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GLP-1 and use with insulin
Giorgio Sesti
University “Magna Graecia” of Catanzaro
T2DM anti-hyperglycaemic therapy: general recommendations
Diabetes Care 2012;35:1364-1379; Diabetologia 2012;55:1577-1596.
T2DM anti-hyperglycaemic therapy: general recommendations
Diabetes Care 2012;35:1364-1379; Diabetologia 2012;55:1577-1596.
Why treating with a combination of a glucagon-
like peptide 1 (GLP‑1) receptor agonist and
long-acting insulin ?
Butler et al. Diabetes 2003’52:102-110.
ND IFG T2DM ND T2DM.000
.500
1.000
1.500
2.000
2.500
3.000
3.500
Obese Lean
-50%
-63%
β-c
ell v
olu
me (
%)
Mean relative β-cell volume in obese non-diabetic, IFG and diabetic subjects and lean subjects
Butler, A. et al Diabetes 52: 102-110, 2003Butler AE et al. Diabetes 52:102–110,2003
β-cell apoptosis was 3- fold increased in obese with type 2 diabetes and 10-fold increased in lean with type 2 diabetes vs. their respective control groups
(P <0.05)
(P <0.05)
Schematic view of mechanisms of action of GLP‑1 analogues and long-acting insulin with respect to the pathophysiological phenotype
of T2DM
Nauck & Meier. J Nat Rev Endocrinol 2011;7:193-195. *Shown in rodents or in vitro models only.
LiraglutideGLP-1
Compound (nM)
Ap
op
toti
c b
-cells
(% o
f con
trol)
0
25
50
75
100
0 1 10 100 1000
**
* *
*
**ND
*p < 0.01, **p < 0.005
Bregenholt et al. Biochem Biophys Res Commun 330: 577–584, 2005
Cytokine-induced apoptosis
0
25
50
75
100
0 1 10 100 1000
ND
*
****
** *
*
Fatty-acid-induced apoptosis in neo-natal rat
islets
Compound (nM)
Liraglutide inhibits beta-cell apoptosis in isolated neo-natal rat islets
UKPDS 34. Lancet 1998:352:854–865
6.2% – upper limit of normal range
8.0
6.0
7.5
7.0
6.5
Time (years)
00 2 3 4 51
Rosiglitazone Metformin Glibenclamide
Rosiglitazone vs. metformin–0.13 (–0.22 to –0.05), p=0.002
Rosiglitazone vs. glibenclamide–0.42 (–0.50 to –0.33), p<0.001
6.0
7.0
8.0
9.0
Med
ian
Hb
A1c (
%)
Years from randomisation
ConventionalGlibenclamideMetforminInsulin
Recommended treatment
target ≤7.0%
2 4 6 8 100
ADOPTUKPDS
7.5
8.5
6.5
Over time, glycaemic control deteriorates
Kahn et al. N Engl J Med 2006;355:2427–43
UKPDS 16. Diabetes 1995;44:1249-1258; Lebovitz 1999;7:139-153.
Years from diagnosis
-cell f
un
cti
on
(%
, H
OM
A)
Diabetes diagnosis
β-cell function progressively declines
ADOPTUKPDS
0
20
40
60
80
100
Diet (n=110)Sulphonylurea (n=511)
Metformin (n=159)
–5 –4 –3 –2 –1 0 1 2 3 4 5 6
Extrapolation of β-cell function prior to diagnosis
0 1 2 3 4 50
60
70
80
90
100
Rosiglitazone: -2.0 (-2.6 to -1.3)Metformin: -3.1 (-3.8 to -2.5)Glyburide: -6.1 (-6.8 to -5.4)
Annualised slope (95% CI)
Treatment difference (95% CI) Rosiglitazone vs. metformin, 5.8 (1.9 to 9.8); p=0.003 Rosiglitazone vs. glyburide, -0.8 (-4.7 to 3.1)); p=0.67
Time (years)β
-cell f
un
cti
on
(%
)
Kahn et al. N Engl J Med 2006;355:2427-2443.
Schematic view of mechanisms of action of GLP‑1 analogues and long-acting insulin with respect to the pathophysiological phenotype
of T2DM
*Shown in rodents or in vitro models only. Nauck & Meier. J Nat Rev Endocrinol 2011;7:193-195.
Vilsbøll et al. Diabet Med 2008;25:152-156.
First-phase insulin
secretion
Meanchange vs. baseline
(pmol/l/hr)
p=0.05
Placebo(n=5)
0.65 mg/day(n=5)
1.25 mg/day(n=9)
1.90 mg/day (n=6)
p<0.02
0
5
10
15
20
Liraglutide increased first-phase insulin secretion
Normals, n=11; Type 2 diabetes, n=12.Muller WA et al. N Engl J Med. 283:109–115, 1970.
