Download p - GP Notebook

Coventry Diabetes PLT
Meeting
Jim McMorran
Diabetes GPSI
Coventry PCT
What’s New
• Inhaled Insulin.
• DPP IV inhibitors/GLP1 analogues.
• Rimonabant (Acomplia).
• Insulin pumps.
• Islet cell transplants.
• Non-invasive monitoring.
Inhaled Insulin
• Huge potential advantages
– avoid injections
– rapid absorption
– systemic distribution
• Potential problems with
getting insulin into lungs and
variable day-day absorption
• Technology has solved
many of these problems
Exubera – Advantages
• Not an injection!
• Rapid-acting (comparable to humalog or
novorapid).
• Initial studies suggest that it is at least, if not
more “predictable” than existing short-acting
analogues.
• Equivalent HBA1c reductions to sc insulin in
both Type 1 and Type 2 DM (and equivalent or
slightly less hypos)
• High patient satisfaction in studies.
Issues with inhaled insulin
•
•
•
•
•
•
•
Limited experience
Not licensed in children
? Needle free
Larger doses required
Concerns when upper airways infection
Not approved by NICE
?Effect with in lungs
–
–
–
–
Need 6-12 monthly spirometry
Cannot use in smokers/asthma/COPD
Reduction in FEV1 and DLCO (lung diffusing capacity)
Insulin is potent growth factor
INCRETINS AND THEIR
ROLE AS A TREATMENT
TARGET IN TYPE 2
DIABETES
What is GLP-1?
• A 31 amino acid peptide
• Cleaved from proglucagon in L-cells in the
GI-tract (and neurons in
hindbrain/hypothalamus)
• Secreted in response to meal ingestion
(direct luminal and indirect neuronal
stimulation)
• Member of incretin family
(GIP, GLP-1 and others)
8
The incretin effect
Plasma glucose
270
10
180
5
0
–10 –5
90
60
120
180
0
Isoglycaemic glucose infusion
Insulin response
80
IR-insulin (mU/l)
15
Plasma glucose (mg/dl)
Plasma glucose (mmol/l)
Oral glucose load (50 g/400 ml)
60
Incretin
effect
40
20
0
*
–10–5
Time (min)
*
*** *
60
*
120
Time (min)
180
• Insulin response is greater following oral glucose than i.v
glucose, despite similar plasma glucose concentration
Nauck et al. Diabetologia 1986;29:46–52, *p ≤ 0.05. n=8 healthy volunteers
9
GLP-1 has multiple desirable
effects
• Stimulates insulin secretion, glucosedependently
• Stimulates -cell function
• Increases -cell mass in animal models
• Decreases glucagon secretion, glucosedependently
• Delays gastric emptying, decreases food
intake and body weight
• Has beneficial cardiovascular effects
10
GLP-1 stimulates -cell
function
insulin
release
glucose
sensitivity
insulin
biosynthesis
-cell
-cell
GLUT2
glucokinase
Improved function
Holz et al. Nature 1993;361:362–365. Drucker et al. Proc Natl Acad Sci USA 1987;84:3434–3438.
Bulotta et al. J Mol Endocrinol 2002;29:347–360.
11
GLP-1 stimulates -cell
regeneration
and mass in animal models
Key
Red arrows indicate
effect of GLP-1
-cell neogenesis
-cell proliferation
-cell
-cell apoptosis
-cell hypertrophy
-cell regeneration and increased mass
Farilla et al. Endocrinology 2003;144:5149–5158. Bulotta et al. J Mol Endocrinol 2002;29:347–360.
GLP-1: functional pancreatic
effects
Glucose dependent
insulin secretion
Somatostatin
secretion
Glucagon
secretion
Pancreatic cells:
-cell
-cell
Hepatic
glucose
output
-cell
Ørskov et al. Endocrinology 1988;123:2009–2013. Drucker et al. Proc Natl Acad Sci USA 1987;84:3434–3438.
13
GLP-1: effects on the
gastrointestinal and central
nervous systems
GLP-1
Learning
and memory
(animal models)
Gastric emptying
Satiety
Acid secretion
Food intake
Kieffer, Habener. Endocr Rev 1999;20:876–913. Flint et al. J Clin Invest 1998;101:515–520.
Wettergren et al. Dig Dis Sci 1993;38:665–673. During et al. Nat Med 2003;9:1173–1179.
14
Blood glucose lowering is
safe and effective with GLP-1
Protocol
25
450
20
360
15
270
180
10
5
0
90
Hypoglycaemia threshold 2.8 mmol/l*
Plasma glucose (mg/dl)
Plasma glucose (mmol/l)
Patients reaching a stable glucose
level (fluctuations ≤ 0.2 mmol/l)
• 50 type 2 patients
• OAD discontinued for
3 days
• Overnight fast
• 4-hour GLP-1 i.v. infusion
Interpretations
• No non-responders
• Strict glucose-dependency
• Effective over a
broad range
0
Fasting plasma Nadir plasma
glucose
glucose
Adapted from: Toft-Nielsen et al. J Clin Endocrinol Metab 2001;86:3853–3860.
Open circles are mean ± 1 SD. *50 mg/dl
15
GLP-1 controls blood glucose
and weight in type 2 diabetes
Continuous subcutaneous infusion of GLP-1 or saline for 6 weeks
8-hour BG profiles
Weight
Week 0
Week 1 GLP-1
25
450
Week 6 GLP-1
20
360
15
270
10
180
5
90
0
0
0
1
2
3
4
5
6
7
Weight change (kg)
GLP-1
Plasma glucose (mg/dl)
Plasma glucose (mmol/l)
(GLP-1 patients, n=10)
8
Hours post-injection
0.0
(n=10)
Saline
(n=9)
–0.5
–1.0
–1.5
–2.0
–2.5
–3.0
p = 0.013 absolute values
p = 0.16 change in weight
Adapted from: Zander et al. Lancet 2002;359:824–830. Data are mean ± SE.
