Transcript GC Forxiga Power Point Template - August 2013

ADEA CASE SERIES
Merlin Thomas
Gary Kilov
Nicole Frayne
Giuliana Murfet
Facilitator: Rachel McKeown,
Professional Services Manager, ADEA (NSW)
The right target...
Motivated/adherent
Good self-care
Short duration
Low hypo risk
Long life expectancy
No co-morbidity
Good resources
<7
Non-compliant
Poor self-care
Longstanding
High hypo risk
Short life expectancy
Co-morbidity
Limited resources
COMPROMISE
TARGET
Adapted from Inzucchi et al Diabetes Care 2012
….with the right agent
Motivated/adherent
Good self-care
Short duration
Low hypo risk
Long life expectancy
No co-morbidity
Good resources
Non-compliant
Poor self-care
Longstanding
High hypo risk
Short life expectancy
Co-morbidity
Limited resources
Standard
Adapted from Inzucchi et al Diabetes Care 2012
?
1. BACKGROUND
How does GLP-1 lower
glucose levels in diabetes?
Incretins in -cell biology
3,4
MEAL
vagal
carbohydrate
protein, fatty &
bile acids
L
Distal small intestine
ileum and colon
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
Pancreas
vagal
GLP-1
GLPR
β
α
• 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).
SIGNAL
AMPLIFICATION
OUTPUT
AMPLIFIER
GLUCOSE
FOOD
GLP-1
AMPLIFICATION
of glucose/meal-stimulated
insulin secretion
increased
INSULIN*
(incret-ins)
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)
NO SIGNAL
AMPLIFICATION
NO OUTPUT
AMPLIFIER
No GLUCOSE
NO FOOD
GLP1
NO MORE
INSULIN
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)
-cells
 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
8. Defronzo. Diabetes (2009)
GLP-1 in -cell biology
3,4
MEAL
vagal
carbohydrate
protein, fatty &
bile acids
L
Distal small intestine
ileum and colon
vagal
Pancreas
GLP1
GLPR
β

α
• 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).
No impairment of glucagon response (which protects
against hypoglycaemia) during an infusion of GLP-1
Control
GLP-1
7. Nauck et al. JCEM (2002)
Incretins in the stomach
MEAL
carbohydrate
protein, fatty &
bile acids
Stomach
vagal afferents
L
Distal small intestine
ileum and colon
GLP1
GLPR



Reduced gut motility
Delayed stomach emptying
Delayed digestion and
absorption of carbohydrates2
11. Shah & Vella Rev Endocr Metab Disord (2014); 12. Marathe et al. Diabetes Care (2013)
Exenatide slows emptying of the stomach as
measured by the half-life of a 99TC -labelled meal13
T(50) h of labelled meal
6
*
5
*
4
3
2
1
0
Placebo
13. Linnebjerg et al. Regl Pept (2008)
Exenatide (5µg)
Exenatide (10µg)
Incretins in the brain
MEAL
carbohydrate
protein, fatty &
bile acids
L
brain
vagal
GLP1
GLPR
Distal small intestine
ileum and colon




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)
Incretin biology and DPP4
MEAL
vagal
carbohydrate
protein, fatty &
bile acids
Short circulating
half life (<2 min)
• Pancreas
• Stomach
L
GLP1
• Liver
• Brain
Distal small intestine
ileum and colon
DPP4
2. Campbell & Drucker. Cell Metabolism (2013);
GLPR
Rationale for GLP analoges
GLP1 (amidated form)
EXENATIDE
Resistant to DPP4
1,2
From Lizard Saliva to Diabetes Drug
“I want some of that (adaptation) for my patients”
All lower the HbA1c by approximately the
same amount when added-on metformin
40 RCT (n=17795): 6-12 months trials, added-on after MFM failure
McIntosh B et al. Open Med 2011; 5:E35-E48
Exenitide lowers HbA1cin both dual and triple therapy
0.5
MET1
MET + SU3
SU2
†P<0.0002
*P<0.001 vs placebo
+0.1
vs placebo
+0.2 ‡P<0.0001 vs placebo
+0.1
Change in HbA1c
0
-0.4
*
-0.5
-0.5
†
-0.8
*
-1
-0.6
‡
-0.8
‡
-0.9
†
N
113
110
113
123
125
129
247
245
241
Baseline
8.2
8.3
8.2
8.7
8.5
8.6
8.5
8.5
8.5
Placebo BID
30-week data; mean .
Exenatide 5 μg BID
Exenatide 10 μg BID
Pivotal phase 3 clinical studies—combined
intent-to-treat (ITT)
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.
Exenatide was as effective as insulin at lowering HbA1c
Primary endpoint: Change in HbA1c (%)
MET, SU, TZD
Background
Change in HbA1c
0
SU1
SU2
MET +
52 weeks
MET +
26 weeks
n=253
n=248
BL=8.6% BL=8.6%
n=275
n=260
BL=8.2% BL=8.3%
SU3
MET or
16 weeks
N=68
N=70
BL= 8.9% BL= 9%
(combination of 2 or 3)4
26 weeks
n=118
n=116
BL= 8.7% BL=8.5%
MET5
52 weeks
n=36
n=33
BL= 7.6% BL= 7.4%
-0.5
-0.8%
-1
-1.0%
-0.9%
-1.1%
-0.7%
-1.1%
-1.3%
-1.5
-1.3%
-1.4% -1.4%
exenatide 10 µg BID plus orals
Insulin aspart 70/30
Insulin glargine
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.
CASE#1
Starting GLP-1R agonists
Graham presents to his GP
Patient 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
Graham,
aged 50
Medical history
• Diabetes diagnosed 18 months ago
• Dyslipidaemia and hypertension
diagnosed 3 years ago
Laboratory parameters
HbA1c 7.9%
 Total cholesterol: 3.8 mmol/L
 Normal albuminuria and eGFR

