GLP-1 Receptor Agonists
ADEA CASE SERIES
Merlin ThomasGary KilovNicole Frayne Giuliana Murfet
Facilitator: Rachel McKeown,Professional Services Manager, ADEA (NSW)
Motivated/adherentGood self-careShort durationLow hypo riskLong life expectancy No co-morbidityGood resources
Non-compliantPoor self-careLongstanding
High hypo riskShort life expectancy
Co-morbidityLimited resources
<7 COMPROMISETARGET
Adapted from Inzucchi et al Diabetes Care 2012
The right target...
Motivated/adherentGood self-careShort durationLow hypo riskLong life expectancy No co-morbidityGood resources
Non-compliantPoor self-careLongstanding
High hypo riskShort life expectancy
Co-morbidityLimited resources
Standard ?Adapted from Inzucchi et al Diabetes Care 2012
….with the right agent
How does GLP-1 lower glucose levels in diabetes?
1. BACKGROUND
α
β
Incretins in -cell biology3,4
L
MEAL
GLPRGLP-1
Distal small intestine ileum and colon
Pancreas
• Amplified insulin secretion
• Improved glucose sensitivity
• -cell proliferation/neogenesis
• Reduced -cell apoptosis
3. Campbell & Drucker. Cell Metabolism (2013); 4. Diakogiannaki, et al. Physiol. Behav. (2012).
carbohydrate protein, fatty &
bile acids
vagal
Up to 70% of total post-prandial insulin production is determined by incretins
The effect and contribution varies with the size of the glucose challenge / the meal composition
vagal
AMPLIFIER
SIGNAL AMPLIFICATION OUTPUT
GLUCOSE GLP-1 increasedFOOD AMPLIFICATION INSULIN*
(incret-ins) of glucose/meal-stimulatedinsulin secretion
Incretins regulate a proportional response
What happens to theincretin effect in diabetes?
As a consequence of hyperglycaemia and/or other metabolic manifestations of diabetes itself incretin effect is reduced by ~50% in diabetes8
Normal secretion of GLP-1, but.. Down-regulation of GLP-1 receptor8
Less substrate to act on (β-cells, δ-cells, etc) Gastroparesis8
Resistance to GLP-1 (which needs pharmacological doses to overcome it)8,10
8. Nauck et al. Diabetologia (2013); 9. De Frionzo Diabetes (2009) 10. Vilsbøll T, et al. Diabetologia. (2002)
AMPLIFIER
NO SIGNAL AMPLIFICATION NO OUTPUT
No GLUCOSE NO MORENO FOOD INSULIN GLP1
Incretins and hypoglycaemia
Reduced risk of hypoglycaemia
No increase in insulin when glucose levels are low during a
continuous infusion of GLP-11
7. Nauck et al. JCEM (2002)
What happens to -cells in diabetes?
8. Defronzo. Diabetes (2009)
Diabetes is associated with the blunting of hyperglycaemia or postprandial suppression of glucagon secretion
Reduced incretin effect Hyperplasia of -cells Increased sensitivity to glucagon
Contributes to the inappropriately increased rate of hepatic glucose output characteristic of T2DM
=ALPHA CELL ANARCHY
α
β
GLP-1 in -cell biology3,4
L
MEAL
carbohydrate protein, fatty &
bile acids
GLPRGLP1
Distal small intestine ileum and colon
Pancreas
• Augmented suppression of glucagon release
• Partly via increased insulin
• Partly via somatostatin (?)
3. Campbell & Drucker. Cell Metabolism (2013); 4. Diakogiannaki, et al. Physiol. Behav. (2012).
vagal
vagal
No impairment of glucagon response (which protects against hypoglycaemia)
during an infusion of GLP-1
7. Nauck et al. JCEM (2002)
ControlGLP-1
Incretins in the stomach
L
MEAL
GLPRGLP1
Distal small intestine ileum and colon
Stomach
11. Shah & Vella Rev Endocr Metab Disord (2014); 12. Marathe et al. Diabetes Care (2013)
carbohydrate protein, fatty &
bile acids
FULL
vagal afferents
Reduced gut motility Delayed stomach emptying Delayed digestion and
absorption of carbohydrates2
Exenatide slows emptying of the stomach as measured by the half-life of a 99TC -labelled meal13
13. Linnebjerg et al. Regl Pept (2008)
Placebo Exenatide (5µg) Exenatide (10µg)0
1
2
3
4
5
6
T(50
) h o
f lab
elle
d m
eal
*
*
L
MEAL
GLPRGLP1
Distal small intestine ileum and colon
brain
Enhanced glucose disposal Increased satiety/fullness Reduced appetite Reduced food intake
2. Campbell & Drucker. Cell Metabolism (2013); 11. Shah & Vella Reviews in Endocrine and Metabolic Disorders (2014)
carbohydrate protein, fatty &
bile acidsvagal
Incretins in the brain
Incretin biology and DPP4
L
MEAL
GLPRGLP1
Distal small intestine ileum and colon
2. Campbell & Drucker. Cell Metabolism (2013);
carbohydrate protein, fatty &
bile acids
vagal
• Pancreas
• Stomach
• Liver
• Brain
DPP4
Short circulating half life (<2 min)
Resistant to DPP4
GLP1 has a 1-4 min half-life (designed for grazing?)
