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Michael Horowitz Discipline of Medicine, University of Adelaide and
Endocrine and Metabolic Unit , Royal Adelaide Hospital, Adelaide, South Australia
Differential properties of GLP-receptor agonists: The role of gastric emptying
Dualities of interest
• In the past 2 years Michael Horowitz has been a member of advisory boards and/or has acted as a Consultant for Sanofi-Aventis, Merck Sharpe and Dohme, Boehringer-Ingelheim, Novartis, Astra Zeneca/BMS and Satiogen, and has received honoraria for these activities.
GLB.DIA.14.04.84
‘Diabetes is a disease of the stomach’
Arataeus of Cappuducia (~AD80)
Monnier et al, Diabetes Care (2009)
Breakfast Lunch Dinner 0.00 4.00
Postprandial Postabsorptive Fasting
Duration of the postprandial, postabsorptive, and fasting states
Role of the gut in glycaemic control
GIP CCK
GLP-1 PYY
nutrient
satiation
insulin secretion
slow gastric emptying
Overview • measurement of gastric emptying • prevalence and determinants of
disordered gastric emptying and gastrointestinal symptoms in diabetes-impact of glycaemia
• effects of gastric emptying on glycaemia • effects of endogenous and exogenous
GLP-1 on gastric emptying • effects of GLP-1 agonists on gastric
emptying-relationship to glycaemia
Trituration Solid ‘Liquid’
Small intestine
Liquid
Emptying forces and
controls
Stomach
Chyme
20 s
50 ml.s-1
20 mlDuodenal outflow
Tran sp ylori c flow
Transpyloric flow
Malbert et al, J Physiol (1989)
Control of gastric emptying
+ _ •
• Myogenic • Neural • Humoral
Small intestinal receptors
Pacemaker
Measurement of gastric emptying before ethics committees
The Holy Roman Emperor, Frederick II (1193-1250) ordered two men to be fed a large meal and then sent one hunting and ordered the other to rest to determine under which condition ‘digestion’ is aided. Frederick had both men executed and disemboweled to discover that the stomach of the man who had rested was empty, while that of the man who had been hunting was full.
‘Under circumstances characterised by���hostility and resentment, we observed in ���Tom, and in other subjects, engorgement of���the gastric mucosa and enhanced contractile ���activity in the stomach’
Dr Stewart Wolf with longtime patient, Tom Little, at the Oklahoma Medical Research Foundation in 1956
Wolf S, Wolff SG, Human gastric function, New York; Oxford University Press (1943)
‘We need to learn to measure what we value, not value what we can easily measure’
(Marcus Aurelius AD 121-180)
Methods to assess gastric motor function
• scintigraphy • stable isotope breath tests • ultrasound • Smart Pill® • SPECT • MRI • absorption kinetics of oral drugs eg. paracetamol • radiology (barium studies / radiopaque markers) • intubation/aspiration
Gastric emptying
Manometry Electrogastrography
Gastric emptying in longstanding type 1 and type 2 diabetes
Horowitz et al, Eur J Nucl Med (1991)
0
20
40
60
80
100
0
10
20
30
40
50
60
70
P<0.001 P<0.02
Controls n = 25
Controls n =25
Diabetics n = 87
Diabetics n = 87
T50 (min)
Retention at 100 min (%)
Solid (100g minced beef)
Liquid (150ml 10% dextrose)
Solid gastric emptying measured with a carbon breath test in outpatients with type 1 and 2
diabetes (n=186)
Samsom et al, Diabetes Care (2003)
0
50
100
150
200
250
healthy volunteers
diabetic patients
T50 (min)
P<0.001
Chang et al, Diabetes Care (2012)
A 25 year (1985 – 2010) longitudinal evaluation of gastric emptying in diabetes (n=13)
