registrar training talk
DESCRIPTION
Ali Could you e-mail me the web link. I have forgotten it. Also could wetalk about using its format to design diabetes web site. Thanks MollieTRANSCRIPT
NEW KIDS ON THE BLOCK
Dr Mollie DonohoeDr Amanda Stride
22 September 2009
• What are GLP mimetics?
• What do the studies show?
• What are current NICE guidelines?
• What are we doing in clinical practice?
Incretins
• Incretins are hormones secreted by intestinal endocrine cells in response to nutrient intake1
• Incretins influence glucose homeostasis via multiple actions including glucose-dependent insulin secretion2, postprandial glucagon suppression and slowing of gastric emptying3
• Incretins were identified when it was observed that orally ingested glucose provoked a higher insulin response than comparable glucose administered intravenously4
This is called the “incretin effect”The incretin effect accounts for ~60% of total insulin
release following a meal41Drucker DJ. Diabetes Care 2003;26:2929–2940; 2Nauck MA, et al. Diabetologia 1993;36:741–744; 3Nauck MA, et al. Diabetologia 1996;39:1546–1553; 4Nauck M, et al. Diabetologia 1986;29:46–52.
GLP-1 effects in humansunderstanding the natural role of
incretins
Adapted from 1Nauck MA, et al. Diabetologia 1993;36:741–744; 2Larsson H, et al. Acta Physiol Scand 1997;160:413–422; 3Nauck MA, et al. Diabetologia 1996;39:1546–1553; 4Flint A, et al. J Clin Invest 1998;101:515–520; 5Zander et al. Lancet 2002;359:824–830.
GLP-1 secreted upon the ingestion of food
1.-cell:cell:Enhances glucose-dependent Enhances glucose-dependent
insulin secretion in the pancreasinsulin secretion in the pancreas11
3.Liver:3.Liver: reduces hepatic glucose reduces hepatic glucose
outputoutput22
2.2.αα--cell:cell:Suppresses postprandialSuppresses postprandial
glucagon secretionglucagon secretion11
4.Stomach:4.Stomach: slows the rate of gastric slows the rate of gastric
emptyingemptying33
5.Brain:5.Brain:Promotes satiety and Promotes satiety and
reduces appetitereduces appetite4,54,5
Incretin Effect
Augmentation of glucose-stimulated insulin secretion by intestinally derived peptides, which are released in presence of glucose or nutrients in the gut
Mean (SE); *P 0.05Data from Nauck MA, et al. J Clin Endocrinol Metab 1986;63:492–498. Plasma glucose values converted to mmol/L from mg/dL using conversion factor of 0.0555; C-peptide values converted to nmol/L from ng/mL using conversion factor 0.333.
Plasma glucose (mmol/L)
Time (min)
The incretin effect β-cell response to oral vs IV glucose
C-peptide (nmol/L)
Oral glucose (50 g)Isoglycaemic intravenous (IV) glucose
12
2
0
Crossover of healthy subjects (N = 6)
0 60 120 180
4
6
8
10
Pla
sm
a g
luc
os
e (
mm
ol/
L)
0 60 120 180
0.0
0.5
1.0
1.5
2.0
*
*
*
*
**
*
Incretin Effect
C-p
ep
tid
e (
nm
ol/
L)
Time (min)
The incretin effect is reduced in patients with type 2 diabetes
0
20
40
60
80
Ins
uli
n (
mU
/L)
0 30 60 90 120 150 180
Time (min)
** *
** **
0
20
40
60
80
0 30 60 90 120 150 180
Time (min)
**
*
*P ≤.05 compared with respective value after oral load. Nauck MA, et al. Diabetologia 1986;29:46–52.
Patients with type 2 diabetesControl subjects
Intravenous Glucose
Oral Glucose
Ins
uli
n (
mU
/L)
The New Kids: The New Kids: Exenatide and LiraglutideExenatide and Liraglutide
• Incretin mimetics – exhibits gluco regulating Incretin mimetics – exhibits gluco regulating actions similar to GLP-1.actions similar to GLP-1.
• Resistant to degradation by Resistant to degradation by dipeptidypeptidase.dipeptidypeptidase.
• Exenatide Exenatide approved by FDA as adjunctive Rx approved by FDA as adjunctive Rx in Type 2 on metformin/SU or both not in Type 2 on metformin/SU or both not achieving adequate control of BG.achieving adequate control of BG.
• LiraglutideLiraglutide – once daily human GLP – once daily human GLP analogue.analogue.
