differential treatment options with modern incretin...
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Differential Treatment Options With Modern Incretin-mediated Therapies
Moderator:John Wilding, MDProfessor of MedicineUniversity Hospital AintreeLiverpool, United Kingdom
Panelists: Tina Vilsbøll, MDHead of Diabetes ResearchGentofte HospitalUniversity of CopenhagenCopenhagen, Denmark
Panelists (cont.):Jean-Pierre Courrèges, MDHead of Internal MedicineDiabetology Vascular Diseases UnitCentre Hospitalier NarbonneNarbonne, France
Stephan Matthaei, MDProfessor of MedicineDiabetes Center QuakenbrückHannover, Germany
Incretin-based Therapies
DPP-4 inhibitors Protect native GLP-1 from
inactivation by DPP-4
GLP-1 receptor agonistsMimic native GLP-1
Sitagliptin
Vildagliptin
Saxagliptin
Exenatide(Exendin-based therapy)
Liraglutide(Human GLP-1 analogue)
Drucker DJ, Nauck MA. Lancet. 2006;368:1696-1705.
Physiological Effects of GLP-1
Gastric emptying1,2
Stomach
Insulin secretion1
Glucagon secretion1,2
Insulin biosynthesis1
Beta cell proliferation*1
Beta cell apoptosis*1
Preserved hypoglycemic counter-regulation3
*In animal models Muscle(indirect effect)
Glucose uptake1Food intake2
Brain
Pancreas
Glucose production1
Liver(indirect effect)
GLP-1 from intestinal L cells
1. Baggio LL, Drucker DJ. Gastroenterology. 2007;132:2131-2157; 2. Drucker DJ. Diabetes Care. 2003;26:2929-2940; 3. Drucker DJ, Nauck MA. Lancet. 2006;368:1696-1705.Figure adapted from reference 1.
Glucose-dependent insulin secretion
Glucagon secretion
Somatostatin secretion
Ørskov C, et al. Endocrinology. 1988;123:2009-2013; Drucker J, et al. Proc Natl Acad Sci USA. 1987;84:3434-3438.
Pancreatic cells: -cell -cell -cell
GLP-1: Functional Pancreatic Effects
Hepatic glucose output
Insulin synthesis
GLP-1 Analogues and DPP-4 Inhibitors: Two Different Incretin-based Treatment Options
Girard J. Diabetes Metab. 2008;34:550-559; Gautier JF, et al. Diabetes Metab. 2005;31:233-242.
indirect action of DPP-IV inhibitors:
endogenous
DPP-4 inhibitorsGLP-1 analogues
direct action of GLP-1 analogues on targets:
exogenous
Insu
lin S
ecr
etio
n R
ate
(p
mo
l/kg
/min
)
Time (min)
1
0
0 60 120 180 240
4.3(77)
3.7(67)
3.0(54)
2.3(41)
Controlled plasma glucose plateau mmol/L (mg/dL)
Liraglutide (n = 11)
Placebo (n = 11)
Nauck M, et al. Diabetes. 2003;52(suppl 1):A128.
Glucose-dependent Effect: GLP-1 Analogues Do Not Induce Insulin Secretion at Low Glucose Levels
Data are mean ± SEM
Clinical Effects of DPP-4 Inhibitors vs GLP-1 Analogues
DPP-4 inhibitors GLP-1 receptor agonists
Administrationoral: 100 x 1or 50mg x 2
s/c Injection: 5/10ug x 2or 1.2/1.8mg x 1
Half-life 2.5 hrs or 12-14 hrs 2.4 hrs or 11-15 hrs
HbA1c vs placebo -0.7 to -1.0% -1.0 to -1.5%
Postprandial G + +++
Weight Neutral +++
Systolic blood pressure Neutral ++
Gastric flow 0 +++
Hypoglycemic risk 0 / + with SU 0 / + with SU
Tolerability excellent Nausea / GI side effects
GLP-1 Levels Are Pharmacological With a GLP-1 Analogue and Physiological With a DPP-4 Inhibitor
GLP-1 levels after 7 days of liraglutide6 µg/kg x 1/day (n = 13)
GLP-1 levels after 28 days of vildagliptin 100 mg x 2/day (n = 9)
Degn KB, et al. Diabetes. 2004;53:1187-1194; Mari A, et al. J Clin Endocrinol Metab. 2005;90:4888-4894.
