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Dr Larry Distiller BSc MB BCh FCP(SA) FRCP FACE Specialist Physician / Endocrinologist Centre for Diabetes and Endocrinology, Houghton Hon Visiting Professor, Cardiff University School of Medicine
Insulin resistance Beta-cell function
Blood glucose
Euglycaemia Type 2 diabetes
Adequate Inadequate
Obesity Sedentary lifestyle Aging Genetics Glucotoxicity FFA levels
Adapted from Matthaei et al. Endocrine Reviews 2000;21:585-618. Adapted from Edelman. Adv Intern Med 1998;43:449-500.
Insulin response
Bianchi C et al. Diabetes Voice 2011;56:28-31
And many more in development
What are the incretins and gliptins?
Why should we use them?
When should they be used?
Should we be using them?
What are the incretins and gliptins?
Potent enhancers of glucose induced insulin secretion
Glucose-dependant insulinotropic
polypeptide, (GIP), formerly called gastric inhibitory polypeptide
Glucagon-Like Polypeptide 1 (GLP-1)
L-cell
(ileum)
K-cell
(jejunum)
Proglucagon
GLP-1 [7–37]
GLP-1 [7–36 NH2]
ProGIP
GIP [1–42]
Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422 Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Data from Drucker DJ. Diabetes. 1998;47:159-169
Stomach: Helps regulate gastric
emptying
Promotes satiety and reduces appetite
Liver: Glucagon reduces
hepatic glucose output Beta cells: Enhances glucose-dependent
insulin secretion
Alpha cells: Postprandial
glucagon secretion
GLP-1: Secreted upon the
ingestion of food
Slower gastric emptying - Direct effect on gastric emptying
Feeling of satiety - Blocks satiety centre centrally
Reduction in post-prandial glucose levels - Direct effect on insulin secretion (incretin effect) - Suppression of glucagon
N = 6; Mean (SE); *P0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498
C-p
ep
tid
e (
nm
ol/
L)
Time (min)
0.0
0.5
1.0
1.5
2.0
Incretin Effect *
*
*
*
* *
*
Oral Glucose
Intravenous (IV) Glucose
Pla
sma
Glu
cose
(m
g/d
L)
200
100
0
Time (min)
60 120 180 0 60 120 180 0
The incretin effect is severely reduced or even abolished in patients with Type 2 diabetes
Secretion of GIP is near-normal in most patients
with Type 2 diabetes, but insulinotropic effect of GIP is largely ablated in type 2 diabetes, even when infused at supraphysiologic levels
The secretion of GLP-1 is significantly impaired
Nauck MA, Baller B, Meier JJ. Gastric inhibitory polypeptide and
glucagon-like peptide-1 in the pathogenesis of type 2 diabetes. Diabetes. 2004;53(suppl 3):S190-S196.
Nauck MA, Baller B, Meier JJ. Gastric inhibitory polypeptide and
glucagon-like peptide-1 in the pathogenesis of type 2 diabetes. Diabetes. 2004;53(suppl 3):S190-S196.
Nauck MA, Baller B, Meier JJ. Gastric inhibitory polypeptide and
glucagon-like peptide-1 in the pathogenesis of type 2 diabetes. Diabetes. 2004;53(suppl 3):S190-S196.
Nauck MA, Baller B, Meier JJ. Diabetes.2004;53(suppl 3):S190-S196.
Time, min
IR In
suli
n,
mU
/L
0.6
0.5
0.4
0.3
0.2
0.1
0
80
60
40
20
0
180 60 120 0
Control Subjects (n=8)
Patients With Type 2 Diabetes (n=14)
Time, min
IR In
suli
n,
mU
/L
0.6
0.5
0.4
0.3
0.2
0.1
0
80
60
40
20
0
180 60 120 0
Oral glucose load
Intravenous (IV) glucose infusion
Incretin Effect
The incretin effect is diminished
in type 2 diabetes.
Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.
Data are mean±SEM. GIP, gastric inhibitory peptide; type 2 diabetes patients (n=8) Vilsbøll et al. Diabetologia 2002:45:1111–9
GLP-1 (but not GIP) increases both early- and late-stage insulin secretion
Mean (SE); n=10; *p<0.05; type 2 diabetes patients (n=10) Nauck et al. Diabetologia 1993;36:741–4
Placebo (PBO)
Native human GLP-1
The Problem
Native GLP-1 and GIP are broken down by DPP-4 in 1-2 minutes
The Solution ?
