Nuovi approcci
alla terapia personalizzata
del paziente con diabete di tipo 2
Riccardo C. Bonadonna
Dipartimento di Medicina
Università di Verona e AOUI di Verona
Presenter Disclosure Information
Riccardo C. Bonadonna
Research Support: None
Speaker’s Bureau: Sanofi Aventis, MSD, BMS, Eli Lilly Ltd
Board Member/Advisory Panel: MSD, Eli Lilly Ltd, Amgen,
Sanofi Aventis
Stock/Shareholder: None
Consultant: None
Employee: None
Other: None
The position statement of ADA and EASD
• Individualisation of treatment is the
cornerstone of success
• Patient-centered care is…an approach to
“providing care that is respectful of and
responsive to individual preferences, needs,
and values and ensuring that patient values
guide all clinical decisions”
Inzucchi SE et al.; Diabetologia 2012
Alcuni bisogni di questo paziente
• Rieducazione nutrizionale
• Rieducazione motoria
• Tre cali:
– Peso
– Appetito
– Glicemia post-prandiale
• Limitare il rischio delle ipoglicemie
• Limitare il numero di iniezioni
Dipendenza
psicofisica
A
classification
of
GLP-1
RAs
Comparison of prandial vs. non-prandial GLP-1 receptor agonists
Parameters
Prandial GLP-1 Ras
Non-prandial GLP-1 Ras
(short-acting, exendin-4 derived)
(short-acting, GLP-1 derived*)
Exenatide, Lixisenatide
Albiglutide*, Dulaglutide*,
Exenatide-LAR, Liraglutide*
2-5h
12h-several days
Fasting blood glucose levels
Modest reduction
Strong reduction
Post-prandial glucose levels
Strong reduction
Modest reduction
Modest stimulation
Strong stimulation
Post-prandial insulin secretion
Reduction
Modest stimulation
Glucagon secretion
Reduction
Reduction
Deceleration
No effect
Reduction
Reduction
No effect or small increase (0-2
bpm)
Moderate increase (2-5 bpm)
1-5kg
2-5kg
20-50%, attenuates slowly (weeksmany months)
20-40%, attenuates quickly (~4-8
weeks)
Compounds
Half-life
Effects
Fasting insulin secretion
Gastric emptying rate
Blood pressure
Heart rate
Body weight reduction
Induction of nausea
Meier J et al.; Nat Rev Endocrinol 2012
Lixisenatide prolongs gastric emptying time and blunts aftermeal glucose excursions in patients with type 2 diabetes
300
Time (min)
250
Placebo
Lixisenatide
¶ P=0.003
Lixisenatide vs Placebo
¶
200
150
100
50
0
-50
-100
Change from baseline in gastric
emptying t 1/2
Lorenz M et al.; Regulat Pept, 2013
Lixisenatide decreases the absolute amounts of insulin and
glucagon released after breakfast in patients with type 2 diabetes
Post-breakfast AUC (h.pmol/L)
1200
1000
800
Placebo
Lixisenatide
¶ P=0.004
Lixisenatide vs Placebo
Post-breakfast change AUC (h.pmol/L)
Placebo
14
12
Lixisenatide
¶ P=0.007
Lixisenatide vs Placebo
10
¶
600
400
200
0
Insulin AUC
8
6
¶
4
2
0
Delta Glucagon AUC
Lorenz M et al.; Regulat Pept, 2013
Domanda
• Exenatide e lixisenatide sono due farmaci
sovrapponibili?
Lixisenatide vs Exenatide.
The GetGoal-X study.
Lixisenatide vs Exenatide in addition to:
Metformin ≥ 1.5 g/day
1 wk
20 µg qd
Lixisenatide
15 µg
1 wk
10 µg
Key Inclusion Criteria:
 Type 2 DM
 HbA1c ≥7.0% – ≤10.0%
 Stratified by A1c
(<8.0%/≥8.0%)
All patients: background treatment at a stable dose
Diet & lifestyle counselling every 3 months from D1
R
5 µg bid
4 wks
10 µg bid
Single-blind
Screening run-in
W-3
W-1
W0
Exenatide
Main double-blind treatment period
W4
Rosenstock J et al.; Diabetes Care 2013
W12
Variable extension period
W24
Primary
endpoint
3 d F/U
W44
End of
treatment
F/U Visit
Lixisenatide has similar glucose lowering efficacy and
somewhat less weight lowering efficacy compared to
exenatide. The GetGoal-X study.
Glucose control
Body weight
Rosenstock J et al.; Diabetes Care 2013
Lixisenatide causes nausea and hypoglycemia significantly
less frequently than exenatide. The GetGoal-X Study.
¶
¶
¶
P < 0.05 or less for Lixisenatide vs Exenatide
Rosenstock J et al.; Diabetes Care 2013
GetGoal program:
Lixisenatide in patients uncontrolled on 1 or 2 OADs
Placebo-controlled trials
Basal
insulin 
OADs
Active comparator-controlled trial
2 OADs
GetGoal-L
Add-on to basal
insulin ± MET
1 OAD
GetGoal-S
Diet and
exercise
Add-on to SU ± MET
GetGoal-M
Add-on to MET
GetGoal-Mono
Add-on to MET
Add-on to
pioglitazone ± MET
GetGoal-M-Asia
Add-on to MET± SU
GetGoal-Mono Japan
GetGoal-X
Monotherapy
Add-on to MET
Add-on to basal
insulin ± SU
GetGoal-P
GetGoal-F1
Monotherapy
GetGoal-L-Asia
GetGoal-Duo1
Add-on to insulin
glargine +MET ±TZD
Lixisenatide in aggiunta alla terapia con insulina
basale: le evidenze
Lixisenatide added to basal insulin.