Time (h)
30
60
90
120
8 1612 20 24
0
GLP
-1 (
pm
ol/
L)
Time (h)
30
60
90
120
8 1612 20 240
GLP
-1 (
pm
ol/
L)
Liraglutide dose
Vildagliptin dose
x 1/day
-1.2 -1.5 -0.9
-2.0
-1.5
-1.0
-0.5
0.0
Ch
an
ge
in H
bA
1c(%
)
Liraglutide 1.2 mg OD Liraglutide 1.8 mg OD Sitagliptin 100 mg OD
GLP-1 vs DPP-4 Study:HbA1c Change From Baseline
***
***
*** P < .0001
Mean (1.96 SE); Data are from the full analysis set LOCF (last observation carried forward)
Pratley RE, et al. Lancet. 2010;375:1447-1456; Data on file: 1860/26Feb10/HbA1c.
P < .0013
Baseline 8.4% 8.4% 8.5%
n = 211 214 210
Efficacy and Safety of Incretin-Based Therapies: Clinical Trial Data
White J, J Am Pharm Assoc. 2009; 49 (suppl 1): S30 – S40
Postprandial Plasma Glucagon Concentration During Meal Ingestion:At Baseline and After Treatment With Exenatide or Sitagliptin
DeFronzo RA, et al. Curr Med Res Opin. 2008;24:2943-2952.
Postprandial Plasma Glucose Concentration During Standard Meal:At Baseline and After Treatment With Exenatide or Sitagliptin
DeFronzo RA, et al. Curr Med Res Opin. 2008;24:2943-2952.
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Liraglutide 1.2 mg Liraglutide 1.8 mg Glimepiride Placebo
GLP-1 vs Glimepiride, Add-on to Metformin (LEAD-2):
Hypoglycemia With GLP-1 Is Similar to Placebo
Novo Nordisk A/S, data on file. LEAD-2_Minor_hypoglyc_data; Nauck MA, et al. Diabetes Care.2009;32:84–90.
Eve
nts
pe
r P
atie
nt
Year *
*P < .001 vs liraglutide 1.2 and 1.8 mgHypoglycemia defined as BG < 3.1 mmol/L
‡‡
n = 240 n = 242 n = 242 n = 121
‡difference between liraglutide and placebo not recorded
4 mg
Effect of Exenatide Compared to Premixed Insulin on Body Weight
Nauck MA, et al. Diabetologia. 2007, 50, 259-267.
5.4 kg
Insulin
Exenatide
GLP-1 Analogue vs DPP-4 Inhibitor:Weight Loss After 6 Months
Liraglutide 1.8 mg Sitagliptin 100 mgLiraglutide 1.2 mg
P < .0001
Liraglutide group (1.2 mg or 1.8 mg) vs sitagliptin group
- 1.0
- 2.9
- 3.4
Ch
ange
in W
eig
ht
(kg)
Pratley RE, et al. Lancet. 2010;375:1447–1456.
GLP-1 Analogue vs DPP-4 Inhibitor:Weight Loss Over 6-Month Period
Pratley RE, et al. Lancet. 2010;375:1447-1456.
day day day
Summary of Randomized Controlled Trials With GLP-1 Analogues: Liraglutide
Drab S. Pharmacotherapy. 2010;30(6):609-624.
-2.3
0.4
-2.8
P = .0467
P = .0128
-2.8-2.6
-0.9
-6.7
-4.0
0.5
P = .0001
Met add-on1
n = 236 241 239
SU add-on2
n = 244 231 229
Met + TZD add-on3
n = 176 178 173
Met + SU add-on4
n = 227 228
Met = metformin; ns = not significant; SU = sulphonylurea; TZD = thiazolidinedione (glitazone)
1. Nauck MA, et al. Diabetes Care. 2009;32:84-90.2. Marre MA, et al. Diabet Med. 2009;26(3):268-278.3. Zinman B, et al. Diabetes Care. 2009;32:1224-1230 (LEAD-4).4. Russell-Jones D, et al. Diabetologia. 2009;52(10):2046-2055.
