Incretins Therapy For Type 2 Diabetes Mellitus Dr' Majeed Mustafa, FRCP Ed' Consultant Endocrinologi

1
Incretins Therapy For Type 2Diabetes
MellitusDr. Majeed Mustafa, FRCP
(Ed.)Consultant Endocrinologist
DiabetologistGDC Hospital , November 15th 2008
2
The Incretin Effect OGTT and Matched IV
Infusion
Nauck et al. Diabetologia 198629 4652
3
History of Incretins

• 1902 Bayliss and Starling proposed that
  intestinal mucosa contained a hormone which
  stimulated the exocrine secretion of the pancreas
  (Secretin).
• 1906 Moore propposed the same concept
  secretin proposed as gut hormone that enhanced
  postprandial insulin release
• 1969 Term entero-insular axis coined by Unger
• La Barre proposed the name incretin for a
  hormone extracted from
• the upper gut mucosa which caused hypoglycemia
• 1960s Berson and Yalow developed RIA for insulin
  after which several
• groups found plasma insulin levels were higher
  after PO than IV glucose
• when BG was the same

4
History of Incretins

• 1970 JC Brown , GIP was isolated and sequenced
  from intestinal
• mucosa
• Brown and Dupre showed that GIP stimulated
  insulin secretion
• GIP was renamed glucose-dependent
  insulinotropic peptide
• 1982 Lund and co-workers sequenced the
  anglerfish proglucagon
• peptide
• 1983 G. Bell, et al cloned the human
  Proglucagon gene
• The human proglucagon sequence was
  subsequently deduced
• 1988 Göke discovered GLP-1 (7-36)

5
Incretins
Type of gastrointestinal hormone that cause
an increase in the amount of Insulin
released from the beta cells of the islets
of Langerhans after eating, even before
blood glucose levels become elevated.
6
Incretins

• Glucagon-like peptide-1 (GLP-1)
• Gastric inhibitory peptide (GIP)
• (glucose-dependent insulinotropic peptide)
• Both GLP-1 and GIP are rapidly inactivated
• by the enzyme dipeptidyl peptidase 4 (DPP-4).

7
Synthesis and Secretion of GLP-1 and GIP
8
The Incretins Structure
GLP-1 Glucagon-Like Peptide 1
A
G
F
S
S
V
L
G
A
H
E
T
T
D
Y
E
S
Q
A
K
A
F
K
L
R
I
E
V
W
G
G
GIP Gastric Inhibitory Polypeptide Glucose-Depend
ent Insulinotropic Polypeptide
A
G
F
S
I
Y
M
K
H
Y
E
T
I
D
A
D
S
I
Q
Q
N
F
A
K
G
L
D
K
V
N
D
L
K
W
Q
W
K
T
I
N
Q
H
Amino acids shown in yellow are homologous with
the structure of glucagon.
Drucker. Diabetes Care. 2003262929.
9
GLP-1 is Derived From Proglucagon
10
GLP-1 and GIP Are the Two Major Incretins
GLP-1glucagon-like peptide 1 GIPglucose-depende
nt insulinotropic polypeptide Adapted from
Drucker DJ Diabetes Care 20032629292940 Ahrén
B Curr Diab Rep 20033365372 Drucker DJ
Gastroenterology 2002122531544 Farilla L et
al Endocrinology 200314451495158 Trümper A et
al Mol Endocrinol 20011515591570 Trümper A et
al J Endocrinol 2002174233246.
11
Incretin Actions in Different Target Tissues
Heart
Satiety Appetite
Brain
Stomach
Oxygen consumption Cardiac output
Gastric emptying
Pancreas
Liver
Glucose dependant Insulin biosynthesis ß
cell proliferation ß cell apoptosis
Glucagon secretion
GI Tract
Glucose production
Glucose uptake
Muscle
12
GLP-1 Secretion and Metabolism
13
The Pathophysiology of Type 2 Diabetes Includes
Three Main Defects
Insulin deficiency
Pancreas
Excess glucagon
Hyperglycemia
Muscle and fat
Liver
Adapted from Buse JB et al. In Williams Textbook
of Endocrinology. 10th ed. Philadelphia,
Saunders, 200314271483 Buchanan TA Clin Ther
200325(suppl B)B32B46 Powers AC. In
Harrisons Principles of Internal Medicine. 16th
ed. New York McGraw-Hill, 200521522180
Rhodes CJ Science 2005307380384.
14
Insulin Response to IV GlucoseNormal and
Type 2 Diabetic Subjects40206080100
Glucose
Robertson Porte. J Clin Invest. 197352870-876
15
Beta-Cell Function Is Abnormal in Type 2 Diabetes

