GLP-1 analogs and DPP-4 inhibitors - Denver, · PDF fileGLP-1 analogs and DPP-4 inhibitors...
Transcript of GLP-1 analogs and DPP-4 inhibitors - Denver, · PDF fileGLP-1 analogs and DPP-4 inhibitors...
GLP-1 analogs and DPP-4 inhibitors
Saturday 16 July, 2011
Keystone, Colorado
Matthew C. Riddle
Professor of Medicine
Oregon Health & Science University Oregon
Presenter Disclosure
I have received the following forms of support:
Research grants Amylin, GSK, Lilly, sanofi-aventis
Honoraria for consulting Amylin, Lilly, NovoNordisk, Roche, sanofi-aventis
Honoraria for speaking Lilly, sanofi-aventis
Hours after beginning a meal
1 2 3 4 5 60
Toft-Neilsen M-B et al. J Clin Endocrinol Metab 2001;86: 3717-3723
Cummings DE et al. Diabetes 2001;50: 1714-1719
Patterns of hormones which regulate
plasma glucose and food intake
AmylinInsulin
Ghrelin
GLP-1
Meal
Glucagon
It’s not just insulin !
Ways to enhance GLP-1 receptor stimulation
GLP-1 – chronic infusion
Oral DPP-4 inhibitors
Vildagliptin (Galvus)
Sitagliptin (Januvia)
Saxagliptin (Onglyza)
Linagliptin (Tradjenta)
Short-acting GLP-1 agonist
Exenatide (Byetta)
Long-acting GLP-1 agonists
Liraglutide (Victoza)
Exenatide Q weekly (Bydureon)
Intermediate-acting agonist
Lixisenatide (Lyxumia)
Effects of GLP-1 infusion
Larsen J et al. Diabetes Care 2001; 24: 1416-21
24-h GLP-1 sc infusion
16-h GLP-1 sc infusion
Day 7Day 0
100
150
200
250
300
350
400
06 08 10 12 14 16 18 20 22 00 02 04
400
100
150
200
250
300
350
06 08 10 12 14 16 18 20 22 00 02 04
mg/dl
Time of day
mg/dl
Effect gone in 4 hours
Glucose profiles in 40 patients with T2DM
Main effect on basal glycemia
6-week GLP-1 sc infusion by pump
GLP-1Salinemg/dL
450
360
270
180
90
0
0 1 2 3 4 5 6 7 8
450
360
270
180
90
0
0 1 2 3 4 5 6 7 8
Zander M et al. Lancet 2002; 359: 824-30
Week 6 -- on sc infusions
Glucose profiles in 20 patients with T2DM
Hours
Week 0 -- off OAD 3 wks
4-weeks vildagliptin orallyResponses to breakfast
5,0
8,0
11,0
14,0 Glucose mmol/L
0
25
50
75
-30 30 90 150 210
Minutes
Insulin pmol/L
50
75
100
125
-30 0 30 60 90 120
Placebo
Vilda 100mg
Glucagon pg/mL
0
5
10
15
20
25GLP-1 pmol/L
Ahrén B et al. J Clin Endocrinol Metab 2004;89:2078-84
Minutes
Effects of DP-4 Inhibitors
Sitagliptin is as effective as ½ dose metformin1091 patients randomized to PLBO, sitagliptin, or both
Goldstein BJ et al. Diabetes Care 2007;30: 1979-87
1.0
0
2.0
Placebo-adjusted reduction of A1c from 8.8% baseline (%)
Metformin
2000 mgMetformin
1000 mgSitagliptin
100 mg
-1.30%
-0.99% -0.83%
Effects of GLP-1 agents
Agonists DPP-4 inhibitors
Potentiate insulin secretion ++ +
Suppress glucagon ++ +
Reduce calorie intake ++ +
Slow gastric emptying + or ++ -
Tachphylaxis to GLP-1 effects
Reduced effect with ongoing Rx
Potentiate insulin secretion No
Suppress glucagon No
Reduce calorie intake No
Slow gastric emptying Yes
Tachyphylaxis to GLP-1 effects
9 healthy subjects
8.5 hour GLP-1 or placebo infusions
Meal tests as 0 and 4 hours
Responses to meals vs placebo
0 hours 4 hours
Glucose No increase Blunted
Gastric emptying Markedly slowed Less slowed
Insulin Much reduced Less reduced