Ch
ange
in S
BP
Fro
m B
ase
line
(m
mH
g)Effect of Liraglutide on Systolic Blood Pressure
-5.6-6
-5
-4
-3
-2
-1
0
1
P = ns
P = ns
-1.1
Rosiglitazone††Liraglutide 1.8 mg
Liraglutide 1.2 mg
Glimepiride† Placebo
Glargine †††
P < .0001
P < .0001
† Glimepiride dose: LEAD-1; 2-4 mg/day, LEAD-2 and LEAD-5; 4 mg/day †† Rosiglitazone dose: LEAD-1; 4 mg/day, LEAD-4; 8 mg/day
††† Glargine dose: Individually titrated to reach FPG of ≤ 5.5 mmol/L
Liraglutide Improves Cardiovascular Biomarkers: BNP, PAI-1, and hsCRP
Liraglutide vs Exenatide (LEAD-6):HbA1c Reduction (26 weeks and extension)
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
P < .0001
Baseline 8.2%
n = 227
Baseline 8.1%
n = 236
Ch
ange
in H
bA
1c
(%)
3.Data on File LEAD 6-13, Novo Nordisk.
Mean (2SE)
Liraglutide 1.8 mg OD
-1.12
-0.89
Liraglutide 1.8 mg OD Liraglutide 1.8 mg
P < .0001P = NS
1.Buse J, et al. Lancet. 2009;374(9683):39-47.2.Buse J, et al. Diabetes Care. 2010;33:1300-1303.
Exenatide 10 μg BID
Liraglutide vs Exenatide (LEAD-6):Both GLP-1 Treatments Lower Body Weight
Mean (2 SE)Estimated treatment difference in changes for full population at week 26 NS
Adapted from data on file, Novo Nordisk.
86
90
94
98
0 4 8 12 16 20 24 28 32 36 40
Bo
dy
wei
ght
(kg)
0Liraglutide
Exenatide
Time (weeks)
Exenatide group switched to liraglutide (week 26)
Liraglutideliraglutide
Exenatideliraglutide
*Statistical significance of difference not reported
*
0
2
4
6
8
10
12
14
0 4 8 12 16 20 24
Su
bje
cts
(%
)
Time (weeks)
Liraglutide 1.8 mg Liraglutide 1.2 mg Glimepiride Placebo
GLP-1 vs Glimepiride (Add-on to Metformin, LEAD-2): Nausea Prevalence Declining Over 6-Month Period
26
Proportion of subjects with nausea by week and treatment – safety population
Data on file (LEAD2/01), Novo Nordisk.
GLP-1 Analogue vs DPP-4 Inhibitor:Nausea Incidence Declining Over 6-Month Period
Pratley RE, et al. Lancet. 2010;375:1447-1456.
day day day
Liraglutide vs Exenatide (LEAD-6): Nausea With Liraglutide Appears More Transient Than With Exenatide
Pro
po
rtio
n o
f Su
bje
cts
(%)
Time (weeks)
0 2 4 6 8 10 12 14 16 18 20 22 24 26
10
8
6
4
2
0
12
14
18
20
16
Exenatide 10 μg BID
*** P < .0001 for treatment differences (estimated treatment rate ratio for liraglutide vs exenatide, 0.448)
***
Data are number (%) of patients exposed to treatment (safety population)
Liraglutide 1.8 mg OD
Buse J, et al. Lancet. 2009;374:39–47 (LEAD-6).
Liraglutide 1.8 mg OD
* Time of day = 07:00–09:00
** Time of day = 17:00–19:00
Exenatide 10 µg BID
Arrows show the timing of injections
18
16
14
12
10
8
6
4
2
0
140
120
100
80
60
40
20
0
Time Since First Dose of the Day (h)n = 14
0 2 4 6 8 10* **
12 14 16 18 20 22 24
Tota
l Lir
aglu
tid
e C
on
cen
trat
ion
(n
mo
l/L)
Exe
nat
ide
Co
nce
ntr
atio
n (
pm
ol/
L)
Rosenstock J, et al. Diabetes. 2009;58(suppl 1):A150.
