Part I F Hosseinpanah Obesity Research Center Research Institute for Endocrine sciences Shahid Beheshti University of Medical Sciences November 23 2014 The incretin effect Up to 70 of postglucose insulin secretion is due to the effects of incretins ID: 933706
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Slide1
Incretin-based therapiesPart I
F.
Hosseinpanah
Obesity Research Center
Research Institute for Endocrine sciences
Shahid
Beheshti
University
of Medical Sciences
November 23, 2014
Slide2The incretin effect
Up to 70% of post-glucose insulin secretion is due to the effects of incretins
The incretin effect is
due to gut hormones – the incretin hormones
5
10
500
1000
0
Glucose (mmol/l)
Insulin (pmol/l)
Time (min)
Incretin
Glucose
i.v.
pr. OS
Time (min)
Slide3GLP-1
GIP
Potentiates glucose-induced insulin secretion
Upregulates insulin gene expression and all steps in insulin biosynthesis
Upregulates expresssion of other genes essential for β-cell functionEnhances β-cell proliferation and survival in animal models and isolated human islets
Potentiates glucose-induced insulin secretion
Upregulates insulin gene expression and all steps in insulin biosynthesisUpregulates expresssion of other genes essential for β-cell functionEnhances β-cell proliferation and survival in islet cell lines
Other effectsSuppresses hepatic glucose output by inhibiting glucagon secretion in a glucose-dependent mannerInhibits gastric emptying and appetite; reduction of food intake and body weight
Does not inhibit glucagon secretion
Minimal effects on gastric emptying; no significant effects on appetite or body weightGLP-1 and GIP Are the Two Major Incretins
Holst et al, FEBS letts 1987; Ørskov et al Endocrinology 1988; Wettergren et al , Dig Dis Sci. 1993 ; Flint et al J Clin Invest 1998 ;Holst JJ, Physiol Rev 2007; Trümper A et al. Mol Endocrinol. 2001;15:1559–1570; Trümper A et al. J Endocrinol. 2002;174:233–246; Wideman RD et al.
Horm Metab Res. 2004;36:782–786.
Slide4Time (minutes)
Plasma glucose (mM)
Isoglycaemic iv and oral glucose challenge
in lean patients with 2DM and matched controls
Knop et al, Diabetes 2007
Slide5Insulin and C-peptide
CTRL
T2DM
Time (minutes)
Time (minutes)
Plasma insulin (pM)
Plasma C-peptide (pM)
Knop F et al
Diabetes 2007
Slide6Meal-Stimulated Incretin Secretion is Impaired in Patients with Type 2 Diabetes
T2DM=type 2 diabetes; NGT=normal glucose tolerance; IGT=impaired glucose tolerance
Reprinted from
Toft-Nielsen M-B et al. J Clin Endocrinol Metab. 2001;86:3717–3723.
meal
**
*
*
*
*
*
GIP (pmol/L)
AUC, p<0.05 (T2DM vs NGT)
AUC, p<0.05
0
30
60
90
120
0
60
120
180
240
Time (min)
20
15
15
5
0
GLP-1 (pmol/l)
NGT
IGT
T2DM
Slide7Insulin Responses to Physiological Concentrations of GLP-1 and GIP are Severely Impaired in T2DM
0
1000
2000
3000
4000
0
30
60
90
120
Time (min)
0
200
400
0
30
60
90
120
Time (min)
Healthy subjects
Patients with T2DM
Højberg et al. EASD, 2007, Oral Presentation O-249
(Friday 11:00-12:00)
Saline
GLP-1
(0.5 pmol/kg/min)
GIP
(1.5 pmol/kg/min)
15 mM hyperglycaemic clamp +
Insulin (pmol/L)
Insulin (pmol/L)
Slide8Insulin Responses to Hyperglycaemic Clamp during supraphysiological i.v. GIP and GLP-1
All subjects were obese (BMI 29 kg/m
2
); patients with type 2 diabetes (n=8); control subjects (n=6).IV=intravenous.Adapted from Vilsbøll Tl et al. Diabetologia. 2002;45:1111–1119.