Insulin and Glucagon Dynamics in Response to Meals Are Abnormal in Type 2 Diabetes
-60 0 60 120 180 240
360
330
300
270
240
110
80
140
130
120
110
100
90
120
90
60
30
0
Glucose (mg%)
Insulin (μ/ml)
Glucagon (μIμ/ml)
Meal
(minutes)
Type 2 diabetes
Normals
Delayed/depressedinsulin response
Non-suppressed glucagon
Glucagon secretion
Pancreatic cells: -cell -cell -cell
Hepatic glucose production
Insulin secretion
Excessive hepatic glucose production
Schematic view of mechanisms of action of GLP‑1 analogues and long-acting insulin with respect to the pathophysiological phenotype
of T2DM
*Shown in rodents or in vitro models only. Nauck & Meier. J Nat Rev Endocrinol 2011;7:193-195.
Liraglutide significantly reduced the 24-h AUC of glucagon in T2DM
Placebo
Liraglutide
Degn KB et al. Diabetes 53:1187–1194, 2004
Garber et al. Diabetes Obes Metab 2011;13:348-356.
Change in FPG over time: LEAD-3 2-year completers
0 8 16 24 32 40 48 56 64 72 80 88 96 1046.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
10.0
Liraglutide 1.8 mg Liraglutide 1.2 mg Glimepiride 8 mg
Time (weeks)
FP
G (
mm
ol/
l)
Observed mean±2SE, no imputation for missing values.
7.45 mmol/l7.58 mmol/l
8.54 mmol/l
0
Jones KL, et al. J Nucl Med 37:1643-1648, 1996
Gastric emptying rate is an important determinant of PPG in early Type 2 Diabetes
Schematic view of mechanisms of action of GLP‑1 analogues and long-acting insulin with respect to the pathophysiological phenotype
of T2DM
*Shown in rodents or in vitro models only. Nauck & Meier. J Nat Rev Endocrinol 2011;7:193-195.
Gastric emptying is inhibited in a dose-dependent manner by GLP‑1 administration
Meier J J et al. J. Clin. Endocrinol. 88: 2716–2725, 2003
Flint et al. Adv Ther 2011;28:213-226.
PPG profile of liraglutide 1.8 mg (baseline corrected)
Ch
an
ge f
rom
baselin
e
(mm
ol/
l)
Time since start of meal (hours)
-1
2
1
0
3
4
5
-0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0
Liraglutide 1.8 mg
Placebo
GLP-1
Energy intake
SatietyGastric emptying
GLP-1 action on the GI and central nervous systems
• In the arcuate nucleus, mRNA expression of the anorectic neurotransmitter CART was significantly increased following liraglutide treatment.
• Liraglutide prevented the increase in orexigenic NPY mRNA seen in weight-matched (food-restricted) rats.
CART
0
2.5
0.5
1.0
Gen
e e
xp
ressio
n
(arb
itra
ry u
nit
s)
Vehicle Liraglutide
2.0
1.5
Weight-matched
P<0.05P<0.05
0
2.5
0.5
1.0
Gen
e e
xp
ressio
n
(arb
itra
ry u
nit
s)
Vehicle Liraglutide
2.0
1.5
Weight-matched
p<0.05p<0.05NPY
Vrang et al. Diabetes 59 (Suppl 1) 583 P, 2010
Liraglutide increases anorectic neurotransmitter CART mRNA expression and prevents fasting induced orexigenic NPY mRNA
expression in rats
0 8 16 24 32 40 48 56 64 72 80 88 96 104
-4
-3
-2
-1
0
1
2
3
4
Liraglutide 1.8 mg Liraglutide 1.2 mg
Ch
an
ge in
bod
y w
eig
ht
(kg
)
-2.8 kg-2.3 kg
+1.0 kg
Time (weeks)
Change in body weight over time — 2-year completers of LEAD-3
Observed mean±2SE (standard error), no imputation for missing valuesGarber et al. Diabetes Obes Metab 2011;13:348–56 (LEAD-3 2-year extension)
Pratley RE et al. Lancet 375: 1447–1456, 2010
Liraglutide vs. sitagliptin for type 2 diabetes patients who did not have adequate glycaemic control with metformin: Change in body
weight
–3.38 kg
–2.86 kg
–0.96 kg
Dose–response relationships for the effects of GLP-1
Holst JJ et al Trends in Mol Med 2008
Network meta-analysis of pairwise comparisons of randomized controlled trials evaluating the use of anti-hyperglycemic agents in
addition to metformin vs. placebo: At least one event of overall hypoglycaemia (odds ratio)
Liu S-C et al. Diabetes Obes and Metab 14: 810–820, 2012
Series10
2
4
6
8
10
12
14
16
18
20
8.86000000000001
10.51
0.45 0.4
1.12999999999999 0.92
4.77
17.78
SU Glinides TZDs Acarbose DPP-4 GLP-1 Basal Biphasic
inhibitors agonists insulin insulin
At
least
on
e e
ven
t of
overa
ll h
yp
og
lycaem
ia (
od
ds
rati
o)
The combination of basal insulin and GLP‑1-based therapies addresses complimentary targets such as:
Fasting and pre-prandial glucose by suppressing hepatic glucose production and improving β-cell function
Post-prandial glucose by decelerating gastric emptying
…and may help alleviate some of the problems of insulin
therapy:
Weight gain
Hypoglycaemia
Elevated doses of insulin
In clinical practice, combination therapy could arise:
1. By adding insulin to pre-existing GLP-1RA therapy
2. By adding GLP-1RAs to established insulin therapy
Clinical outcomes
DeVries et al. Diabetes Care 2012;35:1446-1454.