GLP1 (amidated form)
Rationale for GLP analoges1,2
DPP4
EXENATIDE
plasma half-life of 2.4 hours and an action time of about 6-8 hours
The Gila monster
“I want some of that (adaptation) for my patients”
From Lizard Saliva to Diabetes Drug
All lower the HbA1c by approximately the same amount when added-on metformin40 RCT (n=17795): 6-12 months trials, added-on after MFM failure
McIntosh B et al. Open Med 2011; 5:E35-E48
Series1
-1
-0.5
0
0.5
+0.1 +0.1+0.2
-0.4*-0.5
† -0.6‡
-0.8*-0.9†
-0.8‡
Exenitide lowers HbA1cin both dual and triple therapy
N 113 110 113
Baseline 8.2 8.3 8.2
123 125 129
8.7 8.5 8.6
247 245 241
8.5 8.5 8.5
Ch
an
ge
in
Hb
A1c
*P<0.001 vs placebo †P<0.0002 vs placebo
30-week data; mean .
Placebo BID Exenatide 5 μg BID Exenatide 10 μg BID
‡P<0.0001 vs placebo
1. DeFronzo RA ,et al. Diabetes Care 2005;28:1092–100. 2. Buse JB, et al. Diabetes Care 2004;27:2628–35. 3. Kendall DM, et al. Diabetes Care 2005;28:1083–91.
Pivotal phase 3 clinical studies—combined intent-to-treat (ITT)
MET1 SU2 MET + SU3
Exenatide was as effective as insulin at lowering HbA1c
Abbreviations: BL, baseline; MET, metformin, SU, sulphonylurea; TZD, thiazolidinedione
1. Nauck MA, et al. Diabetologia 2007; 50(2): 259–67. 2. Heine RJ, et al. Ann Intern Med 2005; 143(8): 559–69. 3. Barnett AH, et al. Clin Ther 2007; 29(11): 2333–48. 4. Davies MJ, et al. Diabetes Obes Metab 2009; 11(12): 1153–62. 5. Bunck MC, et al. Diabetes Care 2009; 32(5): 762–8.
Primary endpoint: Change in HbA1c (%)
Series1
-1.5
-1
-0.5
0
-1.0%-1.1%
-1.4% -1.3%
-0.8%-0.9%
-1.1%
-1.4% -1.3%
-0.7%
MET + SU1MET, SU, TZD
(combination of 2 or 3)4
n=253BL=8.6%
n=248BL=8.6%
n=275BL=8.2%
n=260BL=8.3%
N=68BL= 8.9%
n=118BL= 8.7%
n=116BL=8.5%
n=36BL= 7.6%
n=33BL= 7.4%
exenatide 10 µg BID plus orals Insulin aspart 70/30 Insulin glargine
Background
Ch
an
ge
in H
bA
1c
N=70BL= 9%
52 weeksMET + SU2
26 weeksMET or SU3
16 weeks 26 weeksMET5
52 weeks
Starting GLP-1R agonistsCASE#1
Laboratory parameters HbA1c 7.9% Total cholesterol: 3.8 mmol/L Normal albuminuria and
eGFR
Graham presents to his GPPatient history• Age 50 years• Married, 3 children• Works as a taxi driver• BP 132/85 mmHg• BMI 30 kg/m2
• Non-smoker• Diet and exercise not optimal
Medical history• Diabetes diagnosed 18 months ago
• Dyslipidaemia and hypertension diagnosed 3 years ago
Graham, aged 50
Current Medications• Metformin 1500 mg/day• Rosuvastatin 20 mg/day• Telmisartan/hydrochlorothiazide
80/12.5 mg fixed dose combination
What are Graham’s treatment priorities?