Homology to native GLP-1 with two GLP-1 agonists
97% amino acid homology to human GLP-1
peptide1
53% amino acid homology to human
GLP-1 peptide2
Study duration: Liraglutide 26 weeks; exenatide 30 weeks.1Victoza SmPC, 20092Vilsbøll et al. International Diabetes Monitor 2009;21:1-7
What do studies show?
Exenatide versus insulin glargine in patients with suboptimally controlled
type 2 diabetes
Primary Objective
• To compare effects of exenatide and insulin glargine on glycaemic control in patients with type 2 diabetes that is suboptimally controlled with metformin (MET) and sulphonylurea (SU)
• 26-week treatment, BD fixed dose exenatide versus OD insulin glargine (titrate to fasting blood glucose level <5.6 mmol/L)
• Primary endpoint: Change in HbA1c from baseline
• ITT sample: N = 549 randomised patients with 1 post-baseline measurement
Heine R, et al. Ann Intern Med 2005;143:559–569.
Change in HbA1c over time, ITT population
Time (weeks)
0 12 260
6.5
Hb
A1c
(%)
Insulin glargine, mean dose at endpoint = 25.0 U/day (N = 260)
Exenatide, 10 μg (N = 275)
ITT population: exenatide (N = 275) insulin glargine (N = 260), Mean ± SD shownHeine R, et al. Ann Intern Med 2005;143:559–569.
7.0
7.5
8.0
8.5
Exenatide Reduced Postprandial Glucose
Excursions
Blo
od
Glu
co
se
(m
mo
l/L
)
6
8
10
12
14BaselineWeek 26
6
8
10
12
14BaselineWeek 26
Exenatide Insulin Glargine
F
as
tin
g
Pre
-mid
da
y m
ea
l
Pre
-ev
en
ing
me
al
3 A
M
Po
st-
ev
en
ing
me
al
Po
st-
mid
da
y m
ea
l
Po
st-
mo
rnin
g m
ea
l
Fa
sti
ng
Pre
-ev
en
ing
me
al
3 A
M
Po
st-
ev
en
ing
me
al
Po
st-
mid
da
y m
ea
l
Po
st-
mo
rnin
g m
ea
l
P
re-m
idd
ay
me
al
ITT sample; Mean ± SE shown.Heine RJ, et al. Ann Intern Med. 2005;143:559-569.
Change in body weight over time, ITT population
Exenatide (N = 275)Insulin Glargine (N = 260)
ITT population: exenatide (N = 275) insulin glargine (N = 260), Mean ± SD shown; * P < 0.0001, exenatide versus insulin glargine at same time pointHeine R, et al. Ann Intern Med 2005;143:559–569.
Time (weeks)
Ch
an
ge
in
bo
dy
we
igh
t (k
g)
0 2 4 8 12 18 26
-3
-2
-1
0
1
2
**
**
**
+ 1.8 kg
- 2.3 kg
Safety and tolerability
• Exenatide is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance of <30ml/min).
• Not recommended for patients with severe gastrointestinal disease.
• There was an increased risk of hypoglycaemia with sulphonylurea.
– To reduce the risk of hypoglycaemia, reduction of dose of sulphonylurea should be considered.
• Nausea was the most commonly reported adverse event (>5%) reported in phase II placebo-controlled studies.
• Most episodes were mild to moderate and decreased over time in most patients.
