Dr Larry Distiller BSc MB BCh FCP(SA) FRCP FACE Specialist ...

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

Obesity Sedentary lifestyle Aging Genetics Glucotoxicity FFA levels
Insulin resistance
Beta-cell function
Blood glucose
Adequate
Insulin response
Inadequate
Euglycaemia
Type 2 diabetes
Adapted from Matthaei et al. Endocrine Reviews 2000;21:585-618.
Adapted from Edelman. Adv Intern Med 1998;43:449-500.

And many more in
development
Bianchi C et al. Diabetes Voice 2011;56:28-31

• 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)
ProGIP
Proglucagon
GLP-1 [7–37]
GIP [1–42]
GLP-1 [7–36 NH 2 ]
K-cell
(jejunum)

GLP-1: Secreted upon the
ingestion of food
Promotes satiety and
reduces appetite
Alpha cells:
Postprandial
glucagon secretion
Beta cells:
Enhances glucose-dependent
insulin secretion
Liver:
Glucagon reduces
hepatic glucose output
Stomach:
Helps regulate gastric
emptying
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

• 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

Plasma Glucose (mg/dL)
C-peptide (nmol/L)
Oral Glucose
Intravenous (IV) Glucose
200
2.0
1.5
*
*
*
*
Incretin Effect
* *
*
100
1.0
0.5
0
0.0
0
60 120 180
Time (min)
0
60 120 180
Time (min)
N = 6; Mean (SE); *P0.05
Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-498

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.
• 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. Diabetes.2004;53(suppl 3):S190-S196.

IR Insulin, mU/L
IR Insulin, mU/L
80
60
Control Subjects
(n=8)
Incretin
Effect
0.6
0.5
0.4
80
60
Patients With Type 2 Diabetes
(n=14)
The incretin effect
is diminished
in type 2 diabetes.
0.6
0.5
0.4
40
0.3
40
0.3
0.2
0.2
20
0.1
20
0.1
0
0
0
0
0
Time, min
Oral glucose load
60 120
180
0
60 120
Time, min
180
Intravenous (IV) glucose infusion
Adapted from Nauck M et al. Diabetologia. 1986;29:46–52. Copyright © 1986 Springer-Verlag.

GLP-1 (but not GIP) increases both early- and late-stage insulin secretion
Data are mean±SEM. GIP, gastric inhibitory peptide; type 2 diabetes patients (n=8)
Vilsbøll et al. Diabetologia 2002:45:1111–9

Mean (SE); n=10; *p

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
Following injection, exenatide is measurable in plasma
for up to 10 hours
Nielsen LL, et al. Regul Pept. 2004;117:77-88
Kolterman OG, et al. Am J Health-Syst Pharm. 2005;62:173-181

• 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

Ingestion of
food
Release of
active incretins
GI tract GLP-1 and GIP
Pancreas
Beta cells
Alpha cells
Glucose
dependent
Insulin
(GLP-1 & GIP)
Glucose
uptake by
peripheral tissue
Blood glucose in
fasting and
postprandial states
DPP-4
inhibitor
Inactive
GLP-1
X
DPP-4
enzyme
Inactive
GIP
Glucosedependent
Glucagon
(GLP-1)
Hepatic
glucose
production
GLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.

GLP-1 Analogues
• Supra-physiological levels of GLP-1
DPP4-Inhibitors
• 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
• Supra-physiological levels of GLP-1
• Significant and sustained weight loss
• Injected therapy
• Potential GIT Side-effects
• Low rates of hypoglycaemia
• Improved CV risk factors
insulin secretion
glucagon release
food intake, slow gastric emptying
DPP4-Inhibitors
• Approaches physiological levels of GLP-1
• Weight neutral
• Oral therapy
• Minimal GIT side-effects
• Low rates of hypoglycaemia
• Limited data on CV risk factors
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
HbA 1c (%)
Body weight (kg)
Existing oral
therapy
Exenatide
5 µg bid
Exenatide
10µg bid
Exenatide
5 µg bid
Exenatide
10 µg bid
Sulphonylurea 1 0.46 § 0.86 § 0.9 1.6*
Metformin 2 0.40 ‡ 0.78 ‡ 1.6 § 2.8 §
Metformin +
0.60 0.80 1.6 † 1.6 †
sulphonylurea 3
*p

A1C (%)
Weight (kg)
104-Week Completers at Week 30
104-Week Completers at Week 104
0.0
Mean baseline A1C: 8.2%
0
Mean baseline weight: 101 kg
-1
-0.5
-2
-3
-1.0
-4
-5
-1.5
-6
104-wk Completers; N = 195; Mean (SE); Weight is a secondary endpoint
Data on file, Amylin Pharmaceuticals, Inc.

Significant *vs. comparator; # Change in HbA 1c 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)

• 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

• 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;

Heart (myocardium)
• Protects against Ischaemia /
reperfusion injury
• Improves myocardial function
Vascular System
• Improves Endothelial function
• Vasorelaxation
GLP-1
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 HbA 1c ~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

‡
Change in A1C, %
‡
Change in FPG, mg/dL
‡
Change in 2-hr PPG, mg/dL
0.0
-0.2
-0.4
-0.6
-0.8
-1.0
A1C
Mean Baseline: 8.0 %
P

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)
C. F. Deacon CF. Diabetes, Obesity and Metabolism 2010;13:7-18

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

Thank you
for your
attention
“Prediction is very difficult, especially about the future”
Niels Bohr