r= 0.56, P<0.05 r= 0.82, P<0.01
Solid (100g minced beef)
Liquid (150mL 10% dextrose)
80
100
60
40
20
0 20 0 40 60 80 100
80
60
40
20
0 10 0 20 30 40 50
(% r
eten
tion
at 1
00 m
in)
T50
(min
)
Pathogenesis of disordered gastric emptying���in diabetes
extrinsic nerves enteric nerves Interstitial cells of Cajal smooth muscle immune cells
‘fixed’ pathological process reversible dysfunction induced by acute glycaemia
‘iv glucose suppresses gastric “hunger” contractions’
Stunkard and Wolff, J Clin Invest (1956)
0
2
4
6
8
10
0
2
4
6
8
10
Effect of hyperglycaemia (~15mmol/L) on gastric emptying in type 1 diabetes
Fraser et al, Diabetologia (1990)
Solid (100g ground beef)
Retention at 100 min
Liquid (150mL 10% dextrose)
50% emptying time
Euglycaemia Euglycaemia Hyperglycaemia Hyperglycaemia
Number of patients
with delayed gastric
emptying
Effect of acute hypoglycaemia (2.6 mmol/L) on gastric emptying in type 1 diabetes (n=20)
Retention (%)
Time (min)
Solid (100g minced beef)
Liquid (150ml water)
0
20
40
60
80
100
0 15 30 45 60 75 90 105 120 0
20
40
60
80
100
0 15 30 45 60 75 90 105 120
Euglycaemia Hypoglycaemia
* *
* *
*
*
* *
* * * # #
# P<0.05 * P<0.01
Russo et al, J Clin Endocrinol Metab (2005)
0
20
40
60
80
100
1 2 3
Effect of improved glycaemic control (~3 months) on gastric emptying in recently detected type 2 diabetes (n=30)
Laway et al, J Diabetes Complications (2013)
Gas
tric
em
ptyi
ng a
t 240
min
(%)
Healthy Controls
n = 20
HbA1c 4.5 ± 0.1%
Diabetes – Euglycaemia
n = 30
HbA1c 5.0 ± 0.1%
Diabetes – Hyperglycaemia
n = 30
HbA1c 10.5 ± 0.2%
P<0.001
Prevalence of upper gastrointestinal symptoms in type 1 diabetes
loss of appetite early satiation postprandial fullness nausea abdominal distension vomiting
Diabetic patients (%) 16.3 26.8 18.6 22.7 42.3 12.2
Control subjects (%) 3.6 6.1 8.5 9.1 24.4 3.0
P-value
<0.001 <0.001 <0.05 <0.01 <0.01 <0.01
Schvarcz et al, Diabet Med (1996)
0
2
4
6
8
1 0
1 2
1 4
1 6
0 2 0 4 0 6 0 8 0 1 0 0 1 2 0
r=0.32, P<0.005 Number of upper
gastrointestinal symptoms
Jones et al, J Nucl Med (1995)
Relationship between upper gastrointestinal symptoms and gastric emptying of solid in
longstanding type 1 and type 2 diabetes
Solid retention at 100 min (%)
Upper gastrointestinal symptoms in diabetes
• occur frequently • affect quality of life adversely • pathogenesis poorly defined
- disordered motor/sensory function - gastric dysrhythmias - glycaemic control - autonomic/enteric neuropathy - psychiatric comorbidity
• gastric emptying should be measured using scintigraphy or a breath test
• there is a large inter- (1-4 kcal/min), but smaller intra-individual, variation in gastric emptying
• gastric emptying is delayed in 30 - 50% of patients with long-standing type 1 or 2 diabetes (usually modestly) and is occasionally abnormally rapid
• the pathogenesis of gastroparesis is heterogeneous • gastric emptying is slower during acute hyperglycaemia
and accelerated by insulin-induced hypoglycaemia • improved glycaemic control may normalise gastric
emptying • the relationship of upper gastrointestinal symptoms with
the rate of gastric emptying is weak
Relationship between glycaemic response and ���gastric emptying (75g glucose) in normal subjects
Horowitz et al, Diabetologia (1993)
r = 0.65, p <0.01
% emptied at 30 min
AUC glucose 0-30 min
403020100140
160
180
200
220
240
260
n = 16
r = 0.60 p < 0.01
AUC glucose 0-60 min
% emptied at 60 min
3 0 0
4 0 0
5 0 0