Plasma Levels of Liraglutide Compared With Exenatide
Risk of Pancreatitis With GLP-1 Analogues
• Case reports have suggested a link
• ~30 cases with exenatide
• ~7 cases with liraglutide
• Biologically plausible pathways and some animal models suggest increased inflammation
• Postmarketing surveillance suggests higher rate of pancreatitis in diabetes (~3-fold increase) due to
• obesity, high TGs, gallstones
• No increased incidence with GLP-1 analogues
• Exenatide: ~170 cases per 100,000 pt years
• Insulin: ~200 cases per 100,000 pt years
• Placebo (background): ~300 cases per 100,000 pt years
• Needs ongoing surveillance and research
Peptide Structure of GLP-1 Analogues
Exenatide (from Gila monster) 53% homology
Liraglutide ~97% homology to native GLP-1
Drab S. Pharmacotherapy. 2010;30(6):609-624; Knudsen LB. J Med Chem. 2004;47:4128-4134.
GLP-1 AnaloguesExenatide• Discovered in Gila monster venom
• ~50-70% homology to GLP-1
• Resistant to DPP-4 degradation
• Twice-daily s.c. injection (pre meal)
• Lowers HbA1c by ~1%
• Antibodies in 55% to 70% (LAR) of patients
Liraglutide• Modified GLP-1 (single amino-acid change +
addition of fatty acid)
• Binds to albumin, thus resistant to degradation by DPP-4
• Once-daily s.c. injection (any time)
• HbA1c reduction by ~1.2%
• Antibodies in ~8% of patients
DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.Juhl CB, et al. Diabetes. 2002;51:424-429.
Evidence for CV Risk Reduction With GLP-1 Analogues
• CV risk marker reduction • TG/lipids
• PAI-1
• CRP
• BNP
• Sustained blood pressure and weight reduction
• Pooled data from clinical trials• Fewer CV events in liraglutide groups vs control but low numbers (trials not
powered for CV outcome)
• Retrospective US data analysis• CV event rate ~20% lower in exenatide group (~40,000 pts) vs controls
(~400,000 pts)
Need for hard CV outcome trials
Ongoing CV Outcome Trials With GLP-1 Analogues
• LEADER trial with liraglutide• ~9000 patients with type 2 diabetes
• MACE endpoints (CV death, myocardial infarction, stroke)
• Start September 2010, 42-60 months follow-up first results ~2016
• EXSCEL trial with exenatide LAR (once-weekly injection)• ~9500 patients with type 2 diabetes
• Composite endpoint of primary CV events
• Start June 2010, average 5.5 yrs follow-up results ~2017
ClinicalTrials.gov, Sept 2010.
Decline in Beta Cell Function Is Already Advanced at Time of Diagnosis
Adapted from Lebovitz H. Diabetes Reviews. 1999;7:139-153.
0
20
40
100
-4 6-10 -8 -6 -2 0 2 4
80
60
-12 8
T2D diagnosis
Time From Diagnosis (years)
Bet
a C
ell
Fun
ctio
n (
%, H
OM
A)
Effect of GLP-1 Analogue on Beta Cell Function (after 26 weeks treatment, add-on to SU)
Marre M, et al. Diabet Med. 2009;26:268-278.
Solid color = baseline (%) Graded color = change at week 26 (%)
HO
MA
(%
)
P < .05
P < .05*
**
* Difference between liragutide 1.2 mg vs placebo P = .011** No significant difference between liraglutide 1.8 mg and placebo
n = 206 n = 210 n = 210 n = 100
Potential New Indications for GLP-1 Analogues
• Obesity• Reduce weight
• Preserve beta cell function?
• Stop progression from prediabetes to type 2 diabetes?
• Large clinical trials planned
• Type 1 diabetes• Some small studies with positive results
• Larger trials needed
Await results from larger clinical studies
GLP-1 therapy is not a cure for either type 1 or type 2 diabetes
Role of Incretins in the Management of Type 2 Diabetes
• DPP-4 inhibitors and GLP-1 analogues• Oral vs injectable
• Weight neutral vs weight loss
• Modest vs pronounced HbA1c reduction
• GLP-1 analogues• Low risk of hypoglycemia
• Reduction of blood pressure and body weight
• Incidence of nausea declining over time
• No increased incidence of pancreatitis in type 2 diabetes
• Improvement of CV risk markers
• CV outcome studies ongoing
• Potential prospects in obesity and type 1 diabetes