Glucose
Obese Diabetic Patients
Obese Control Subjects
0
1000
2000
3000
4000
5000
-20
80
180
Time (min)
Insulin (pmol/L)
Glucose
Low GIP
High GIP
Low GIP
GLP-1
Slide9Why is Incretin function defective in type 2 diabetes?Secretion of GLP-1 impaired
Beta-cell sensitivity to GLP-1
decreased, but supraphysiological amounts can normalise glucose-induced insulin secretionSecretion of GIP slightly impaired Effect of GIP abolished or grossly impaired
Toft Nielsen et al 1998-2004Vilsboll et al 2000-2007Højbjerg et al 2007
Slide10Type 2 diabetic phenotype Actions of GLP-1
•↑ insulin secretion and biosynthesis •
Improves β-cell function • Impaired β-cell function (glucose sensitivity, proinsulin/insulin ratio) • Upregulates other genes essential for β
-cell function (eg. GLUT 2, glucokinase) • Reduced β-cell mass •↑ β-cell proliferation/differentiation
animal studies •↓ β-cell apoptosis + in vitro • Glucagon hypersecretion •↓
glucagon secretion • Overeating, obesity •↓ gastric emptying, ↑ satiety, ↓ appetite
↓ food intake & weight loss • Macro- and microvascular complications • Beneficial cardiovascular effects
Actions which may be secondary to improved metabolic control • Insulin resistance • Improvements in insulin sensitivity
GLP-1:
Therapeutic Potential in Type 2 Diabetes
Slide11How much of the post glucose insulin secretion depends on Incretins?
30%
50%
70% 90%
Slide120
2
4
6
8
10
12
14
16
00:00
04:00
08:00
12:00
16:00
Snack
Lunch
Breakfast
Diabetic - saline
Non-diabetic
Glucose
(mmol/L)
Time of day
Rachman et al.,
Diabetologia
1997;40:205-211
Proof of hypothesis: Glucose tolerance can be restored by iv GLP-1 in T2DM
Diabetic - GLP-1
(1.2 pmol/kg/min)
Slide13Effects of six weeks’
continuous
subcutaneous
infusion of GLP-1 in patients with type 2diabetesZander et al, Lancet 2002
Slide14Main findings: Zander et al. Lancet 2002Continuous subcutanous infusion of GLP-1 for 6 weeks in type 2 diabetes patients:
Reduced fasting and mean plasma glucose by
4.3 and 5.5 mmol/l, respectivelyReduced HbA1c by 1.3% and normalised fructosamineResulted in a weight loss of 2 kg, presumably because of significantly reduced appetiteImproved insulin sensitivity and enhanced beta-cell secretionHad no significant side effectsSuboptimal dose; suboptimal administration
Slide15Deacon CF, Nauck MA, Toft-Nielsen M-B, Pridal L,
Willms B and Holst JJ:
Both subcutaneously and intravenously administered GLP-1
are rapidly degraded from the NH2-terminus in type II diabeticpatients and healthy subjects. Diabetes 1995; 44: 1126-31.P. 1130:”Inhibition of dipeptidylpeptidase IV may prove a useful adjunct in the management of type II diabetes, as has been the case for the ACE-inhibitors to treat hypertension”
How can we exploit the therapeutic potential of GLP-1?
Slide16Metabolically stable activators of the GLP-1 receptor (exendin derivatives: Byetta, Lixisenatide)Slow release formulations of exendin or GLP-1 analogues (Bydureon and Taspoglutide)Covalent (albiglutide, dulaglutide) or non-covalent (liraglutide) association of GLP-1 with large proteins (albumin – fc fragments) -> long half-lives
Inhibitors of DPP-4 (small orally active molecules)
Small molecule activators of GLP-1R
How can we exploit the therapeutic potential of GLP-1?GLP-1 receptor activators
Slide17GLP-1 receptor activatorsExendin 4, from saliva of the Gila Monster, 53% homologous with GLP-1 and full agonist on the
GLP-1 receptor
Insensitive to DPP-IVCleared slowly by kidneys
Gila Monster