Weight Sustainability
No HYPO
Lower HbA1c
CVD Risk
Compliance
Tolerability Cost
What are Graham’s treatment priorities?
Sustainability
No HYPO
Lower HbA1c
CVD Risk
Compliance
Weight
Cost
Question 1. How well will he tolerate an GLP-1R agonist?
Tolerability
Common side effectsNausea (20-30%)
Vomiting (~10%)
Diarrhoea (~10%)
Injection site reactions
(10-20%)
Nausea and vomiting with exenatide
Exenatide Exenatide LAR
attenuates slowly (weeks to months) attenuates rapidly (4-8 weeks)
30
Tricks for tolerability
• Cautious dose escalation 5µg bd to 10µg bd
• Reducing the size as well as the fat content of meals can sometimes help get patients through.
• Although exenatide can be injected at any time within 60 minutes of meal, starting off at ~15 minutes prior meal and slowly extending this depending on tolerability can also help. Question 1a. What other tricks do you
have?
What are Graham’s treatment priorities?
Weight Sustainability
No HYPO
Lower HbA1c
CVD Risk
Compliance
Tolerability Cost
Question 2. What about driving on a GLP-1RA?
Meta-analysis: Overall hypoglycemia
for medications added-on metformin34 RCT (n=16704): 6-12 months trials, added-on after metformin failure
McIntosh B et al. Open Med 2011; 5:E35-E48
33
GLP-1 actions on the β cell are normally tightly coupled to the level
of ambient glucose. The insulinotropic actions of GLP-1 are rapidly terminated once the plasma glucose falls into the normal range
7 6 5 4 3 2 1
GLP1 doesn’t cause hypoglycemia
34
Closer to the edge, reduced food intake as well as
uncoupling of GLP-1 from its glucose dependence by
sulphonylureas
But they do make it easier for SUs to cause hypoglycemia
7 6 5 4 3 2 1
GLP-1RA
35
Byetta added to metformin does not increase the risk of hypoglycaemia; with
SU consider dose reduction
0
10
20
30
40
EX + SU + MET3
(n=733; ITT population)
EX + SU1
(n=337; ITT population)
EX + MET2
(n=336; ITT population)
Inci
den
ce o
f h
ypo
gly
caem
ia (
%)
3%
14%
36%
13%
19%
28%
5% 5%
Placebo
30-Week, randomised, placebo-controlledExenatide 5 g
5%
Exenatide 10 g
1. Buse JB, et al. Diabetes Care. 2004; 27: 2628–35. 2. DeFronzo RA, et al. Diabetes Care. 2005; 28: 109–100. 3. Kendall DM, et al. Diabetes Care. 2005; 28: 1083–91.
De Heer et al Diabetes 2007
GLP-1 in the presence of a sulfonylurea agent leads to enhanced insulin secretion
and suppressed glucagon even at normal or low glucose concentrations
GLP1
control
What are Graham’s treatment priorities?
Sustainability
No HYPO
Lower HbA1c
CVD Risk
Compliance
Tolerability Cost
Question 3. How will GLP-1R agonist affect his weight?
Weight Loss
Meta-analysis: Body weight change
for medications added-on metformin30 RCT (n=15265): 6-12 months trials, added-on after MFM failure
McIntosh B et al. Open Med 2011; 5:E35-E48
Exenatide 10 μg BID provided long-term glycaemic control without weight gain over 156 weeks*†
Changes in body weight1
-1
-2
-3
-4
-5
-6
-7
-8
-9
-10
0 26 52 78 104 130 156
‡P<0.0001
Mean baseline body weight: 99 ± 18 kg
reduction from baseline
-1.6 kgat week 12
reduction from baseline
-5.3 kgat 3 years
N=217
Ch
an
ge
in
bo
dy
we
igh
t (k
g)
Treatment (weeks)
*Of 527 subjects, 217 completed 156 weeks of the study, of which 84% lost weight and 50% lost at least 5% of baseline body weight.1
†Exenatide is not indicated for the management of obesity, and weight change was a secondary endpoint in clinical trials.