- GLP-1 analogues
- DPP-4 inhibitors
Exenatide (Byetta®, Eli Lilly)
Liraglutide (Victoza®, NovoNordisk) Others in the pipeline
Synthetic version of the salivary protein found in the Gila monster
More than 50 % amino acid
sequence identity with human GLP-1
▪ Binds to known human GLP-1 receptors
▪ Resistant to DPP-4 inactivation
Nielsen LL, et al. Regul Pept. 2004;117:77-88 Kolterman OG, et al. Am J Health-Syst Pharm. 2005;62:173-181
Following injection, exenatide is measurable in plasma for up to 10 hours
A slightly modified version of the GLP-1
molecule that attaches to albumin and therefore is released slowly, adopting the pharmacokinetic profile of albumin
The plasma half-life for this compound is
12 hours. It therefore provides exposure for over 24 hours following a single subcutaneous injection
Vildagliptin (Galvus® ,Novartis) Saxagliptin (Onglyza®, AstraZenica) Sitagliptin (Javunia® , Merck)
Linagliptin (Tradjenta®, BI / Eli Lilly)
Alogliptin
Release of active incretins GLP-1 and GIP Blood glucose in
fasting and postprandial states
Ingestion of food
Glucagon (GLP-1)
Hepatic glucose
production
GI tract
DPP-4 enzyme
Inactive GLP-1
X DPP-4
inhibitor
Insulin (GLP-1 & GIP)
Glucose- dependent
Glucose dependent
Pancreas
Inactive GIP
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.
Beta cells
Alpha cells
Glucose uptake by
peripheral tissue
GLP-1 Analogues DPP4-Inhibitors
• Supra-physiological levels of GLP-1 • Approaches physiological levels of GLP-1
*GLP-1 levels for liraglutide calculated as 1.5% free liraglutide
Degn et al. Diabetes 2004;53:1187–94; Mari et al. J Clin Endocrinol Metab 2005;90:4888–94
GLP-1 Analogues DPP4-Inhibitors
• Supra-physiological levels of GLP-1 • Approaches physiological levels of GLP-1
• Significant and sustained weight loss • Weight neutral
• Injected therapy • Oral therapy
• Potential GIT Side-effects • Minimal GIT side-effects
• Low rates of hypoglycaemia • Low rates of hypoglycaemia
• Improved CV risk factors • Limited data on CV risk factors
insulin secretion glucagon release food intake, slow gastric emptying
insulin secretion glucagon release
What are the incretins and gliptins?
Why should we use them?
When should they be used?
Should we be using them?
Why should we use them?
Exenatide (twice daily)
Liraglutide (once daily)
Change from baseline to 30 weeks
HbA1c (%) Body weight (kg)
Existing oral therapy
Exenatide
5 µg bid
Exenatide 10µg bid
Exenatide 5 µg bid
Exenatide 10 µg bid
Sulphonylurea1 0.46§ 0.86§ 0.9 1.6*
Metformin2 0.40‡ 0.78‡ 1.6§ 2.8§
Metformin + sulphonylurea3
0.60¶ 0.80¶ 1.6† 1.6†
*p<0.05; †p0.01; ‡p<0.002; §p<0.001; ¶p<0.0001;
all versus placebo
1. Buse J, et al.2004 2. DeFronzo R, et al.2005 3. Kendall D, et al. 2005.
-1.5
-1.0
-0.5
0.0
104-Week Completers at Week 30 104-Week Completers at Week 104
104-wk Completers; N = 195; Mean (SE); Weight is a secondary endpoint Data on file, Amylin Pharmaceuticals, Inc.
