"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
JAMA Jan 16, 2002
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, 2001
Prevalence of The Met Syn : US Adults
45
Men
Prevalence (%)
40
Women
35
30
25
20
15
10
5
0
20–29
30–39
40–49
50–59
Age (years)
Ford ES, et al. JAMA. 2002;287:356-359.
60–69
70
Prevalence Rates (%) of Insulin Resistance
in Selected Metabolic Disorders
Bonora E, et al. Diabetes 1998;47:164349
Met Syn: Survival Curves
Cardiovascular Disease
Mortality
Coronary Heart Disease Mortality
20
All Cause Mortality
20
Cumulative Hazard (%)
20
15
15
15
RR (95% CI), 3.55 (1.96-6.43)
RR (95% CI), 3.77 (1.74-8.17)
10
10
5
5
0
0
2
0
4
8 10
6
Follow-up, Y
12
834
234
292
100
10
5
0
2
0
No. at Risk
Metabolic Syndrome
Yes
No
866
288
852
279
Metabolic Syndrome:
RR (95% CI), 2.43 (1.64-3.61)
866
288
8
6
4
Follow-up, Y
852
279
Yes
Lakka H-M, et al. JAMA. 2002;288:2709-2716.
834
234
No
10
12
0
2
4
6
8
10
12
Follow-up, Y
292
100
866
288
852
279
834
234
292
100
UKPDS: -Cell Loss Over Time
-Cell Function (%)*
100
75
Patients treated
with insulin,
metformin,
sulfonylureas‡
50
25
IGT†
0
-12 -10
Type 2
Postprandial
Hyperglycemia Diabetes
Phase I
-6
-2
0
Type 2
Diabetes
Phase II
2
6
Type 2 Diabetes
Phase III
10
Years From Diagnosis
*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.
14
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.
Incretin Effect: Amplification of the Beta-cell
Response to Oral vs IV Glucose Challenge
Oral Glucose
IV Glucose
2.0
*
C-Peptide (nmol/L)
Venous Plasma Glucose (mmol/L)
11
5.5
1.5
*
*
*
Incretin Effect
*
1.0
*
*
0.5
0.0
0
01 02
60
120
Time (min)
180
01 02
60
120
Time (min)
180
Mean ± SE; N=6; *P0.05; 01-02=glucose infusion time
Nauck. J Clin Endocrinol Metab. 1986;63:492. Copyright 1986, The Endocrine Society.
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
• 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
©2006, ICHE
Nauck. Diabetologia. 1986;29:46.
Incretin Effect Reduced in T2DM
Compared With NGT
38.9
40
34.7
Insulin
(mmol/L/min)
35
30
23.5
25
20
15
11.3
10
5
0
Glucose:
©2006, ICHE
NGT
T2DM
Oral (50 g)
IV (isoglycemic infusion)
Incretin
Effect
Contributions of Incretin Factors (%)
-Cell Secretory
Response
NGT=normal glucose tolerance
80
72.8
70
60
50
30.0
40
30
20
10
0
NGT
T2DM
Nauck. Diabetologia. 1986;29:46.
GLP-1 Secretion Impaired in T2DM
GLP-1 (pmol/L)
20
15
Breakfast
*
*
*
*
NGT
IGT
T2DM
*
*
*
10
5
*
0
0
60
*P<0.05 vs T2DM
NGT=normal glucose tolerance
IGT=impaired glucose tolerance
©2006, ICHE
120
180
240
Time (min)
Toft-Nielsen. J Clin Endocrinol Metab.
2001;86:3717; with permission.
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
Change in Weight
0
-0.2
-0.4
-0.6
After 30 wk
-0.8
After 82 wk
-1
-1.2
-1.4
Change From Baseline (kg)
Change From Baseline (%)
Change in A1C
0
-1
-2
After 30 wk
-3
After 82 wk
-4
-5
-6
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:



CNS:




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


GLP-1 from L-cells and CNS increases satiety.
GLP-1 crosses BBB
Muscle:


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.
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
Agent
Base
Peptide/Protract.
Mechanism
Half-Life/Dosing
Frequencya
Administration
Development
Status
Exenatide QW
Exendin-4
• Microsphere with
biodegrad. polymer
> 1 week
1X weekly
Subcutaneous
injection
FDA review
Albiglutide
GLP-1
• Dimer
• Bound to albumin
• DPP-4 site AA
subst.
6-8 days
≤ 1X weekly
Subcutaneous
injection
Phase 3 trials
Taspoglutide
GLP-1
• Sustained-release
• DPP-4 site AA
subst.
• NEP site AA subst.
≈ 6-7 days
≤ 1X weekly
Subcutaneous
injection
Phase 3 trials
≈ 4 days
1X weekly
Subcutaneous
injection
Phase 3 trials
2.7 - 4.3 hours
1X daily
Subcutaneous
injection
Phase 3 trials
LY2189265
Lixisenatide
GLP-1
• DPP-4-protected
• IgG4-Fc-linked
Exendin-4
• 6 C-terminal lysines
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
–
•
–
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
–
–
•
Wide baseline incidence: 4.21-45.33/100,000 annual incidence rates for
first attack
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