• A range of functional abnormalities is present
• Abnormal oscillatory insulin release
• Increased proinsulin levels
• Loss of 1st-phase insulin response
• Abnormal 2nd-phase insulin response
• Progressive loss of beta-cell functional mass

Adapted from Buchanan TA Clin Ther 200325(suppl
B)B32B46 Polonsky KS et al N Engl J Med
198831812311239 Quddusi S et al Diabetes Care
200326791798 Porte D Jr, Kahn SE Diabetes
200150(suppl 1)S160S163.
16
Insulin and Glucagon Response to a Large
Carbohydrate Meal in Type 2 Diabetes
Type 2 diabetes mellitus (n12) Nondiabetic
controls (n11)
150
120
Meal
Insulin (µU/ml)
90
60
30
0
130
Glucagon (µµg/ml)
120
Nonsuppressed glucagon
110
100
90
60
0
60
120
180
240
360
330
300
Glucose (mg/100 ml)
270
240
110
80
140
Time (minutes)
Insulin measured in five patients Adapted from
Müller WA et al N Engl J Med 1970283109115.
17
ß-Cell Mass Is Significantly Decreased in Obese
IFG and T2DM Patients
P lt .05 vs NGTP lt .001 vs NGT Butler A, et
al. Diabetes. 200352102-110.
18
UKPDS 16 Declining Beta-Cell Function Was
Associated with Increasing Hyperglycemia
100
10
9
75
8
Beta-cell function ()
HbA1c ()
50
7
25
6
Diet/conventional therapy (n110) Metformin
(n159) Sulfonylurea (n511)
Diet/conventional therapy (n297) Metformin
(n251) Insulin or sulfonylurea (n695)
5
0
0
1
2
3
4
5
6
0
1
2
3
4
5
6
Years
Years
Beta-cell function assessed by HOMA
HbA1c results shown from obese patients
UKPDSUnited Kingdom Prospective Diabetes Study
HbA1cglycosylated hemoglobin Adapted from UKPDS
Group Diabetes 19954412491258.
19
Belfast Diet StudyBeta-Cell Function Declined
While Insulin Sensitivity Remained Stable in Type
2 Diabetes
Insulin sensitivity
Beta-cell function
60
80
60
40
40
HOMA beta
HOMA sensitivity
20
20
0
0
0
2
4
6
0
2
4
6
Years from diagnosis
Years from diagnosis
Data from the first six years of 10-year
follow-up of the Belfast Diet Study Data from 67
newly diagnosed subjects with type 2 diabetes
mellitus (N432) who required oral
antihyperglycemic therapy or insulin due to
secondary failure of diet therapy during years 5
to 7 HOMAHomeostasis Model Assessment data
expressed as percentages of values in lean
nondiabetic reference population Adapted from
Levy J et al Diabet Med 199815290296.
20
Incretin Effect After Oral Glucose Was Diminished
in Type 2 Diabetes
Oral/Intravenous Glucose Infusion Study
Healthy controls (n8)
Type 2 diabetes (n14)
80
80
60
60
40
40
IR insulin (mU/L)
IR insulin (mU/L)
20
20
0
0
10
60
120
180
5
10
60
120
180
5
Time (minutes)
Time (minutes)
p?0.05 vs. respective value after oral
load IRimmunoreactive Adapted from Nauck M et al
Diabetologia 1986294652.
21
Incretin Effect After Oral Glucose Was
Diminished in Type 2 Diabetes
Oral/Intravenous Glucose Infusion Study
Healthy controls (n8)
Type 2 diabetes (n14)
Oral glucose (50 g/400 ml)
Isoglycemic intravenous glucose
20
20
15
15
Venous plasma glucose (mmol/L)
Venous plasma glucose (mmol/L)
10
10
5
5
0
0
10
60
120
180
5
10
60
120
180
5
80
80
60
60
IR insulin (mU/L)
IR insulin (mU/L)
40
40
20
20
0
0
10
60
120
180
5
10
60
120
180
5
Time (minutes)
Time (minutes)
p?0.05 vs. respective value after oral
load IRimmunoreactive Adapted from Nauck M et al
Diabetologia 1986294652.
22
GLP-1 Levels Decreased in Type 2 Diabetes
Meal Test Study
NGT (n33) Type 2 diabetes (n54)
20