Liraglutide phase 3 programme
Early in treatment pathway Later in treatment pathway
1. Nauck M et al. Diabetes Care 2009;32:84–902. Marre M et al. Diabet Med 2009;26:268–2783. Zinman B et al. Diabetes Care 2009;Epub ahead of print 16 March4. Russell-Jones D et al. Diabetologia 2009, in press
Comb = Oral combination therapy; Glim = glimepiride; Met = metformin;Mono = Oral monotherapy; Rosi = rosiglitazone; SU = sulphonylurea; TZD = thiazolidinedione (glitazone)
Trial Met add-on1
Lead 2
SU add-on2
Lead 1
Met + TZD add-on3
Lead4
Met + SU add-on4
Lead 5
Background regimen
Met 2 g Glim 4 mg Met 2 g + Rosi 8 mg
Met 2 g + Glim 4 mg
Comparators
Glim 4 mgPlacebo
Rosi 4 mgPlacebo
Placebo Insulin glarginePlacebo
• Liraglutide administration: s.c. once daily, any time of day, irrespective of meals
• Liraglutide injected into upper arm, abdomen or thigh, using a prefilled pen
• Forced titration 0.6 mg 1.2 mg 1.8 mg according to protocol; dose reduction not allowed
• Trials were powered for superiority vs placebo and non inferiority vs. active comparators
• Primary endpoint: change in HbA1c from baseline• Secondary endpoints included other measures of glucose control, weight,
tolerability and beta-cell function
1. Marre M et al. Diabet Med 2009;26:268–2782. Nauck M et al. Diabetes Care 2009;32:84–903. Zinman B et al. Diabetes Care 2009;Epub ahead of print 16 March4. Russell-Jones D et al. Diabetologia 2009, in press
Liraglutide phase 3 programme: Design
Met = metformin; SU = sulphonylurea; TZD = thiazolidinedione (glitazone)
Liraglutide phase 3 programme:
Change in HbA1c
1. Nauck M et al. Diabetes Care 2009;32:84–902. Marre M et al. Diabet Med 2009;26:268–2783. Zinman B et al. Diabetes Care 2009; e-pub ahead of print 16 March4. Russell-Jones D et al. Diabetologia 2009, in press
44
%
58
%
54
%
35
%
42
%
22
%
42
%
36
%
3
5%
p<0.0001p=0.00139
% r
each
ing A
DA
targ
et
(HbA
1c
<7
.0%
)
Met + SU add-on4SU add-on2Met add-on1
Met + TZDadd-on3
-1.0 -1.0 -1.0-1.08 -1.13
-0.44
-1.5 -1.5
-1.33
-1.09
Chang
e in H
bA
1c
from
base
line (
%)
-1.6
-1.4
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
p<0.0001
44
%
52
%
54
%
58
%
42
%
35
%
22
%
35
%
36
%
42
%
RosiglitazoneLiraglutide 1.8 mgLiraglutide 1.2 mg GlimepiridePlaceboGlargine
-0.5
28
%
+0.2
Effects of liraglutide on body weight
1. Nauck M et al. Diabetes Care 2009;32:84–902. Marre M et al. Diabet Med 2009;26:268–2783. Zinman B et al. Diabetes Care 2009; e-pub ahead of print 16 March4. Russell-Jones D et al. Diabetologia 2009, in press
-2.8-2.6
+1.0
p<0.0001
+0.3
+2.1
-0.2
p<0.0001
SU* add-on2 Met add-on1 Met + TZDadd-on3
Met + SU add-on4
-2.0
-1.0
+0.6
-1.8
+1.62
p<0.0001
Met = metformin; SU = sulphonylurea; TZD = thiazolidinedione (glitazone)
*Patients were taken off metformin before the trial – this may explain that weight loss was not observed2
RosiglitazoneLiraglutide 1.8 mgLiraglutide 1.2 mg GlimepiridePlaceboGlargine
Chang
e in b
ody w
eig
ht
from
base
line (
kg
)
-4
-3
-2
-1
0
1
2
3p<0.0001
p<0.0001
-2.3
0.4
-2.8
p=0.0467
p=0.0128
-2.8-2.6
-0.9
-6.7
-4.0
0.5
p=0.0001
Met add-on1 SU add-on2 Met + TZDadd-on3
Met +SU add-on4
Met = metformin; ns = not significant; SU = sulphonylurea; TZD = thiazolidinedione (glitazone)
1. Nauck M et al. Diabetes Care 2009;32:84−902. Marre M et al. Diabet Med 2009;26(3):268−2783. Zinman B et al. Diabetes Care 2009; e-pub ahead of print 16 March4. Russell-Jones D et al. Diabetologia 2009, in press
Chang
e in S
BP f
rom
base
line (
mm
Hg
)Effect of liraglutide on systolic blood pressure
-5.6-6
-5
-4
-3
-2
-1
0
1
p=ns
p=ns
-1.1
RosiglitazoneLiraglutide 1.8 mgLiraglutide 1.2 mg GlimepiridePlaceboGlargine
Exenatide v Liraglutide
• What evidence is there?