IDet + liraglutide 1.8 mg (n=162)
Liraglutide 1.8 mg (n=161)
Adults 18–80 years with T2DM
HbA1c:
7.0–10.0% (MET only) 7.0–8.5% (MET + SU)
MET (≥1500 mg)or MET (≥1500 mg) + SU (≤50% max. dose)
for ≥3 months
Open-label study with two randomised and one non-randomised
treatment arm
Conducted in 7 European countries,
Canadaand the US
Liraglutide 1.8 mg
Run-in period:12 weeks
Randomisation
Liraglutide 1.8 mg (n=498)
Liraglutide 0.6 mg 1 week
HbA1c <7.0%Observational group
Randomised period: 26 weeks
IDet, insulin detemir; MET, metformin; SU, sulphonylurea
Liraglutide 1.2 mg1 week
Metformin ≥1500 mg/day; SU discontinued
DeVries et al. Diabetes Care 2012;35:1446-1454.
39% of run-in completers had
HbA1c ≥7.0%
61% of run-in completers had
HbA1c <7.0%
HbA1c ≥7.0% (1:1 randomisation)
Randomised treatment group
Randomised control group
Trial design
Mean (2SE); data are from the FAS, no imputation.
-12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
-1.6
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
Randomised control group (RC; MET + liraglutide 1.8 mg)Randomised treatment group (RT; MET + IDet + liraglutide 1.8 mg)Observational group (O; MET + liraglutide 1.8 mg)
Ch
an
ge in
Hb
A1c (
%)
Time (weeks)
Run-in(Weeks -12 to 0)
Randomised period(Weeks 0 to 26)
RC: 8.29RT: 8.22O: 7.72
RC: -0.66RT: -0.60
O: -1.34
(final value 7.5)RC: -0.76
(final value 7.1)RT: -1.13
(final value 6.6)O: -1.12
Mean change in HbA1c by week
DeVries et al. Diabetes Care 2012;35:1446-1454.
4
5
6
7
8
9
10
11
12
13
Mean (2SE); data are from the FAS, no imputation. p-values are for treatment differences in changes from randomisation (Week 0) for the meal (FAS LOCF)
Self
-measu
red
pla
sm
a
glu
cose (
mm
ol/
l)
p=0.0003
Randomisation (Week 0)
Randomised control group (metformin+liraglutide 1.8 mg)Randomised treatment group(metformin+IDet+liraglutide 1.8 mg)
0
p=0.0244 p=0.0141
Week 26
Randomised control group (metformin+liraglutide 1.8 mg)Randomised treatment group(metformin+IDet+liraglutide 1.8 mg)
Before breakfast
90 min afterbreakfast
Before lunch
Before dinner
90 min afterlunch
90 min afterdinner
Bedtime
Seven-point glucose profiles
DeVries et al. Diabetes Care 2012;35:1446-1454.
-12 -10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24 26
-6
-5
-4
-3
-2
-1
0
Randomised control group (RC; metformin+liraglutide 1.8 mg)
Randomised treatment group (RT; metformin+IDet+liraglutide 1.8 mg)
Mean (2SE); data are from the FAS, no imputation.
Ch
an
ge in
bod
y w
eig
ht
(kg
)
Time (weeks)
Run-in(Weeks −12 to 0)
Randomised period(Weeks 0 to 26)
Baseline:RC: 98.6RT: 99.5O: 99.0
RC: 3.46RT: 3.53
O: 4.35
RC: 4.74O: 4.78
RT: 4.00
Mean body weight change by week
DeVries et al. Diabetes Care 2012;35:1446-1454.