Nauck MA et al. Diabetes 2011;60: (on-line 24 March)
Plasma glucose
mg/dL
Time of day/Hours
180
260
220
140
100
0800 1200 1600 2000 2400 0400 0800
180
140
220
100
0 4 8 12 2416 20
Degn KB et al. Diabetes 2004;53: 1187-94Ahrén B et al. J Clin Endocrinol Metab 2004;89:2078-84
Liraglutide vs placebo
Vildagliptin vs placebo
Ways to enhance GLP-1 receptor stimulation
GLP-1 – chronic infusion
Oral DPP-4 inhibitors
Vildagliptin (Galvus)
Sitagliptin (Januvia)
Saxagliptin (Onglyza)
Linagliptin (Tradjenta)
Short-acting GLP-1 agonist
Exenatide (Byetta)
Long-acting GLP-1 agonists
Liraglutide (Victoza)
Exenatide Q weekly (Bydureon)
Intermediate-acting agonist
Lixisenatide (Lyxumia)
Single-dose lixisenatide:
Effect on postprandial glucose Drug naïve T2DM patients, standard meal 1 hour after injection
Christensen M et al, IDrugs 2009 12(8):503-513
Blood
glucose
(mg/dL)
Hours after injection
0
100
200
300
400
Injection Meal
0 1 2 3 4 50
100
200
300
400
1 µg (n=4) 3 µg (n=4)
10 µg (n=4) 20 µg (n=4) 40 µg (n=4)
Placebo (n=10)
Not approved by FDA
28-day treatment with lixisenatide:
Effect on fasting and postprandial glucoseT2DM patients on metformin and/or SU, subgroup treated with
up to 20 mcg taken in AM
Baseline
28 days of treatment
Breakfast Lunch Dinner
Hours after morning injection
Blood
glucose
(mg/dL)
-1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
300
250
200
150
100
50
Distiller LA, Ruus R. Diabetologia 2008; 51 (Suppl1): A155
Strong effect on postprandial increment after breakfast,
less after lunch and none after dinner
Lixi injection
-1.0
-0.2
-0.5†
-0.5
**
-0.7
* -0.8
*
0n = 107 n = 55 n = 50 n = 53 n = 51
LS mean
change
of A1c (%)
-0.1
-0.2
-0.3
-0.4
-0.7
-0.8
-0.9
-0.5
-0.6
Placebo 20 µg 30 µg10 µg5 µg
Lixisenatide QD
*p < 0.0001, **p < 0.005, †p < 0.05 vs. placebo
-3.9
*
n = 51 n = 53 n = 52 n = 53
-2.1 -2.2-2.6
20 µg 30 µg10 µg5 µg
-0.9
*
-0.7
*-0.8
*
-0.8
*
n = 51 n = 54 n = 52 n = 53
20 µg 30 µg10 µg5 µg
Lixisenatide BID
Lixisenatide BID
7.5%
-4.5
n = 108 n = 54 n = 50 n = 52 n = 51
LS mean
change
of weight (kg) -2.0-2.4
-3.0† -3.5
*
-1.9
0
-0.5
-2.0
-1.0
-1.5
Placebo 20 µg 30 µg10 µg5 µgLixisenatide QD
88 kg
-2.5
-3.0
-3.5
-4.0
Ratner R et al. Diab Med 2010; 27:1024-32
Lixisenatide dose-ranging studyReduction of A1c and weight
A family of GLP-1 agonists
with different durations of action?
Danne T et al. Diabetes Care. 2003;26:3087-3092. Hirsch IB. Medscape Gen Med. 2005;7:49. Available at:
http://www.medscape.com/viewarticle/515847. Rave K et al. Diabetes Care. 2005;28:1077-1082.
0 1 2 53 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Insu
lin
acti
on
Hours
Lixisenatide 8–16 h ?
Exenatide 4-8 hr ?
Native GLP-1 <1 hr ?
Liraglutide >24 h
Exenatide QW > 1 wk
A family of GLP-1 agonists
with different durations of action?
Danne T et al. Diabetes Care. 2003;26:3087-3092. Hirsch IB. Medscape Gen Med. 2005;7:49. Available at:
http://www.medscape.com/viewarticle/515847. Rave K et al. Diabetes Care. 2005;28:1077-1082.
0 1 2 53 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Insu
lin
acti
on
Hours
Lixisenatide 8–16 h ?