15
GLP-1 (pmol/L)
10
5
0
0
60
120
180
240
Time (minutes)
plt0.05, type 2 diabetes vs. NGT Meal started at
time 0 and finished at 1015 minutes. Adapted
from Toft-Nielsen M-B et al J Clin Endocrinol
Metab 20018637173723.
23
Release of GLP-1 Is Impaired in Patients With T2DM
20




NGT IGT T2DM

Breakfast

15

GLP-1 (pmol/L)
10

5
0
0
60
120
180
240
Time (min)
Plt0.05 vs T2DM NGTnormal glucose
tolerance IGTimpaired glucose tolerance
Toft-Nielsen. J Clin Endocrinol Metab.
2001863717
24
GLP-1 Action Remained Intact in Patients with
Type 2 Diabetes
Hyperglycemic Clamp Study
GLP-1 infusion (low rate) GLP-1 infusion (high
rate)
60
51.4
PNS
50
38.2
40
Insulin (nmol liter 1 min)
30
20
PNS
7.4
7.5
10
0
Type 2 diabetes (n9)
NGT (n9)
Low rate0.4 pmol kg1 min1 High
rate1.2 pmol kg1 min1vs. corresponding NGT
group Study included four examinations per
patient 1) an oral glucose challenge and
hyperglycemic clamp experiments with
administration of 2) glucagon 3) GIP and 4)
GLP-1. Only results for GLP-1 are shown. Adapted
from Nauck MA et al J Clin Invest
199391301307.
25
Incretins and Type 2 Diabetes
Reduced incretin effect is not a primary
event in the development of type 2 diabetes,
but rather a consequence of the diabetic state.
Filip K. Knop et al ,Reduced Incretin Effect in
Type 2 Diabetes Cause or Consequence of the
Diabetic State? Diabetes.  200756(8)1951-1959
26
Effects of GLP-1 on Insulin and Glucagon Shown
to Be Glucose Dependent in Type 2 Diabetes
Placebo GLP-1 infusion
15.0
12.5
10.0
Glucose(mmol/L)
7.5
5.0
Infusion
250
200
Insulin(pmol/L)
150
100
50
20
Glucagon(pmol/L)
15
10
5
0
60
120
180
240
Time (minutes)
N10 patients with type 2 diabetes. Patients were
studied on two occasions. A regular meal and
drug schedule was allowed for one day between the
experiments with GLP-1 and placebo. plt0.05
GLP-1 vs. placebo Adapted from Nauck MA et al
Diabetologia 199336741744.
27
GLP-1 Increased Proliferation and Inhibited
Apoptosis of Beta Cells in Zucker Diabetic Rats
Beta-cell proliferation
Beta-cell apoptosis
30
2.5
25
2.0
20
1.4-fold increase(plt0.05)
3.6-fold decrease(plt0.001)
1.5
Apoptotic beta cells ()
Proliferating beta cells ()
15
1.0
10
0.5
5
0
0
Control
GLP-1treatment
Control
GLP-1 treatment
Study in Zucker diabetic rats that received a
two-day infusion of GLP-1 or saline followed by a
glucose tolerance test. Pancreatic sections were
drawn to measure islet mass, ß-cell
proliferation, and apoptosis. Adapted from
Farilla L et al Endocrinology 200214343974408.
28
GLP-1 Preserved Morphology of Human Islet Cells
In Vitro
GLP-1treated cells
Control
Islets treated with GLP-1 in culture were able
to maintain their integrity for a longer period
of time.
Day 1
Day 3
Day 5
Adapted from Farilla L et al Endocrinology
200314451495158.
29
Current Oral Therapies Do Not Address the
Multiple Defects in Type 2 Diabetes
Impaired insulinaction
Inadequate glucagonsuppression (?-cell
dysfunction)
Glucoseinflux from GI1 tract
Chronicß-celldecline
Acuteß-celldysfunction
Sulfonylureas
a-Glucosidaseinhibitors
TZDs2
unmet need
unmet need
Metformin
Glinides
? Plasma glucose and disease progression
1 Gastrointestinal 2 Thiazolidinedione DeFronzo
RA. Br J Diabetes Vasc Dis. 20033(suppl
1)S24S40
30
Pharmacologic Approaches to Enhancing GLP-1
Action in Diabetes