Slide18Which one of the following statements is
incorrect
regarding Incretin function in type 2 diabetes?GLP-1 secretion is impaired
Beta-cell sensitivity to physiological levels of GLP-1 is normalGIP secretion is impairedGIP effect is abolished or severely impaired
Slide19Arg
His
Ala
Thr
Thr
Ser
Phe
Glu
Gly
Asp
Val
SerSer
Tyr
Leu
Glu
Gly
Ala
Ala
Gln
Lys
Phe
Glu
Ile
Ala
Trp
LeuGlyVal
Gly
Arg
Glu
Asp
His
Gly
Thr
Thr
Ser
Phe
Glu
Gly
Asp
Leu
Ser
Lys
Gln
Met
Glu
Glu
Ala
Val
Glu
Arg
Phe
Leu
Ile
Glu
Trp
Leu
Pro
Lys
Gly
Gly
Ser
Ser
Gly
Gly
Ala
Pro
Pro
Ser
Asp
His
Gly
Thr
Thr
Ser
Phe
Glu
Gly
Asp
Leu
Ser
Lys
Gln
Met
Glu
Glu
Ala
Val
Glu
Arg
Phe
Leu
Ile
Glu
Trp
Leu
Pro
Lys
Gly
Gly
Ser
Ser
Gly
Gly
Ala
Pro
Pro
Ser
Lys
Lys
Lys
Lys
Lys
Lys
Lys
His
Gly
Thr
Thr
Ser
Phe
Glu
Gly
Asp
Val
Ser
Ser
Tyr
Leu
Glu
Gly
Ala
Ala
Gln
Lys
Phe
Glu
Ile
Ala
Trp
Leu
Val
Gly
Arg
Lys
His
Gly
Thr
Thr
Ser
Phe
Glu
Gly
Asp
Val
Ser
Ser
Tyr
Leu
Glu
Gly
Ala
Ala
Gln
Lys
Phe
Glu
Ile
Ala
Trp
Leu
Val
Gly
Arg
rH-Albumin
7
36
9
Lys
His
Ala
Thr
Thr
Ser
Phe
Glu
Gly
Asp
Val
Ser
Ser
Tyr
Leu
Glu
Gly
Ala
Ala
Gln
Lys
Phe
Glu
Ile
Ala
Trp
Leu
Gly
Val
Gly
Arg
Native human GLP-1
Exenatide (BID and QW)
Lixisenatide
Albiglutide
Liraglutide
Single substitution [lys34→gly] and addition [glu26]; acylation with C-16 fatty acid (palmitoyl) confers albumin binding and heptamer formation
Isolated from the saliva of the Gila Monster; 53% AA homology (1-30) to native human GLP-1
Same structure as exenatide + SIP tail (lysine hexamer)
Circulates as GLP-1(7-37)
or
GLP-1(7-36) amide
Two linked copies of recombinant human GLP-1(7–36) fused to albumin; Single substitution [ala8→gly]; fusion to albumin
GLP-1 receptor agonists that have been compared
Slide20More than half a century’s incretin research before the discovery of the first GLP-1 analogue
*Pubmed search for “GLP-1 or glucagon-like-peptide-1”
Slide21R&D effort that led to the approval of liraglutide
Slide22Liraglutide is a once-daily, human GLP-1 analogue
Knudsen
et al. J Med Chem
2000;43:1664–9; Degn et al. Diabetes 2004;53:1187–94
Slide23Liraglutide is based on a mechanism of FA binding to albumin
Structure of albumin with seven FA binding sites
Simard
et al.
Proc Natl Acad Sci 2005;102:17958–63
Slide24Liraglutide has a delayed absorption from the subcutis
Steensgaard
et al. Diabetes
2008;57(Suppl. 1):A164 (abstract 552-P)
Slide25Homology to native human GLP-1 and antibody formation
Study duration: liraglutide 26 weeks; exenatide 30 weeks
Montanya
et al. Clin Ther
2009;31:2472–88; DeFronzo et al. Diabetes Care 2005;28:1092
Slide26Liraglutide is significantly more stable against the DPP-4 enzyme than GLP-1
Knudsen
et al. Diabetologia
1999;42(Suppl. 1):A199
Slide27What is plasma half life of liraglutide?
1.
13 h
2. 10 h
3. 20 h4. 8 h
Slide28Once-daily liraglutide covers 24 h in type 2 diabetes
Degn
et al.
Diabetes
2004;53:1187–94
Slide29What percentage of patients develope anti
liraglutide
antibody
??30%49%8.6% 15%
Slide30Liraglutide has multiple direct effects on human physiology
*In animal studies
Slide31Liraglutide provides multiple clinical benefits
Liraglutide
is the first once-daily, human GLP-1 analogue to provide glycaemic control throughout the continuum of care in type 2 diabetes Liraglutide provides:substantial and sustained reduction in blood glucose levelsclinically significant weight lossreduction in SBPimprovement in beta-cell function
Liraglutide SPC
Slide32Overview of LEAD TrialsF. Hosseinpanah, M.D.