Exenatide 4-8 hr ?
Liraglutide >24 h
Action profiles of insulin formulations
Danne T et al. Diabetes Care. 2003;26:3087-3092. Hirsch IB. Medscape Gen Med. 2005;7:49. Available at:
http://www.medscape.com/viewarticle/515847. Rave K et al. Diabetes Care. 2005;28:1077-1082.
0 1 2 53 4 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Insu
lin
acti
on
Hours
NPH 12–16 h
Regular 6–8 h
Aspart, glulisine, lispro 4–5 h
Detemir 6-18 h
Glargine ~24 h
Blevins T et al. JCEM 2011;96:1301-1310
Effects of Exenatide BID vs Exenatide QW 252 T2DM patients on one or more OAD
24 weeks randomized open-label treatment
Δ A1c %
Δ FPG
mg/dL
Δ weight
kg
- 0.7% A1cP<0.0001
QW vs BID
- 23 mg/dLp<0.001
- 0.9 kg(NS)
Drucker DJ et al. Lancet 2008;372: 1240-50
Effects of Exenatide BID vs Exenatide QW 295 T2DM patients on diet ± OAD
30 weeks randomized open-label treatment
SMBG
profile
Δ FPG
mmol/L
Δ glucagon
ng/L
- 0.33% A1cP=0.0023
QW vs BID
Mainly
basal vs PP
effect
Same wt
reduction(3.7 vs 3.6 kg)
Buse J et al. Lancet 2009;374:39-47
Effects of Liraglutide vs Exenatide BID464 T2DM patients on 1-2 OAD
26 weeks randomized open-label treatment
- 0.33% A1cP=0.001
Lira vs Ex BID
More
basal vs PP
effect
Same wt
reduction(3.2 vs 2.9 kg)
Δ A1c %
% to A1c
targets<7.0% <6.5%
SMBG
profile
FPG
mmol/L
Weight
kg
A1c %
Effects of Exenatide BID vs Glargine551 T2DM patients on metformin + sulfonylurea
26 weeks Rx with titrated glargine or exenatide 10 mcgBID
A1c and weight: changes from baseline
A1c %
Δ Wt kg
Exenatide
Glargine
Heine RJ et al. Ann Intern Med 2005;143:559-569
Heine RJ et al. Ann Intern Med 2005;143:559-569
Effects of Exenatide vs Glargine551 T2DM patients on metformin + sulfonylurea
26 weeks Rx with titrated glargine or exenatide 10 mcgBID
SMBG and BG after test meal: changes from baseline
Exenatide Glargine
SMBG
Meal test
Buse JB et al. Ann Intern Med 2011;154:103-112
*p<0.05, ** p<0.01
Exenatide
30 weeks
Placebo
30 weeks
7-point glucose profilesLS Means ± SE
Exenatide BID added to titrated glargine ± OAD
A1c ~6.7%, weight difference 2.7 kg
Not approved by FDA
Riddle MC et al. ADA Annual Scientific Sessions 2010, Late-breaking abstract , Poster 18-LB
6
7
8
A1c %
9
Met + glargine
+ exenatide
n=16
Met + glargine
+ placebo
n=17
8/17 randomized
47% <6.5% A1c
2/17 randomized
12% <6.5% A1cp=0.03
A1c
6.5%
Distribution of A1c after 24 weeks
Titrated glargine added to exenatide+metformin
Not approved by FDA
A1c lowering power of GLP-1 agentsPlacebo-adjusted reductions (A1c%)
DPP-inhibitors Added to Met Added to Met+SU
Sitagliptin 0.7 vs baseline
Saxagliptin 0.6 0.9
Linagliptin 0.7
GLP-1 receptor agonists
Exenatide 0.9 1.0
Lixisenatide
Liraglutide 1.8 mg 1.1 1.1
Exenatide QW 1.5 vs baseline
Preliminary safety concerns with GLP-1 agents“Pancreatitis, pancreatic and thyroid cancer
with glucagon-like peptide-1 based therapies”
Elashoff M et al. Gastroenterology 2011;141: 150-6
Springer J & Stammschulte U. Gastroenterology 2011;141:20-3
Review of FDA adverse event reporting system database 2004-2009
Odds Rations from case-control analysis of pancreatitis and cancers.