A
1C (
%)
W
eig
ht
(kg
) -6
-5
-4
-3
-2
-1
0 Mean baseline A1C: 8.2% Mean baseline weight: 101 kg
Significant *vs. comparator; #Change in HbA1c from baseline for overall population (LEAD-4,-5) add-on to diet and exercise failure (LEAD-3); or add-on to previous OAD monotherapy (LEAD-2,-1)
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)
• Weight and blood pressure did not differ between add-on and switch concept
*Change calculated by ANCOVA analysis
Nauck et al. Diabetes 2009;58(Suppl. 1):A122 (abstract 459-P)
Liraglutide 1.8 mg/day
Liraglutide 1.2 mg/day
Glimepiride 8 mg/day
• Waist circumference was reduced from baseline by 3.0 cm with liraglutide 1.8 mg
• Waist circumference increased by 0.4 cm with glimepiride (p<0.0001)
***p<0.0001 for change from baseline
Garber et al. Lancet 2009;373(9662):473–81 (LEAD-3)
• Both liraglutide and exenatide were combined with met and/or SU
Buse et al. Lancet 2009;374:39–47 (LEAD-6)
Buse et al. Lancet 2009;374:39–47 (LEAD-6)
Mean (2SE)
Buse et al. Lancet 2009;374:39–47 (LEAD-6)
Buse et al. Lancet 2009;374:39–47 (LEAD-6)
GLP-1 receptors are expressed in multiple organs including: Pancreas
Peripheral tissue
Central nervous system
Heart
Kidney
Lung
Gastrointestinal tract
GLP-1 appears to have a range of neurotrophic
neuroprotective and cardioprotective effects
GLP-1 receptors have been localized t0: ▪ Cardiomyocytes
▪ Endocardium
▪ Microvascular endothelium
▪ Coronary artery smooth muscle cells;
GLP-1
Heart (myocardium) • Protects against Ischaemia /
reperfusion injury • Improves myocardial function
Vascular System • Improves Endothelial function • Vasorelaxation
The Kidney • Increased diuresis and Na+ excretion Adapted from:
Chilton R et al. The American Journal of Medicine 2011;124, S35–S53
Promote Weight loss
Lower Triglyceride and raise HDL
Lower Blood pressure (?)
Improve endothelial dysfunction
Reduce CRP and other inflammatory markers
Increase myocardial insulin sensitivity
Increase myocardial glucose uptake
Koska J et al Diabetes Care 2010;33:1028-1030 Courreges JP et al Diabetes Medicine 2008;25:1129-1134 Nikolaidis LA st al. Circulation 2004;110:955-961 Bhashyam S. Et al Circ Heart Fail 2010;3:512-521
In Addition: Reduced monocyte adhesion to endothelial cells promoted
by inhibition of the inflammatory response to macrophages
Development of atherosclerotic lesions was suppressed in mice
GLP-1 was found to enhance coronary blood flow after induced ischaemia in rats
In one study, exenatide treated animals were shown to have as much as
40 % reduction in MI size when compared with controls
Chilton R et al. The American Journal of Medicine 2011;124, S35–S53
No effect of Exenatide 10 µg on QT interval
No relevant increases in the QTc interval using liraglutide once daily
No prolongation of the QT interval using exenatide once weekly
Chatterjee DJ et al. J Clin Pharmacol 2009;49:1353-59 Amylin Pharmaceuticals. Data on file.
LifeLink Study 39,000 patients treated with exenatide were compared with [approximately] 390,000 patients treated with all other interventional strategies
Significant decrease in cardiovascular events with Exenatide (hazard ratio, 0.81; [95 % confidence interval, 0.68-0.95; P=0.01]), indicating a 16 % decrease in cardiovascular events
Best JH et al. Diabetes Care 2011;34:90-95
Vilsboll T et al. BMJ 2012;344:d7771doi: Published Jan 2012
Vilsboll T et al. BMJ 2012;344:d7771doi: Published Jan 2012
Exenatide Liraglutide
Administration s.c. Twice daily s.c. Once daily
Mean Reduction in HbA1c ~o.8-1.1 % ~1.1-1.5 %
Mean reduction in FPG ~0.6 mmol/l ~1.7 mmol/l
Mean reduction in body weight 2.87 kg 3.24 kg
Persistence of nausea (after 26 weeks) 10 % 5 %
Liraglutide appears the better option on all fronts, but this may change with once-weekly exenatide which seems better than daily liraglutide
Adapted from: Buse et al. Lancet 2009;374:39–47 (LEAD-6)
Vildagliptin (Galvus® ,Novartis) Saxagliptin (Onglyza®, AstraZenica) Sitagliptin (Javunia® , Merck)
Linagliptin (Tradjenta®, BI / Eli Lilly)
Alogliptin
–0.8
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
Ch
an
ge in
A1C
, %
Mean Baseline: 8.0 % P<0.001*
†
‡
A1C
(95 % CI: –1.0, –0.6)
* Compared with placebo. † Least squares means adjusted for prior antihyperglycaemic therapy status & baseline value. ‡ Difference from placebo.
n=229
Mean Baseline: 170 mg/dL
P <0.001*
–17
-25
-20
-15
-10
-5
0
Ch
an
ge
in
FP
G, m
g/d
L
†
‡
FPG
(95 % CI: –24, –10)
n=234
Mean Baseline: 257 mg/dL
P<0.001*
–47
-60
-50
-40
-30
-20
-10
0
Ch
an
ge i
n 2
-hr
PP
G,
mg
/dL
†
‡
2-hr PPG
(95 % CI: –59, –34)
n=201
C. F. Deacon CF. Diabetes, Obesity and Metabolism 2010;13:7-18
Triangle, sitagliptin (100 mg qd) Circle, vildagliptin (50 mg bid or 100 mg qd) Square, saxagliptin (5 mg qd); Diamond, alogliptin (25 mg qd) Star, linagliptin (5 mg qd)
Sitagliptin administration at a single dose of 100 mg in patients with CAD:
Preserved LV function
Enhanced LV response to stress
Improved global and regional LV performance compared
with placebo
Read PA. Circ Cardiovasc Imaging 2010; 3: 195–201
No definitive evidence for this as yet.