The GetGoal-L study.
Lixisenatide vs Placebo in addition to:
Basal insulin ± metformin
1 wk
20 µg
Lixisenatide
15 µg
1 wk
10 µg
Key Inclusion Criteria:
 Type 2 DM
 HbA1c ≥7.0% – ≤10.0%
 Stratified by A1c
(<8.0%/≥8.0%)
All patients: background treatment at a stable dose
Diet & lifestyle counselling every 3 months from D1
R
10 µg
1 wk
15 µg
1 wk
20 µg
Single-blind
Screening run-in
W-3
W-1
W0
Placebo
Main double-blind treatment period
W4
Riddle MC et al.; Diabetes Care 2013
W12
Variable extension period
W24
Primary
endpoint
3 d F/U
W44
End of
treatment
F/U Visit
Lixisenatide added on basal insulin (±metformin) reduces HbA1c,
body weight and daily insulin dose. The GetGoal-L study
Riddle MC et al.; Diabetes Care 2013
After-meal glucose excursion (mmol/L)
Lixisenatide added on basal insulin (± metformin) reduces
post-prandial glucose excursions. The GetGoal-L study
10
8
¶ P<0.0001
Lixisenatide vs Placebo
6
Basal insulin
(±metformin) + placebo
(n=204)
4
2
¶
0
Basal insulin
(±metformin) +
lixisenatide (n=194)
-2
-4
-6
Baseline
Week 24 LOCF
LS mean change
Riddle MC et al.; Diabetes Care 2013
Lixisenatide added to basal insulin + metformin.
The GetGoal-Duo study.
Lixisenatide in addition to::
Basal insulin + metformin (±TZDs)
1 wk
20 µg
Lixisenatide
15 µg
1 wk
10 µg
Key Inclusion Criteria:
 Type 2 DM
 HbA1c ≥7.0% – ≤10.0%
 Stratified by A1c
(<8.0%/≥8.0%)
All patients: background treatment at a stable dose
Diet & lifestyle counselling every 3 months from D1
R
10 µg
1 wk
15 µg
1 wk
20 µg
Single-blind
Screening run-in
W-3
W-1
W0
Placebo
Main double-blind treatment period
W4
Riddle MC et al.; Diabetes Care 2013
W12
Variable extension period
W24
Primary
endpoint
3 d F/U
W44
End of
treatment
F/U Visit
Lixisenatide added on basal insulin + metformin reduces
HbA1c, body weight and insulin doses.
The GetGoal-Duo study
Riddle MC et al.; Diabetes Care 2013
After-meal glucose excursion (mmol/L)
Lixisenatide added on basal insulin + metformin reduces
post-prandial glucose excursions. The GetGoal-Duo study
8
6
¶ P<0.0001
Lixisenatide vs Placebo
4
Basal insulin + metformin
(±TZDs) + placebo (n=211)
2
¶
0
Basal insulin + metformin
(±TZDs) + lixisenatide
(n=194)
-2
-4
-6
Baseline
Week 24 LOCF
LS mean change
Riddle MC et al.; Diabetes Care 2013
Conclusioni
• Gli agonisti del GLP1-R sono ulteriormente
classificabili in agonisti prandiali (breve durata
d’azione, derivati da exendin-4) e non-prandiali (lunga
durata d’azione)
• Lixisenatide ed exenatide, i due GLP1-R prandiali,
presentano sensibili differenze in effetti terapeutici e
collaterali e in facilità d’uso
• Lixisenatide, in virtù dei suoi spiccati effetti nel
periodo post-prandiale, si presta a essere usata in
combinazione/aggiunta all’insulina basale per
raggiungere un controllo ottimale anche delle
iperglicemie post-prandiali, con ulteriori effetti
benefici su peso, appetito e pressione arteriosa
Grazie per
l’attenzione
Human pancreas and incretin therapy
Nondiabetic Controls
DM
DM on Incretins
Nondiabetic Controls
DM
2,5
DM on Incretins
% Area
2
140
120
1,5
Weight (g)
100
1
80
60
40
0,5
20
0
0
Beta cell area
Alpha cell area
Pancreas weight
Butler AE et al.; Diabetes (in press)
Human pancreas and incretin therapy.
Diabetic patients not on incretin therapy
ID Code
Age
Diabetes
duration
Age at
diabetes
diagnosis
BMI
Rx
Cause of
Death
6028
33
17
16
30
Insulin
Gunshot
6059
18
0.3
17
39
None
CV
6108
57
2
55
30
Met
ICH/Stroke
6110
20
0.2
20
40
None
ICH/DKA
6109
48
-
48
33
None
ICH/DKA
6114
42
2
40
31
Met
Asphyxia
6124
62
3
59
34
Met
ICH/Stroke
6127
44
10
34
30
Insulin
ICH/Stroke
6133
45
20
25
40
Insulin
CV
6139
37
1.5
35.5
45
None
Seizure
6142
29
14
15
34
None
Meningitis
6149
39
20
19
29
Insulin
ICH/Stroke
Butler AE et al.; Diabetes (in press)