

-12 -10 -6 -2 0 2 6 10 14Years From Diagnosis

Patients treated with insulin, metformin, sulfonylureas‡

*Dashed line shows extrapolation forward and backward from years 0 to 6 from diagnosis based on Homeostasis Model Assessment (HOMA) data from UKPDS.†IGT=impaired glucose tolerance‡The data points for the time of diagnosis (0) and the subsequent 6 years are taken from a subset of the UPKDS population and were determined by the HOMA model.Lebovitz HE. Diabetes Rev. 1999;7:139-153.

UKPDS: -Cell Loss Over Time

History: GLP1-RAs

1902 Bayliss & Starling: role of a gut-derived hormone (“secretin”) stimulated

pancreatic juices. Introduced the word “hormone” (Gr: impetus).

1932 LaBarre term “incretin” to refer to a substance derived from the gut that

caused hypoglycemia but did not cause exocrine secretion after eating.

1964–1967 Clinical proof that a gut-derived factor positively modulated insulin

secretion; that more insulin was secreted from oral glucose than IV glucose .

1971 John Brown: Isolated, sequenced gastric inhibitory peptide (GIP), and

renamed it glucose dependent insulinotropic peptide after finding that plasma

glucose has to be elevated in order for GIP to induce insulin secretion.

1985 The second incretin, GLP-1, described.

2002 Exendin-4, a GLP-1 receptor agonist extracted from Gila monster lizard

saliva, shown to stimulate insulin secretion in a glucose-dependent manner in

subjects with and without T2DM.

Mean ± SE; N=6; *P0.05; 01-02=glucose infusion timeNauck. J Clin Endocrinol Metab. 1986;63:492. Copyright 1986, The Endocrine Society.

Ve

no

us

Pla

sm

a G

luc

os

e (

mm

ol/

L)

Time (min)

C-P

ep

tid

e (

nm

ol/

L)

11

5.5

001 60 120 180 01 60 120 180

0.0

0.5

1.0

1.5

2.0

Time (min)02

02

Incretin Effect

Oral Glucose IV Glucose

**

*

*

**

*

Incretin Effect: Amplification of the Beta-cell Response to Oral vs IV Glucose Challenge

Two Incretins: GIP and GLP-1

Both secreted by enteroendocrine cells by sensing an increase in the concentration of

carbs/fats in the lumen of the GI tract .

Both degraded by DPP-4 (dipeptidyl peptidase-4). T/2 < 2min.

Both stimulate beta cells to secrete ~80% more insulin in response to the same amount of

blood glucose.

GIP GIP produced by K cells in the proximal small intestine . GIP enhances insulin induced lipoprotein lipase activity, triglyceridegenesis, beta cell

proliferation and survival.

GLP-1 L-cells in the small bowel and ascending colon synthesize GLP-1 and GLP-2 Posttranslational product of the proglucagon gene encode glucagon, GLP-1 and GLP-2 Tissue-specific post-translational processing of proglucagon, product secretion and

degradation.

In T2DM: hyperglycemia down-regulates GIPR expression/activity but not GLP-1 receptor

expression/activity.

Defective GLP-1 secretion in pts with impaired glucose tolerance, resulting in reduced

concentrations of post-prandial GLP-1, contributing to a blunted insulin secretory response to

meals.

Incretin effect in T2DM

Nauck. Diabetologia. 1986;29:46.©2006, ICHE

• Infuse glucose to maintain glycemia at same

• levels as following a 50-g oral challenge

• Record -cell secretory responses to oral• and IV administration of glucose

• Compare healthy with T2DM

Nauck. Diabetologia. 1986;29:46.

Incretin Effect Reduced in T2DM Compared With NGT

0

5

10

15

20

25

30

35

40

NGT T2DM0

10

20

30

40

50

60

70

80

NGT T2DM

IncretinEffect

Insu

lin

(mm

ol/L

/min

)

Glucose:IV (isoglycemic infusion)Oral (50 g)

30.0

72.8

23.5

34.7

11.3

38.9

-Cell SecretoryResponse

NGT=normal glucose tolerance

Co

ntr

ibu

tio

ns

of

Inc

reti

n F

act

ors

(%

)

©2006, ICHE

0

5

10

15

20

0 60 120 180 240

NGTIGTT2DM

Breakfast

**

*****

*

Time (min)

Toft-Nielsen. J Clin Endocrinol Metab. 2001;86:3717; with permission.

GLP-1 Secretion Impaired in T2DMG

LP

-1 (

pm

ol/L

)

*P<0.05 vs T2DMNGT=normal glucose toleranceIGT=impaired glucose tolerance

©2006, ICHE

GLP Degraded by DPP-4

DPP-4 requires an Ala, Pro or HOPro at the penultimate N-terminal position.