6 0 0
7 0 0
8 0 0
9 0 0
1 0 0 0
0 1 0 2 0 3 0 4 0 5 0 6 0
Relationship between glycaemic response and gastric emptying (75g glucose) in type 2 diabetes
Jones et al, J Nucl Med (1996)
Gonlachanvit et al, Dig Dis Sci (2003)
150
200
250
300
350
100
● ●
●
● ● ● ●
●
●
● ● ●
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● ● ● ● ● ● ● ●
● ● ●
● ●
0 120 180 240 300 60
* *
*
*
* * *
** ●
0 120 60 180 240 300
20
40
60
80
100
0
● ● ● ● ● ● ● ● ● ●
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* * * *
* * * *
*
** **
** ** **
* * * ●
● ● ● ● ● ● ● ●
● ● ● ● ● ●
●
● ● ● ● ● ●
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●
● ● ● ● ● ● ● ●
0 120 60 180 240 300 0
20
40
60
80
100 ●
* *
* * * * * *
** ** ** ** **
** **
** **
Effects of erythromycin (200 mg iv) and morphine (8 mg iv) on solid and liquid gastric emptying and
blood glucose in type 2 diabetes (n=9)
Retention (%)
Retention (%)
mg/dl
Solid GE Liquid GE Blood glucose Placebo Erythromycin Morphine
Time (min)
* P < 0.05 vs Placebo ** P < 0.01 vs Placebo
• gastric emptying is a major determinant of postprandial glycaemia in health and type 2 diabetes
• slowing gastric emptying decreases postprandial glycaemic excursions in health and (non insulin-treated) type 2 diabetes
Relationship between alcohol absorption ���and gastric emptying
AU
C b
lood
alc
ohol
(mg
100m
l-1 m
in)
Liquid emptying at 60 min (%)
Horowitz et al, Am J Physiol (1989)
Liquid immediately after solid Liquid alone Liquid 90 min after solid
The confounder- GLP-1 slows ���gastric emptying
4
6
8
10
12
0 30 60 90 120 150 1800
20
40
60
80
100
0 30 60 90 120 150 180
Effects of exendin(9-39) on gastric emptying and glycaemia in healthy subjects (n = 10)
Ret
entio
n (%
)
Time (min)
P = 0.03
mm
ol/l
Exendin Placebo
4
6
8
10
12
-30 0 30 60 90 120150 180
BSL PLAC
BSL EX
Gastric emptying Blood glucose
P < 0.005
Deane et al, J Clin Endocrinol Metab (2010)
4
6
8
10
12
-30 0 30 60 90 120150 180
BSL PLAC
BSL EX
Effect of exogenous GLP-1 on gastric emptying in healthy young subjects (n = 10)
* #
* # *
# * # *
# * # *
# * 100
75
50
25
0 0 15 30 45 60 75 105 90 120 0 15 30 45 60 75 105 90 120
Retention (%)
* * * * * *
#
Time (min)
Solid (100 g minced beef)
Liquid (150 ml 10 % dextrose)
Saline GLP-1 [0.3] GLP-1 [0.9]
* GLP-1 [0.3] and [0.9] vs. control: P < 0.05 # GLP-1 [0.3] vs. GLP-1 [0.9]: P < 0.05
100
75
50
25
0
Little et al, J Clin Endocrinol Metab (2006)
*
# *
* *
*
*
-45 105 90 75 60 45 30 15 0 -15 -30 120 Time (min)
4
5
6
7
8
mmol/l
90 60 30 0 -30 120 10 20 30 40 50 60 70
mU/l # *
*
Blood glucose Plasma insulin
Effect of exogenous GLP-1 on blood glucose and plasma insulin in healthy young subjects (n = 10)
* GLP-1 [0.3] and [0.9] vs. control: P < 0.05 # GLP-1 [0.3] vs. GLP-1 [0.9]: P < 0.05
Saline GLP-1 [0.3] GLP-1 [0.9]
Little et al, J Clin Endocrinol Metab (2006)
GLP-1 slows gastric emptying in the critically ill* when emptying is‘normal’but not when it is delayed
Deane et al, Crit Care Med (2010)
‘normal’ gastric
emptying (n=14)
*
delayed gastric
emptying (n=11)
Gastric emptying coefficient
*P < 0.01
More rapid emptying
Slower emptying
*Non-diabetic patients admitted to intensive care, mechanically ventilated
Hypo – GLP-1
Hypo – Placebo Retention
(%)
Time (min)
GLP-1(1.2 pmol/kg/min iv) attenuates the acceleration of gastric emptying by hypoglycaemia
in healthy subjects (n=10)
Eu – GLP-1 Hypo – GLP-1
Hypo – Placebo Eu - Placebo
BGL 2.6 mmol/L