Exenatide 10.68
Pancreatic cancer
Thyroid cancer
Other cancers
Exenatide 2.95
Exenatide 4.73
Exenatide 1.08
Sitagliptin 6.74
Sitagliptin 2.72
Sitagliptin 1.48
Sitagliptin 0.80
Pancreatititis
Preliminary CV findings with a DPP-4 inhibitor“Linagliptin has simlar efficacy to glimepiride but improved cardiovascular safety over 2
years in patients with type 2 diabetes inadequately controlled by metformin”
1519 patients with T2DM treated with metformin
Randomized double-masked to linagliptin 5 mg or glimepiride up to 5 mg
Baseline A1c 7.7%
Glimepiride Linagliptin Difference
A1c reduction % -0.5 -0.4 Noninferior
Change of weight kg +1.3 -1.4 p=0.0001
CV death, MI, stroke, angina 1.7 % 3.4 % RR 0.50
p=0.04
Gallwitz B et al. ADA annual scientific sessions, June 2011, poster presentation 39-LB
Preliminary CV findings with GLP-1 agonistsCV benefit in animal model
Huber J et al. ADA annual scientific sessions, June 2011, Abstract # 968-P
Langendorff-perfused rat heart model (intact animal)
Infarction induced by 45 min LAD occlusion, 120 min reperfusion
Vehicle or GLP-1 agonist administered before/during reperfusion
Change of infarct size vs vehicle:
Native GLP-1 -32%
Liraglutide -29%
Lixisenatide -36%
Interpretation: direct (or indirect?) myocardial protection
Blonde L et al. Diab Obesity Metab 2006;8: 436-447
CV risk factors after exenatide treatmentT2DM patients treated with exenatide + SU/met
n=314 completing 30 wks randomized and 52 wks open label followup
Change from baseline to 82 weeks
A1c - 1.1 %
Weight - 4.4 kg
Triglycerides - 38.6 mg/dL
LDL-C - 1.6 mg/dL
HDL-C + 4.6 mg/dL
BP-syst - 1.3 mmHg
BP-diast - 2.7 mmHg
Long-term placebo-controlled outcome trials
of GLP-1 agentsTECOS Sitagliptin CV outcome study
2008-2014
14,000 patients with T2DM and known CVD
CAROLINA Cardiovascular outcome study of linagliptin versus glimepiride in
patients with type 2 diabetes
2010-2018
6000 patients with T2DM and high CV risk
LEADER Liraglutide effect and action in diabetes: evaluation of CV outcome
results - a long-term evaluation
2010-2016
8800 patients with T2DM and high CV risk
EXSCEL Exenatide study of CV event lowering: a trial to evaluate CV outcomes
after treatment with exenatide once-weekly in patients with T2DM
2010-2017
9500 patients with T2DM
ELIXA Evaluation of CV outcomes in patients with T2DM after acute coronary
syndrome during treatment with Lixisenatide
2010-2013
6000 patients with T2DM and acute coronary syndrome
Current costs of GLP-1 agents vs othersDrugstore.com quotations 7-8-11
Daily dose 90 day supply
Sitagliptin (Januvia) 100 mg $620
Saxagliptin (Onglyza) 5 mg $620
Glimepiride 4 mg $42 ($10 at Fred Meyer)
Glipizide extended 5 mg $36
Exenatide (Byetta) 10 mcg BID $825
Liraglutide (Victoza) 1.2 mg $860
NPH insulin (Humulin vial) 30 units $191
Glargine (Lantus vial) 30 units $332
Thanks for your attention !
Lixisenatide QD Lixisenatide BID
% with
nausea
0
5
10
15
20
25
30
35
40
Placebo 5 µg 5 µg10 µg 10 µg20 µg 20 µg 30 µg 30 µg
11.5
25.5
35.2
14.3
22.2
n=6 n=14 n=19 n=8 n=12
7.3
n=4
4.6
n=5
7.5
n=4 n=18
33.0
Ratner R et al. Diab Med 2010; 27:1024-32
Lixisenatide dose-ranging studyFrequency of nausea
A1c Patterns in UKPDS and ADOPT
UKPDS 34. Lancet 1998;352: 854-65 Kahn SE et al. N Engl J Med 2006;355:24 27-
43
9
8
7
6
0 2 4 6 8 10
Years
A1c
%
ADOPTUKPDS
Glyburide
Metformin ADOPTUKPDS
Chlorpropamide UKPDS
Rosiglitazone ADOPT