• Weight loss >1.5 kg per week has been observed in patients treated with exenatide2
• Weight loss of this rate may have harmful consequences2
‡
1. Klonoff DC et al. Curr Med Res Opin 2008; 24: 275–86. 2. Byetta Approved Product information 17 September2012 .
> 85% patients lose weight
Potential for weight loss with Exenatideversus weight gain with insulin glargine
-3
-2
-1
0
1
2
Insulin glargineExenatide
Chan
ge in
bod
y w
eigh
t (kg
)
0 2 4 8 12 18 26Insulin glargine n = 267 266 261 253 251 246 244Byetta n = 281 277 275 261 245 235 231
*P < 0.0001 compared with insulin glargine measure at the same time point.
Weeks
**
**
**
Adapted from Heine RJ, et al. Ann Intern Med 2005; 143(8): 559–69.
†Exenatide is not indicated for the management of obesity, and weight change was a secondary endpoint in clinical trials.
(Mean baseline body weight 87.5 kg)
(Mean baseline body weight 88.3 kg)
What are Graham’s treatment priorities?
Weight Sustainability
No HYPO
Lower HbA1c
CVD Risk
Compliance
Tolerability Cost
Q4. How well will an GLP-1RA keep working?
50 y.o.
42
Exhaustion (nike effect)Sustainability – the NIKE effect
Exenatide 10 μg BID provides sustained HbA1c reduction over 156 weeks*
Mean change in HbA1c from baseline10
9
8
7
6
5
4
3
2
1
0 26 52 78 104 130 156
†P<0.0001
Mean baseline HbA1c: 8.2%
reduction from baseline
-1.1%at week 12
reduction from baseline
-1.0%at 3 years
†
Me
an
Hb
A1c
(%
)
Treatment (weeks)
Adapted from Klonoff DC, et al. Curr Med Res Opin 2008; 24: 275–86.
*Of 527 subjects, 217 completed 156 weeks of the study, of which 46% achieved HbA1c of ≤7%.
N=217
44
Five-Year Efficacy and Safety Data of Exenatide Once Weekly
DURATION1. Mayo Clin Proc (2015)
What are Graham’s treatment priorities?
Weight Sustainability
No HYPO
Lower HbA1c
CVD Risk
Compliance
Tolerability Cost
Question 5. Will a GLP1RA protect his heart?
CV Outcomes and GLP-1RA
2015 20172016 2018 201920132012 2014
ELIXALixisenatide(N = 6000)
LEADERLiraglutide (N = 9341)
EXSCELExenatide (N = 9500)
REWINDDulaglutide (N = 9622)
SUSTAIN-6Semaglutide (N = 3260)
What are Graham’s treatment priorities?
Weight Sustainability
No HYPO
Lower HbA1c
Cost
Compliance
Tolerability
CVD risk
Question 5. Is it subsidised?
GLP-1RA in addition to insulin
CASE#2
Laboratory parameters HbA1c 8.2% Total cholesterol: 5.8 mmol/L eGFR 125 ml/min/1.73m2
Kevin presents to his GPPatient history• Age 50 years• BP 142/75 mmHg• BMI 37 kg/m2
• Non-smoker• Diet and exercise not optimal
Medical history• Diabetes diagnosed 5 years ago• Failed oral therapy
Now on insulin injections
• But control is still suboptimal
Kevinaged 50
Current Medications• Metformin 2g/day• Insulin 100U/day• Rosuvastatin 20 mg/day• Telmisartan/hydrochlorothiazide
80/12.5 mg fixed dose combination
What are Kevin’s treatment priorities?
Weight Sustainability
No HYPO
Lower HbA1c
CVD Risk
Compliance
Tolerability Cost
Q 6. How well will an GLP1RA work for Kevin(on top of his insulin regimen)?
Over the past 3 years, however, the effectiveness of combining GLP-1 receptor agonists (both
shorter-acting and newer weekly formulations) with basal insulin has been demonstrated, with most studies showing equal or slightly superior
efficacy to the addition of prandial insulin, and with weight loss and less hypoglycemia.
The available data now suggest that either a GLP-1 receptor agonist or prandial insulin could be used
in this setting, with the former arguably safer, at least for short-term outcomes
Inzucchi Diabetes (2015)
1. Buse JB, et al. Ann Intern Med 2011; 154: 103–12 ;
Exenatide lowers HbA1c when used in combination with basal insulin1
Exenatide
1. Buse JB, et al. Ann Intern Med 2011; 154: 103–12.;.
No increased risk of weight gain or hypoglycaemia when exenatide is added to basal insulin1,2**†
Change in weight* Minor hypoglycaemia
Exenatide
THANK YOU FOR YOUR PARTICIPATION
ADEA CASE SERIES
Merlin ThomasGary KilovNicole Frayne