Transcript 0 2
"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.
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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; *P0.05; 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