Design of LEAD-6 and its extension study
Adults 18–80 years with type 2 diabetes
HbA1c:7.0-11.0%
BMI ≤45 kg/m2
Randomised, open-label, parallel-group study at 132 sites in Europe and the USA
Liraglutide (n = 233)0.6 mg OD 1 week 1.2 mg OD 1 week1.8 mg OD 24 weeks
Metformin and/or SU continued at pre-study dose
Exenatide (n = 231)5 g BID 4 weeks10 g BID 22 weeks
Screening 26 weeks1 Extension: 14 weeks2
Liraglutide (n=200)1.8 mg OD 14 weeks
Liraglutide (n=186) 1.8 mg OD 12 weeks
1.2 mg OD 1 week
0.6 mg OD 1 week
BID: twice daily; OD: once daily; BMI: body mass index
1Buse et al. Lancet 2009;374(9683):39-47
2Buse et al. Diabetes 2009;58 (Suppl 1):A159 and poster
UK/LR/0709/0306 Date of Preparation July 2009
Reduction in HbA1c – core and extension phases
LiraglutideExenatide
Exenatide group switched to liraglutide (week 26)
LiraglutideliraglutideExenatideliraglutide
Time (weeks)
ADA HbA1c target
Data for weeks 0–26 are only for patients that participated in the LEAD-6 extension phase
*** Estimated treatment difference in changes for full population p<0.0001
7.21%6.95%
*** p<0.0001
Adapted from Buse et al., poster presented at ADA 2009: 591-P
UK/LR/0709/0306 Date of Preparation July 2009
Extension phase: Further HbA1c reduction after
switching from exenatide
p<0.0001
Exenatideliraglutide Liraglutideliraglutide
Adapted from Buse et al. Diabetes 2009;58 (Suppl 1):A159
UK/LR/0709/0306 Date of Preparation July 2009
Reduction in FPG – core and extension phases
LiraglutideExenatide
Liraglutideliraglutide
Exenatideliraglutide
Time (weeks)
Exenatide group switched to liraglutide (week 26)
*** Estimated treatment difference in changes for full population p<0.0001
8.64
7.73***
p<0.0001
Data for weeks 0–26 are only for patients that participated in the LEAD-6 extension phase
Adapted from Buse et al., poster presented at ADA 2009: 591-P
UK/LR/0709/0306 Date of Preparation July 2009
Both treatments lowered body weight
Mean (2 SE)Estimated treatment difference in changes for full population NS
86
90
94
98
0 4 8 12 16 20 24 28 32 36 40
Body w
eig
ht (k
g)
0LiraglutideExenatide
Time (weeks)
Exenatide group switched to liraglutide (week 26)
Liraglutideliraglutide
Exenatideliraglutide
Data for weeks 0–26 are only for patients that participated in the LEAD-6 extension phase
Adapted from data on file (LEAD 6 ext/04), Novo Nordisk
UK/LR/0709/0306 Date of Preparation July 2009
Proportion of subjects experiencing nausea
Pro
port
ion o
f su
bje
cts
(%)
Time (weeks)0 2 4 6 8 10 12 14 16 18 20 22 24 26
10
8
64
2
0
12
14
18
20
16 Exenatide 10 μg BID
Liraglutide 1.8 mg OD
Data are number (%) of patients exposed to treatment (safety population)
1Buse et al. Lancet 2009;374(9683):39-47
*** p<0.0001 for treatment differences
***
UK/LR/0709/0306 Date of Preparation July 2009
Head-to-Head: liraglutide vs exenatide
In summary,• GLP-1 analogues are effective in lowering glycaemia• Liraglutide showed superior glycaemic-lowering
ability, in regards to HbA1c and FPG, compared with exenatide
• Patients switching from exenatide to liraglutide achieved further improvements without compromising tolerability in:– HbA1c – FPG– Weight– Beta-cell function
Buse et al. Lancet 2009;374(9683):39-47
Buse et al. Diabetes 2009;58 (Suppl 1):A159
UK/LR/0709/0306 Date of Preparation July 2009
Current Guidelines
HbA1c > 6.5% after lifestyle measures
Met
Intensify Regimen
Met + SU
Insulin + Met + SU
Intensify Regimen
Start Insulin
Met + SU + exenatide (BMI > 35kg/m2 and problems with high body weight or insulin not appropriate or weight loss advantageous Or Met + SU + DPP-4 * Or Met + SU + TZD * *if significant risk of hypoglycaemia
Rapid-acting insulin
Met + TZD or Met + DPP-4 (if significant risk of
hypoglycaemia)
SU + TZD or SU + DPP-4 (if significant risk of
hypoglycaemia)
SU
HbA1c > 6.5% HbA1c > 6.5%
HbA1c > 7.5%
HbA1c > 7.5%
HbA1c > 7.5%
HbA1c > 675% HbA1c > 7.5%
HbA1c > 7.5%
NICE recommendations for the management of hyperglycaemia in patients with type 2 diabetes. Continuous lines indicate ‘usual’ or ‘well-validated; regimens;
dashed lines indicate ‘alternative or ‘less well validated’ options.