Plummer et al, Diabetes Care (2014)
There is tachyphylaxis to the effect of GLP-1 on gastric emptying with
sustained exposure
Placebo Acute GLP-1 Intermittent GLP-1
Scintigraphy Scintigraphy
-30 min 4 hours 23.5 hours 28 hours
GLP-1 Placebo
Scintigraphy
-30 min 4 hours 23.5 hours 28 hours Prolonged
GLP-1
Regimen A
Regimen B
642 kcal meal
642 kcal meal
642 kcal meal
Scintigraphy
642 kcal meal
Protocol
Umapathysivam et al, Diabetes (2013)
0
10
20
30
40
50
60
70
80
90
100
0 30 60 90 120 150 180 210 240
Intragastric retention
(%)
Time (min) 642 kcal
meal
Effects of prolonged and intermittent GLP-1 (0.8pmol/kg/min iv) on gastric emptying in healthy males (n=10)
Umapathysivam et al, Diabetes (2013)
Acute GLP-1 Intermittent GLP-1 Prolonged GLP-1 Saline
0
50
100
150
200
250
300
350
400
Placebo Acute Prolonged Intermittent
Post
pran
dial
gly
caem
ia
(mm
ol/L
.60)
Effects of prolonged and intermittent GLP-1 (0.8pmol/kg/min iv) on postprandial glycaemia (AUC0-60) in healthy males (n=10)
*
#P=0.007
Umapathysivam et al, Diabetes (2013)
*P=0.001
• endogenous GLP-1 slows gastric emptying and thereby glucose absorption
• inhibition of gastric emptying by acute administration of exogenous GLP-1 outweighs its insulinotropic effects
• the reduction in postprandial glycaemia by exogenous
GLP-1 is related to slowing of gastric emptying and greater when gastric emptying is relatively more rapid
• exogenous GLP-1 attenuates the acceleration of gastric emptying by hypoglycaemia
• there is tachyphylaxis to the slowing of gastric
emptying by exogenous GLP-1 with sustained exposure
Currently available GLP-1 receptor agonists and compounds in late stage development
Product Generic name Company Dosing Phase
Byetta Exenatide Amylin/Lilly Twice daily Marketed
Victoza Liraglutide Novo Nordisk Once daily Marketed
Bydureon Exenatide-LAR Amylin/Lilly Once weekly Marketed
Lyxumia Lixisenatide Zealand Pharma/Sanofi-Aventis Once daily Marketed
Eperzan Albiglutide GlaxoSmithKline Once weekly EU and US
approval In Q1-2014
LY2189265 Dulaglutide Eli Lilly Once weekly Phase III
NN9535 Semaglutide Novo Nordisk Once weekly Phase II
GLP-1 receptor agonists exhibit differences in their effects on pre- and postprandial glucose • short-acting-‘prandial’ • long-acting-‘non-prandial’
Differentiation of GLP-1 RAs
Parameters Short-acting prandial Long-acting Compounds Exenatide, Lixisenatide Albiglutide, Dulaglutide,
Exenatide-LAR, Liraglutide
Half-life 2-5h 12h-several days
Effects Gastric emptying Marked slowing Minimal effect Fasting blood glucose Modest reduction Marked reduction Post-prandial glucose Marked reduction Modest reduction Fasting insulin Modest stimulation Marked stimulation Post-prandial insulin Reduction Modest stimulation
Glucagon Reduction Reduction
Adapted from Meier et al, Nat Rev Endocrinol (2012)
10µg exenatide 5µg exenatide Placebo
0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 11 12
Residual Activity
(%)
Time (h)
Exenatide bd dose-dependently slows solid gastric emptying in type 2 diabetes (n = 16)
Linnebjerg et al, Regul Pept (2008)
0
1
2
3
4
5
6
30 40 50 60 70 80 90 100 110 120
The magnitude of the effect of exenatide (10µg sc bd) on gastric emptying in type 2 diabetes is dependent on the
rate of gastric emptying on placebo
Rat
io T
50 (1
0µg
exen
atid
e/pl
aceb
o)
Placebo T50 (min)
r= -0.51, P<0.05
Linnebjerg et al, Regul Pept (2008)
Linnebjerg et al, Regul Pept (2008)