• Chronic infusion of rHu GLP-1 Not practical
• GLP-1 receptor agonists Exenatide ( Byetta )
• 
  Liraglutide
• DPP-IV inhibitors Sitagliptin ( Januvia )
• Vildagliptin (
  Glavus )
• Saxagliptin

rHurecombinant human DPP-IVdipeptidyl peptidase
IV
Drucker. Diabetes Care. 2003262929. Dungan.
Clin Diabetes. 20052356.
31

• July 2005 , GDC
• I presented a lecture entitled
• Intestinal Approach For The
• Treatment of Type 2 Diabetes
• Exanatide recently launched
• DPP 4 still under investigations

32
In Vitro and In Vivo DPP-4 Inhibition Increases
Levels of Biologically Active Incretins GLP-1 and
GIP
Meal
DPP-4 inhibitor
DPP-4enzyme
Intestinal GIP and GLP-1 release
GIP (142) GLP-1 (736)
GIP (342) GLP-1 (936)
Rapid degradation(minutes)
GIP and GLP-1 actions
Adapted from Deacon CF et al Diabetes
19954411261131 Kieffer TJ et al Endocrinology
199513635853596 Ahrén B Curr Diab Rep
20033365372 Deacon CF et al J Clin Endocrinol
Metab 199580952957 Weber AE J Med Chem
20044741354141.
33
Single-Dose OGTT Study- Key Findings

• Treatment with a Single-dose of Sitagliptin

Inhibited DPP-4 activity for 24 hours (80
inhibition)
Increased intact incretin levels 2-3 fold
Increased insulin levels(22 ) and decreased
glucagon levels
Reduced glucose levels after oral glucose
challenge (26 )
Data summarized for 200 mg sitagliptin
dose OGTToral glucose tolerance test AUCarea
under the curve G.herman, J Clin Endocrinol
Metab, November 2006, 91(11)4612-4619
34
Placebo-controlled monotherapy Baseline
Characteristics

• 741 patients
• Mean age 54.2
• 51.7 male
• Mean HbA1c 8.0
• Mean duration of disease 4.4 years
• 49 on prior AHAs

35
Placebo-controlled monotherapy Sitagliptin
Reduced HbA1c over 24 weeks
Treatment difference vs placebo Sitagliptin 100
mg -0.79 Plt 0.001 vs. placebo
HbA1c ()
- 0.79 Placebo- adjusted
36
Interpreting Glycemic EfficacyRequires
Understanding of Baseline HbA1c Levels
Protocol 021 (24 weeks) Sitagliptin 100 mg
(n229) Baseline HbA1c 8
HbA1c lt8 (n130) Mean 7.4
HbA1c ?8-lt9 (n62) Mean 8.4
HbA1c ?9 (n37) Mean 9.6
Change from baseline HbA1c (Placebo adjusted)