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?
Compliance
Lower HbA1c
Weight
Sustainability
CVD Risk
No HYPO
Tolerability
Cost
What are Graham’s treatment priorities?
Compliance
Lower HbA1c
Weight
Sustainability
CVD Risk
No HYPO
Tolerability
Cost
Question 1. How well will he tolerate an GLP-1R agonist?
Nausea and vomiting with exenatide
Exenatide
attenuates slowly (weeks to months)
Exenatide LAR
attenuates rapidly (4-8 weeks)
• 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?
30
What are Graham’s treatment priorities?
Compliance
Lower HbA1c
Weight
Sustainability
CVD Risk
No HYPO
Tolerability
Cost
Question 2. What about driving on a GLP-1RA?
Meta-analysis: Overall hypoglycemia
for medications added-on metformin
34 RCT (n=16704): 6-12 months trials, added-on after metformin failure
McIntosh B et al. Open Med 2011; 5:E35-E48
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
33
P-1RA
Closer to the edge, reduced food
intake as well as uncoupling of
GLP-1 from its glucose
dependence by sulphonylureas
7 6 5 4 3 2 1
34
Placebo
30-Week, randomised, placebo-controlled
Incidence of
hypoglycaemia (%)
40
Exenatide 5 g
Exenatide 10 g
36%
28%
30
19%
20
14%
13%
10
5%
3%
5% 5%
0
EX + SU1
EX + MET2
EX + SU + MET3
(n=337; ITT
population)
(n=336; ITT
population)
(n=733; ITT
population)
35
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.
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
De Heer et al Diabetes 2007
What are Graham’s treatment priorities?
Compliance
Lower HbA1c
Weight Loss
Sustainability
CVD Risk
No HYPO
Tolerability
Cost
Question 3. How will GLP-1R agonist affect his weight?
Meta-analysis: Body weight change
for medications added-on metformin
30 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
Mean baseline body weight: 99 ± 18 kg
Change in body weight
(kg)
-3
reduction from baseline
-4
-1.6 kg
-5
at week 12
-6
reduction from baseline
‡
> 85% patients lose weight
-7
-5.3 kg
at 3 years
-8
-9
-10
‡P<0.0001
0
N=217
26
52
78
104
130
156
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 .
Potential for weight loss with Exenatide
versus weight gain with insulin glargine
Change in body weight (kg)
2
1
Insulin glargine (Mean baseline body weight 88.3 kg)
Exenatide (Mean baseline body weight 87.5 kg)
0
*
-1
*
*
-2
*
*
*
-3
Insulin glargine n =
Byetta
n=
0
2
4
8
12
18
26
267
281
266
277
261
275
253
261
251
245
246
235
244
231
Weeks
*P < 0.0001 compared with insulin glargine measure at the same time point.
†
Exenatide is not indicated for the management of obesity, and weight change was a secondary endpoint in clinical trials.
Adapted from Heine RJ, et al. Ann Intern Med 2005; 143(8): 559–69.
What are Graham’s treatment priorities?
Compliance
Lower HbA1c
Weight
Sustainability
CVD Risk
Tolerability
50 y.o.
No HYPO
Cost
Q4. How well will an GLP-1RA keep working?
Exhaustion (nike effect)
42
Exenatide 10 μg BID provides sustained
HbA1c reduction over 156 weeks*
Mean change in HbA1c from baseline
10
9
Mean baseline HbA1c: 8.2%
8
Mean HbA1c (%)
7
6
reduction from baseline
5
-1.1%
-1.0%†
at week 12
at 3 years
reduction from baseline
4
3
2
1
†P<0.0001
0
N=217
26
52
78
104
130
156
Treatment (weeks)
*Of 527 subjects, 217 completed 156 weeks of the study, of which 46% achieved HbA1c of ≤7%.
Adapted from Klonoff DC, et al. Curr Med Res Opin 2008; 24: 275–86.
44
DURATION1. Mayo Clin Proc (2015)
What are Graham’s treatment priorities?
Compliance
Lower HbA1c
Weight
Sustainability
CVD Risk
No HYPO
Tolerability
Cost
Question 5. Will a GLP1RA protect his heart?
SUSTAIN-6
Semaglutide
(N = 3260)
2012
2013
2014
2015
ELIXA
Lixisenatide
(N = 6000)
2016
LEADER
Liraglutide
(N = 9341)
2017
EXSCEL
Exenatide
(N = 9500)
2018
2019
REWIND
Dulaglutide
(N = 9622)
What are Graham’s treatment priorities?
Compliance
Lower HbA1c
Weight
Sustainability
CVD risk
No HYPO
Tolerability
Question 5. Is it subsidised?
Cost
CASE#2
GLP-1RA in
addition to insulin
Kevin presents to his GP
Patient history
•
•
•
•
•
Age 50 years
BP 142/75 mmHg
BMI 37 kg/m2
Non-smoker
Diet and exercise not optimal
Kevin
aged 50
Medical history
• Diabetes diagnosed 5 years ago
• Failed oral therapy
Now on insulin injections
• But control is still suboptimal
Laboratory parameters



HbA1c 8.2%
Total cholesterol: 5.8 mmol/L
eGFR 125 ml/min/1.73m2
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?
Compliance
Weight
Lower HbA1c
Sustainability
CVD Risk
No HYPO
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)
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
1. Buse JB, et al. Ann Intern Med 2011; 154: 103–12.;.
ADEA CASE SERIES
Merlin Thomas
Gary Kilov
Nicole Frayne