Effects of exenatide LAR and exenatide bd on paracetamol absorption in type 2 diabetes (n=51)
AUC (µg min/mL)
Exenatide once a week (LAR) Exenatide bd
Time (min) Time (min) 50 100 150 200 250 300 50 100 150 200 250 300
Baseline Week 14
Drucker et al, Lancet (2008)
0 0
AUC (µg min/mL)
Effect of liraglutide on paracetamol absorption (AUC 0-1h) in type 2 diabetes (n=18)
Flint et al, Adv Ther (2011)
1 week 2 weeks 3 weeks 0.6mg 1.2mg 1.8mg
* *
µg min/mL
Effect of lixisenatide (~20µg) on gastric emptying in type 2 diabetes
Lixisenatide QD (n=17) Placebo (n=17)
Change in gastric emptying from baseline to Day 28
lag
(min
)
Lixisenatide BID (n=14)
-50
0
50
100
150
200
-100
-50
0
50
100
150
200
250
300
T50
(min
)
Lorenz et al, Regul Pept (2013)
Relationship between the effect of lixisenatide (20 µg QD) on blood glucose at day 28 with the change in
gastric emptying from baseline in type 2 diabetes (n=17)
Lorenz et al, Regul Pept (2013)
r= 0.71, P<0.05
Δ in gastric emptying T50 (h) 1 2 3 4 5
AU
C g
luco
se (m
g*h/
dl)
Comparative effects of lixisenatide (20µg) and liraglutide (1.8 mg) on postprandial glucose and
insulin in type 2 patients on metformin at 4 weeks
Glu
cose
(mg/
dl)
Day-1 Day-28
Meal 451 kcal
45 -30
0
30
60
270 210 180 120 90 60
90 P<0.0001
Kapitza et al, Diabetes Obes Metab (2013)
Insu
lin fr
ee (µ
IU/m
l)
0 0
40
60
70
270 210 90 30
50
30
20
60 150
Meal 451 kcal
Day-1 Day-28
Glucose* Insulin
P<0.0001
lixisenatide liraglutide
* 1° study endpoint,
• insulin therapy primarily targets pre-prandial glucose and causes hypoglycaemia and weight gain • some GLP-1 receptor agonists predominantly target
post-prandial glycaemia and their use is associated with a low risk of hypoglycaemia and weight loss • combined use of basal insulin with a GLP-1 agonist
may optimise glycaemic control with a lower risk of hypoglycaemia and weight gain
Combination of basal insulin and GLP-1 agonist in type 2 diabetes
Mea
n H
bA1c
(%)
Week Week 24 LOCF
8.6
8.4
8.2
8.0
7.8
7.6
7.4
7.2 0 4 8 12 16 20 24
8.1%
7.8%
Basal insulin ± MET + placebo (n = 158) Basal insulin ± MET + lixisenatide (n = 304)
Use of once daily lixisenatide in basal insulin treated patients with type 2 diabetes -
changes in HbA1c after 24 weeks - GetGoal-L
Riddle et al, Diabetes Care (2013)
P < 0.001
0
5
10
15
20
25
30
35
Comparative effects of lixisenatide and rapid-acting insulin as add-on to basal insulin in type 2 diabetes –
% of patients achieving HbA1c<7.0%, no weight gain and no symptomatic hypoglycaemia
Raccah et al, J Diabetes Complications
(2014) Basal + LIXI
(n=144) Basal + RAI
(n=144)
P<0.05 OR: 1.90; 95% CI: 1.01, 3.55
(%)
Meta-analysis of 5 randomised controlled trials
• GLP-1 agonists may slow gastric emptying markedly – the magnitude of this effect is dependent on the ‘baseline’ rate of gastric emptying
• the reduction in postprandial glycaemia and impact on postprandial insulin induced by GLP-1 agonists are related to the magnitude of slowing of gastric emptying
• the slowing of gastric emptying induced by liraglutide and exenatide LAR (and presumably other ‘long-acting’ GLP-1 agonists), but not exenatide and lixisenatide (‘short-acting’) diminishes markedly with time, reflecting the pharmacokinetic profile of GLP-1 receptor activation
• ‘baseline’ gastric emptying and the priority for reducing postprandial glucose excursions are likely to be relevant to the choice of GLP-1 agonist in type 2 patients; ‘prandial’ drugs may be optimally combined with basal insulin