Awaiting outcome of TECOS, SAVOR and other trials.
Why should we use them?
When should they be used?
Should we be using them?
When should they be used?
While the effects on glucagon, gastric emptying and satiety may well persist, the major effect of these drugs is still on insulin secretion
Therefore, the better the residual insulin secretory capacity (the more β-cell reserve), the better the expected response
None of these drugs are registered for first-line or monotherapy
But that is probably where they will prove to be most beneficial
Makes therapeutic sense: Basal insulin to target FPG; incretin to target PPG.
Sitagliptin has registration for use with insulin.
Exenatide has FDA approval for use with basal
insulin.
Liraglutide has been shown to be effective when combined with basal insulin.
When should they be used?
Should we be using them?
DPP-4 is found on endothelial and epithelial cells
throughout the vascular bed, and in the kidneys, intestines, exocrine pancreas, gastrointestinal tract,
biliary tract, thymus, lymph nodes, uterus, placenta, prostate, myocardium, and brain, as well as the adrenal, sweat, salivary, and mammary glands.
In addition, DPP-4 is also expressed on circulating T-lymphocytes and is found in soluble form in seminal and cerebrospinal fluid and plasma.
DPP-4 inhibition has not, as yet, been associated with any human disease.
96 DPP-4 inhibitors have shown a very positive safety and
tolerability profile in clinical studies involving thousands of patients with type 2 diabetes
DPP-4 inhibitor treatment has been associated with slightly elevated risks of nasopharyngitis, bronchitis, urinary tract infection and headaches
The debate rages!
Case reports have raised concerns about an increased risk of acute pancreatitis in patients treated with GLP-1 agonists
But Type 2 diabetes itself is said to be associated with a 3-fold increased risk of developing pancreatitis
So - is the incidence of pancreatitis higher with GLP-1
analogues or is it just a case of “awareness”?
A review of 10,000 patients on 19 clinical trials in patients on sitagliptin showed no increased risk of pancreatitis
In all animal studies, there is no evidence that DPP4-I cause pancreatitis
Engel SS et al. In J Clin Pract 2010;64:984-990 C. F. Deacon CF. Diabetes, Obesity and Metabolism 2010;13:7-18
German data base identified 11 cases of pancreatic cancer in association with exenatide
No such “signal” with DPP4-I
Exenatide promotes pancreatic ductal hyperplasia
However, the time between tumour induction, tumour growth and clinical diagnosis is > 10 years
Exenatide exposure was 2-33 months ▪ ? does exenatide promote tumour progression rather than initiation
Liraglutide induces thyroid C-cell focal hyperplasia and C-cell tumours in a dose-related manner in rats, which may lead to medullary thyroid cancer
In a 104-week exenatide carcinogenicity study in rats, an increased incidence of benign thyroid C-cell adenomas was seen
(Rats develop spontaneous C-cell lesions at a high frequency, while C-cell neoplasia is extremely
rare in humans)
This has not been seen in any of the clinical studies performed to
date
Knudsen LB. Endocrinology 2010; 151: 1473–1486 Parks M. N Engl J Med 2010; 362: 774–777
Elashoff M et al Gastroenterology 2011;141:150-156
We don’t know!
There are those who remain opposed to these drugs on basis of uncertainty
There are those who believe in these drugs implicitly
And many in-between! The jury is still out
“ History has taught us that enthusiasm for new classes of drugs, heavily promoted by the
pharmaceutical companies that market them, can obscure the caution that should be exercised when long-term consequences are
unknown”
Peter Butler. Diabetes Care 2010
We are constantly being pressurised by industry to prescribe newer and more expensive drugs
For most of us, there are intangible rewards for doing this
Don’t trust me, I’m a doctor…
“As to the honour and conscience of doctors, they have as much as any other class of men, no more and no less
And what other men dare pretend to be impartial where they have a strong pecuniary interest on one side?”
George Bernard Shaw, 1911
“Prediction is very difficult, especially about the future”
Niels Bohr
Thank you for your
attention
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