Clinical outcomes
In clinical practice, combination therapy could arise:
1. By adding insulin to pre-existing GLP-1RA therapy
2. By adding GLP-1RAs to established insulin therapy
Buse et al. Ann Intern Med 2011;154:103-112.
Insulin Titration
FPG Algorithm (mmol/l)
Dose Change
(U)
<3.1b −4
3.1-3.9b −2
4.0-5.5c 0
5.6-6.6c +2
6.7-7.7c +4
7.8-9.9c +6
≥10c +8
BID, twice daily (≤60 min before morning and evening meals); FPG, fasting plasma glucose; OAMs, oral antihyperglycaemic medications (metformin and/or pioglitazone); T, telephone call. aInsulin titrated to FPG of <5.6 mmol/l 5 weeks after randomisation and throughout remainder of study using "Treat to Target" algorithm adapted from Riddle et al. Diabetes Care 2003;26(11):3080-3086. bValues for at least 1 FPG since the last assessment. cBased on the average of FPGs during the last 3 to 7 days. Note: The increase in the total daily dose should not exceed more than 10 U/day or 10% of the current total daily dose, whichever is greater.
*
Screening Randomisation
5 µg BID
Insulin glargine + OAMscontinued throughout study
Endpoint
Placebo (volume equivalent)
10 µg BID
T T T
Visit
Week of treatment
1
2
3
0
5
4
4
2
6
6 30
13
10
8
14
9
18
10
22
11 12
268
72
1
T T T T T T T
+
T T
1
2
3
0
5
4
4
2
6
6 30
13
10
8
14
9
18
10
22
11 12
268
72
1
1
2
3
0
5
4
4
2
6
6 30
13
10
8
14
9
*
Exenatide
+
Exenatide
(volume equivalent)
T T T
1 3
0
5
4
4
2
6
6 30
13
10
8 9
18
10
22
11 12
268
72
T T T T T T TT T
1 3
0
5
4
4 6
6 30
138 9
Placebo
Insulin Titration
−
Study design
Buse et al. Ann Intern Med 2011;154:103-112.
Baseline 18 30-2.5
-2
-1.5
-1
-0.5
00
-1.83-
1.74000000000002
-0.9500000000
00001 -1.04
Exenatide BID + Glargine
Placebo BID + Glargine
Weeks
Hb
A1
c (%
)
Data are mean±95% CI.
Difference in HbA1c at 30 weeks: -0.69% (95% CI -0.93 to -0.46%; p<0.001)
HbA1c reduction: patients taking exenatide or placebo with insulin glargine
Buse et al. Ann Intern Med 2011;154:103-112.
Data are mean±95% CI.
Body weight change over 30 weeks (p<0.001; all time points)
0 2 4 6 8 10 14 18 22 26 30-3
-2
-1
0
1
2
0
-0.45 -0.7500000000000
07-1.17
-1.47-1.62
-1.74
-2.26
-1.86
-1.6900000000000
1-1.78
0
-0.07 0.04 -0.21-0.05
-0.25
0.130.02
0.630000000000008
1.01 0.960000000000001
Exenatide BID + Glargine
Placebo BID + Glargine
Weeks
Bo
dy w
eig
ht
ch
an
ge
(kg
)
Body weight change: patients taking exenatide or placebo with insulin glargine
Buse et al. Ann Intern Med 2011;154:103-112.
Insulin glargine+exenatide
Insulin glargine+placebo
Categoria 10
5
10
15
20
25
30
35
25
17
0
29
26
1
Pro
port
ion
of
pati
en
ts
exp
eri
en
cin
g h
yp
og
lycaem
ia
(%)
Minor Minor nocturnal Major
Hypoglycaemic events
Buse et al. Ann Intern Med 2011;154:103-112.
Between-group Difference -6.5 (95% CI 12.3 to 0.8); p=0.030
Categoria 10
5
10
15
20
25
30
13
26
Ch
an
ge in
in
su
lin
dose (
U/d
)
Insulin glargine+exenatide Insulin glargine+placebo
Increase insulin dosage from baseline was greater in the placebo group
Buse et al. Ann Intern Med 154:103-112, 2011
Overall conclusions
Adding basal insulin to pre-existing GLP-1RA therapy or adding GLP-1RAs to established insulin therapy may help improve glycaemic control and reduce glycaemic excursions
Improvement in HbA1c by combining GLP-1RAs with insulin is associated with:
Weight loss
No increased risk of hypoglycaemia
Reduction in insulin doses
THANK YOU !
Sesti lecture
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