82-Week Extension Study Exenatide (10 mcg BID) Added to Metformin

-1.4

-1.2

-1

-0.8

-0.6

-0.4

-0.2

0

After 30 wk

After 82 wk

-6

-5

-4

-3

-2

-1

0

After 30 wk

After 82 wk

Change in A1C Change in Weight

Ch

ang

e F

rom

Bas

elin

e (%

)

Ch

ang

e F

rom

Bas

elin

e (k

g)

Ratner. Diabetes Obes Metab. 2006;8:419.

GLP-1 in the Pancreas Beta Cell

Stimulates insulin synthesis, secretion, and glucokinase expression. Stimulates expression of GLUT-2 transporter, thereby increasing efficacy

and potency of glucose as a stimulus for insulin secretion Restores first phase insulin response Increases proinsulin mRNA stability & gene transcription

GLP-1 increases number of beta cells by: Up-regulates beta-cell transcription factor pancreatic duodenal homeobox-

1 protein Transactivates the epidermal growth factor receptor Up regulates glucokinase and glucose transporter-2 Inhibiting beta cell apoptosis

Delta Cell: Stimulates somatostatin secretion. Alpha Cell: Inhibits glucagon secretion in T1 and T2 DM depending on glucose

levels. Probably mediated by paracrine effects via insulin or beta cell product, since

no GLP-1 receptors on the alpha cell.

Extrapancreatic Effects of GLP-1

Stomach: Decreases gastric acid secretion, delays gastric emptying and motility, which helps to spread

glucose absorption out over time, and thus limit hyperglycemia. Neurally mediated central vagal stimulation.

CNS: GLP-1 from L-cells and CNS increases satiety. GLP-1 crosses BBB

Muscle: Increases glucose uptake, glycogen synthase a activity.

Liver: Decreases glucose production Stimulates glycogen synthase a activity

Adipocyte Stimulates glucose uptake, lipogenesis

Cardiovascular Improves LVEF post MI (Nickolaides et al, 2004) Improves endothelial dysfunction in pts with T2DM with CAD (Nystrom 2004) Cardioprotective effects against ischemia

Metformin: decreases hepatic glucose production, decreases GI glucose absorption and increases glucose

uptake by fat and muscle.

W.B.: 54 yo sero (-) T2DM 12/08/09

12/08/09: 295 # Met 500 mg bid Lantus 90 U/d Glu 177, A1C 10.2 C-pep 3 ng/ml, 24 h

UFC (-), IgF1 (-) GAD, IAA (-) Microalbuminuria

12/22/09: Met 1000 bid Lantus 85 U/d Novolog 1/10 g CCF,

1/25 mg/dl >100 Byetta 5 mcg sq bid

Labs

Stopping Lantus

Stopping Novolog

Investigational Agonists

Subcutaneous injection

Subcutaneous injection

Subcutaneous injection

Subcutaneous injection

Subcutaneous injection

AdministrationAgentBase

Peptide/Protract. Mechanism

Half-Life/Dosing Frequencya

Development Status

Exenatide QW Exendin-4 • Microsphere with biodegrad. polymer

> 1 week1X weekly FDA review

AlbiglutideGLP-1 • Dimer• Bound to albumin• DPP-4 site AA subst.

6-8 days≤ 1X weekly Phase 3 trials

TaspoglutideGLP-1• Sustained-release• DPP-4 site AA subst.

• NEP site AA subst.

≈ 6-7 days≤ 1X weekly Phase 3 trials

LY2189265GLP-1• DPP-4-protected• IgG4-Fc-linked

≈ 4 days1X weekly Phase 3 trials

Lixisenatide Exendin-4• 6 C-terminal lysines

2.7 - 4.3 hours1X daily Phase 3 trials

GLP-1 RAs AEs (% of Pts)

• Nausea– LEAD-6 Study: Lira vs Exn bid: 25.5 vs 28%

– DURATION-5: Exn bid vs Exn qW: 14 vs 35%– T-EMERGE-2: Taspo 20 vs Exn bid: 47 vs 30%

• Vomiting– LEAD-6 Study: Lira vs Exn bid: 6 vs 9.9%

– T-EMERGE: Taspo 20 vs Exn bid: 23 vs 11%

• Antibody Formation– LEAD-6 Study: Lira vs Exn bid: 2.6 vs 61.1%

GLP-1 AEs cont.• Pancreatitis

– Wide baseline incidence: 4.21-45.33/100,000 annual incidence rates for first attack

– Diabetics have a 3 fold increased incidence

– Post marketing incidence in 2007 with Exenatide 27/100,000 pt-yrs

– Liraglutide 7 cases pancreatitis/4257 pts a.c.t. 1/2381 in comparator group

• Elevation in Calcitonin– Thyroid C-cell responsiveness to GLP-1 RAs are species specific and

appear to activate rodent but not human C-cells

– 2 yrs of liraglutide exposure no change in CT levels vs comparator

• Hypoglycemia– Does not inhibit counter-regulatory response of glucagon

T1DM and T2DM