Key: BMI = body mass index; DPP-4 = dipeptidyl peptidase-4 inhibitor; GLP-1 = glucagon-like peptide 1; HbA1c = glycated haemoglobin A1c; Met = metformin; SU =sulphonylurea; TZD = thiazolidinedione/glitazone
NICE guidelines 2008 Type 2 NICE guidelines 2008 Type 2 DiabetesDiabetes
Starting ExenatideStarting Exenatide
• BMI >35 in those of European descent (adjusted BMI >35 in those of European descent (adjusted accordingly for other ethnic groups)accordingly for other ethnic groups)
• Specific psychological, biochemical or physical Specific psychological, biochemical or physical problems arising from high body weightproblems arising from high body weight
• HbA1c greater than or equal to 7.5% with HbA1c greater than or equal to 7.5% with conventional oral agents after a trial of conventional oral agents after a trial of metformin and sulphonylureametformin and sulphonylurea
• Would otherwise be starting other high cost Would otherwise be starting other high cost medication e.g. thiazolidinedione or insulinmedication e.g. thiazolidinedione or insulin
NICE guidelines 2008 Type 2 NICE guidelines 2008 Type 2 DiabetesDiabetes
Continuation of ExenatideContinuation of Exenatide
• Greater than or equal to 1% Greater than or equal to 1% reduction in HbA1c at 6 reduction in HbA1c at 6 monthsmonths
• Weight loss greater that 5% at Weight loss greater that 5% at one yearone year
Exeter Guidelines
Individualised dietary and lifestyle education is the mainstay of therapy and should be tried for a period of 3 months before initialising drug therapy.
If patient <45 yrs or BMI <25 consider referral to secondary care for investigation of other aetiology
Add isophane insulin nocte or bd
Metformin commenced 500mg od and titrate to max tolerated dose (if GIT symptoms try starting at 125mg od)
Add gliclazide 80mg od and titrate to max 160mg bd as required
Add pioglitazone 30mgtitrating to 45mg
Add DPP-4 inhibitorSitagliptin 5 -10mg od
Add GLP agonistExenatide5mcg -10 mcg sc bd
or
OrIn patients with strong
reasons for avoiding insulin (eg vocational driving
licence)
HbA1c >6.5%
HbA1c >7%
Step 1
Time scales
or
Step 2
Step 3
3 - 6/12
3 - 6/12
3 - 6/12
HbA1c >7.5%
STEPPED APPROACH TO TREATMENT OF TYPE 2 DIABETES
(All targets should be individualised according to hypo risk and expected microvascular benefit)
Annual costs of drugs lowering BS
• Metformin 850mg tds £37• Gliclazide 160mg bd £123• Rosi 8 mg od £660• Pio 45 mg od £480• Repaglinide 16mg daily £389• Exenatide 5/10mg bd £890• Liraglutide 1.2mg £921• Liraglutide 1.8mg £1413• Sitagliptin 100mg od £434• Rimonobant 20mg od £719• Insulin Glargine 25u/day £237• Insulatard 25u/day £133• Orlistat £400
What are we doing in clinical practice?
Exeter experience
• DSN keeping record of all exenatide starts
• 88 pts to date• 1 on liraglutide
Audit by Angus and Pam
Changes in weight & HbA1c
0
5
10
15
20
25
30
35
Total patients (weight) Target weight achieved Total patients (HbA1c) Target HbA1c achieved
Criteria
Nu
mb
er o
f p
atie
nts
Total On insulin On OHA
Changes in weight (kg) over time
Changes in HbA1c over time
Case presentations
• Any from the floor?• Any comments about your
experience with exenatide or liraglutide?
Case presentation 1 AS
• 54 year old lady, EG• T2DM diagnosed 2004• Hyperchol• Hypertension• NAFLD• Obesity• Fibromyalgia and wheel chair bound
• On metformin 2g, glipizide 5mg, simvastatin 80mg, fenofibrate 67mg bd
Case 1 cont
• HbA1c 10.8%• Chol 7.2, TG 2.89• BP 184/64
• Does not want any treatment that will cause her to put on weight.
• What next?
Case 1 cont
• Risk factor control– Simvastatin to atorvastatin– Add BFZ and amlodipine if necessary– Altered timing of OHAs due to SEs
• HbA1C 9.2%• BP 168/92• Chol 6.8
• What next?
Case 1 cont
• Amlodipine added• Atorvastatin increased• Exenatide
• CBGs fell from 20 to 10. Hypo symptoms so SU stopped
• Over course of next 5 months lots of stopping and starting of all BP and chol meds
• But HbA1c 6.6%
Case 2 AS
• 70 yr old man• T2DM on metformin, gliclazide and pio.• Pio stopped due to fliud retention with
increase in HbA1c.• Therefore insulin added but SU
stopped with rise in HbA1C to 12.0%• Reintroduction of gliclazide lead to fall
in HbA1c to 9.3% but weight gain• What next?