16
Native GLP-1 is rapidly
degraded
by DPP-IV
Human ileum,
GLP-1 producing
L-cells
Capillaries,
Di-Peptidyl
Peptidase-IV
(DPP-IV)
Double immunohistochemical staining for DPP-IV
(red) and GLP-1 (green) in the human ileum
Adapted from: Hansen et al. Endocrinology 1999;140:5356–5363.
17
Native GLP-1 has limited
clinical value because of its
short half-life
i.v. bolus GLP-1 (15 nmol/l)
His Ala Glu Gly Thr Phe Thr Ser Asp
Val
7
9
Ser
Lys Ala Ala Gln Gly Glu Leu Tyr Ser
Glu
Phe
37
Ile Ala Trp Leu Val Lys Gly Arg Gly
Intact GLP-1 (pmol/l)
DPP-IV
1000
Healthy individuals (n=6)
Type 2 diabetes (n=6)
500
0
–5
5 15 25 35 45
Time (min)
Enzymatic cleavage
High clearance
(4–9 l/min)
t½ = 1.5–2.1 minutes
(i.v. bolus 2.5–25.0 nmol/l)
Adapted from Vilsbøll et al. J Clin Endocrinol Metab 2003;88:220–224.
18
GLP-1 analogues
•
•
•
•
Exenetide
originally isolated from saliva of gila monster
53% homology with natural GLP-1
subcutaneous bd injection
– 5mg bd or 10mg bd
• side effects -> principally gastrointestinal
– 50% incidence of nausea on 10mg bd
• antibodies to exenetide in 50%
Gila Monster
•Exenatide
–Synthetic version of salivary protein
found in the Gila monster
GLP-1 analogues
•
•
•
•
•
•
Liraglutide
Maximal action at 9-12 h; half-life 11-15 hours
once daily subcutaneous injection
97% homology with natural GLP-1
Mild, transient GI-symptoms
no liraglutide antibodies
Exenatide Reduced HbA1C and Weight:
Large Phase 3 Clinical Studies –
Combined
Placebo BID
5 µg Exenatide BID
10 µg Exenatide BID
0.5
-0.5
0.1
0
 Weight (kg)
 HbA1C (%)
0
-0.5
-1
-0.6
*
-0.9
*
-1.5
-0.5
-1
-0.7
-1.5
-2
-1.4
*
-1.9
*
ITT 30-wk data; N = 1446; Mean (SE); *P<0.005; Weight was a secondary endpoint
Data on file, Amylin Pharmaceuticals, Inc.
p = 0.29
2
1
0
-1
-2
-3
0
1
2
3
4
5
Mean change in body
weight from baseline (%)
Mean change in body weight
from baseline (%)
Effect on weight (liraglutide in
combination with metformin
2
p < 0.0001
1
0
-1
-2
-3
p < 0.0001
p = 0.83
Time (weeks)
Metformin (n=36)
Liraglutide (n=36)
p = 0.40
Metformin + glimepiride (n=36)
Liraglutide + metformin (n=36)
Adapted from: Nauck et al. Diabetes 2004;52(suppl 2):A83. n=number randomised
Study 1499
23
Liraglutide and hypoglycaemic
risk
Number of patients reporting events in three trials
Liraglutide
Glimepiride Metformin
(0.045–2 mg
OD)
(1–4 mg)
(1000 mg
bid)
Liraglutide
(0.5–2 mg OD) +
Metformin
(1000 mg bid)
Minor events (< 2.8 mmol/l [50 mg/dl])
–
–
–
2/34 (6%)
-
0/36 (0%)
–
0/36 (0%)
0/36 (0%)
7/135 (5%)
5/26 (19%)
–
–
Madsbad et al1
1/135 (0.7%) 4/26 (15%)
Feinglos et al2
5/176 (3%)
Nauck et al3
Symptoms only
Madsbad et al1
2
et alhypoglycaemic
12/176 (7%) events
–
2/34 (6%)
• Feinglos
No major
were reported
Nauck et al3
0/36 (0%)
–
0/36 (%)
1. Madsbad et al. Diabetes Care 2004;27:1335-42 (12 weeks). n randomised=193.
2. Saad et al. Diabetologia 2002;45 (Suppl 2)A44. Feinglos et al. Submitted 2004 (12 weeks).
n randomised=210. 3. Nauck et al. Diabetes 2004;52(suppl 2):A83 (5 weeks). n randomised=144
1/36 (3%)
Study 1310, 2072, 1499
24
DPP-IV Inhibitors (“gliptins”)
•
•
•
•
•
•
Sitagliptin (MK-0431) (Merck)
Vildagliptin (LAF-237) (Novartis)
Saxagliptin (BMS-477118) (BMS)
(NVP-DPP728) (Novartis)
(P93/01) (OSI Pharmaceuticals)
CJC-1134
Summary
• incretin analogues are a novel treatment
modality for T2 diabetes
• administration via injection
• reduce HbA1c by approximately 1%
• associated with weight loss
• gastrointestinal side effects – principally nausea
• low incidence of hypoglycaemia
• ? will be used if poor glycaemic control on
metformin and another agent