Obesity Research Center
Research Institute for Endocrine sciencesShahid Beheshti Universityof Medical SciencesMay 22, 2014Tehran
Slide33Liraglutide Effect and Action in D
iabetes
A series of six randomized controlled phase 3 trials, which was conducted at more than 600 sites in 40 countries involving more than 4000 patients, of whom approximately 2700 received liraglutide
Slide34Design of the LEAD TrialsPrimary objective : To assess the effect of
liraglutide
on glycemic control as measured by change in HbA1c All trials were randomized, parallel group, multicenter trialsThree different dose levels of liraglutide (0.6 mg, 1.2 mg and 1.8 mg/day) were evaluatedThe duration of all LEAD trials was 26 weeks, except LEAD 3, which was 52 weeks
Slide35Purpose: To evaluate the efficacy and safety of liraglutide as mono- or combination therapy in comparison
with commonly used
treatments of type 2 diabetes
Slide36Slide3726-week, double-blind, double-dummy1,091 subjects were randomly assigned (2:2:2:1:2) to once-daily liraglutide (either 0.6, 1.2, or 1.8 mg/day injected subcutaneously), to placebo, or to glimepiride (4 mg once daily)All treatments were in combination therapy with metformin (1g twice daily)
Diabetes Care 32:84–90, 2009
Slide38Hb A1C Changes
Slide39Patients reaching Hb A1C
Slide40Changes in Weight
Slide41Slide4226-week, double-blind, placebo-controlled randomized trial 533 subjects randomized(1:1:1) to once-daily liraglutide (1.2 or 1.8 mg) or liraglutide placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily)
Diabetes Care 32:1224–1230, 2009
Slide43Hb A1C & FPG ChangesA1C values decreased significantly more in the liraglutide groups versus placebo (mean ± SE 1.5 ± 0.1% for liraglutide and 0.5 ± 0.1% for placebo)FPG decreased by 40, 44, and 8 mg/dl for 1.2 and 1.8 mg liraglutide and placebo, respectively
Diabetes Care 32:1224–1230, 2009
Slide44Hb A1C over time
Diabetes Care 32:1224–1230, 2009
Slide45Subjects achieving A1C goals
Diabetes Care 32:1224–1230, 2009
Slide46weight over time
Diabetes Care 32:1224–1230, 2009
Slide47581 patients with type 2 diabetes mellitus on prior OHA for at least 3 months (HbA1c 7–10%) Patients were randomized (2:1:2) to liraglutide 1.8 mg once daily (n=232), placebo (n=115) and open-label insulin
glargine
(n=234), all in combination with metformin (1 g twice daily) and glimepiride (4 mg once daily)Diabetologia (2009) 52:2046–2055
Slide48Changes in Hb A1CHbA1c reduction from baseline with liraglutide was 1.33% (final mean HbA1c 7.0%), with placebo 0.24% (final mean HbA1c 8.1%) and with insulin glargine 1.09% (final mean HbA1c 7.2%)Reduction in HbA1c with liraglutide was significantly greater than reduction observed in insulin glargine group
(−0.24%, 95% CI −0.39, −0.08; p=0.0015)
Diabetologia (2009) 52:2046–2055
Slide49Changes in Hb A1C
Diabetologia (2009) 52:2046–2055
Slide50Changes in Weight
Diabetologia (2009) 52:2046–2055
Slide51Change in HbA1c from baseline in LEAD trials
Slide52Change in body weight from baseline in
LEAD trials
Slide53Safety summary of LEAD trials
Slide54LEADERLEADER® is an international study that investigates a once-daily diabetes treatment developed by Novo Nordisk, and the effect it has on heart disease in people with type 2 diabetes.The study involves around 9,000 people with type 2 diabetes from more than 30 countries worldwide. It started in September 2010 and will run for approximately five
years (01/2016)
Slide55Slide56Slide57Liraglutide is effective across the continuum of care in type 2 diabetesLiraglutide is effective across the continuum of care
as monotherapy
after one oral antidiabetic drug (OAD)after two OADsprior to basal insulin therapy Marre et al. Diabetic Medicine 2009;26:268–78 (LEAD-1); Nauck et al. Diabetes Care 2009;32:84–90 (LEAD-2); Garber et al. Lancet
2009;373:473–81 (LEAD-3); Zinman et al. Diabetes Care 2009;32:1224–30 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:2046–55 (LEAD-5); Buse et al. Lancet 2009;374:39–47 (LEAD-6)
Slide58Liraglutide is effective across the continuum of care in type 2 diabetes
Slide59Liraglutide administration24-h glucose controlonce-daily dosingcan be given at any time of the day
dosing independent of meals
no need for additional self-monitored plasma glucose
Slide60Based on the LEAD studies, liraglutide offers simple dose initiation and titration
Slide61Conclusions
Incretin hormone secretion and actions are impaired in type 2 diabetes.
β-cell responsiveness to GLP-1 is reduced, but larger amounts of GLP-1 can still restore β-cell sensitivity to glucose and improve glucose-induced insulin and glucagon secretion.This can be obtained both with - incretin mimetics (GLP-1 receptor activators) or - incretin enhancers (DPP-4 inhibitors)
Incretin-based therapies of type 2 diabetes may be expected toCause sustained improvements in glycaemia and HbA1c levelsImprove α-cell and β-cell functionImprove insulin sensitivityImprove metabolism
Slide62ConclusionsLiraglutide is effective across the continuum of care in type 2 diabetesLiraglutide administration
2
4-h glucose controlonce-daily dosingcan be given at any time of the daydosing independent of mealsno need for additional self-monitored plasma glucoseLiraglutide offers a simple initiation, titration and maintenance regimen
Slide63ConclusionLiraglutide, as mono or combination therapy with a range of anti diabetic
drugs, can lead to significant improvements
in HbA1c, FPG and PPG, while reducing body weight and SBP significantlyLiraglutide is generally safe and well tolerated, and associated with a low rate of hypoglycemia with mild, transient nausea as the most commonly reported adverse event