• Larger baseline HbA1c values show larger
  treatment effects
• Baseline HbA1c in most studies with Sitagliptin
  was 8
• Label studies for older products had higher
  baseline HbA1c values

37
Placebo-controlled monotherapy Sitagliptin
Improved Both Fasting and Post-meal Glucose In
Monotherapy
Fasting Glucose
Post-meal Glucose
? FPG 17.1 mg/dL (plt0.001)

• in 2-hr PPG 46.7 mg/dL (plt0.001)

189
288
180
252
171
Plasma Glucose mg/dL
216
Plasma Glucose mg/dL
162
Baseline
Baseline
24 weeks
24 weeks
180
153
Placebo (n247) Sitagliptin 100 mg (n234)
Placebo (N204)
Sitagliptin 100 mg (n201)
144
144
0
5
10
15
20
25
0
60
120
0
60
120
Time (weeks)
Time (minutes)
LS mean difference from placebo after 24 weeks
Aschner P et al, PN021. Abstract presented at
American Diabetes Association June 10, 2006
Washington, DC
38
FPG and PPG Contribution to A1C
Fasting
Postprandial
A1C ()
lt7.3
70
30
7.38.4
50
50
8.59.2
55
45
Contributionto A1C
60
40
9.310.2
30
70
gt10.2
Monnier. Diabetes Care. 200326881.
39
Placebo-controlled monotherapy study Sitagliptin
Did Not Increase Risk of Hypoglycemia-and had a
Neutral Effect on Body Weight

• Patients with at least one episode of
  hypoglycemia
• Placebo 2 patients out of 253 (0.8)
• Sitagliptin 100 mg 3 patients out of 238
  (1.3)
• No increase in body weight vs. baseline

Includes one hypoglycemic episode occurring
after initiation of glycemic rescue therapy
with metformin
40
Sitagliptin Metformin A1C Change in Patients
With T2DM
Goldstein BJ et al. Diabetes Care. 2007.
41
Sitagliptin as add-on to pioglitazone
42
Add-on to metformin vs. Adding Glipizide study
Baseline Characteristics

• 1172 patients (11 randomization)
• Mean age 57 years
• 60 male
• Mean HbA1c 7.5, 73 lt 8
• Mean duration of diabetes 6 years
• Prior AHA therapy
• Combination therapy 26
• Monotherapy 70
• Absence 5
• Numbers dont add to 100 due to rounding

43
Adding Sitagliptin vs. Glipizide to Metformin
Sitagliptin Showed Similar Glycemic Efficacy to
Glipizide When Added to Metformin
8.4
8.2
Sitagliptin 100 mg qd (n382)
8.0
Mean change from baseline (for both groups) -
0.67
7.8
7.6
7.4
Mean Change in HbA1c
7.2
7.0
6.8
6.6
6.4
6.2
6.0
0
12
24
38
52
Time (weeks)
per-protocol analysis -0.51 and -0.56 for
sitagliptin and glipizide in LOCF analysis
44
Adding Sitagliptin vs. Glipizide to Metformin
Progressively Greater Reductions in A1C as
Baseline A1C Rises
Study inclusion criteria 6.5-10
Sitagliptin 100 mg q.d.
Baseline A1C Category
Glipizide
N117
N112
N179
N167
Change from baseline in A1C ()
N82
N82
N21
N33
Per Protocol Population
45
Adding Sitagliptin vs. Glipizide to Metformin
Substantial Proportion of Patients Achieved Goal
on Sitagliptin As Add-on to Metformin
A1C lt 7 after 52 Weeks
Patients
Per Protocol Population
46
Adding Sitagliptin vs. Glipizide to Metformin
Sitagliptin vs. Glipizide Weight loss vs. gain
and hypoglycemia risk
Hypoglycemia
50
? between groups 2.5 kg (plt0.001)
40
1.1 kg
32
plt0.001
30
Incidence ()
20
10
4.9
-1.5 kg
0
Week 52
Glipizide (n584)
Glipizide (n584)
Sitagliptin 100 mg (n588)
Sitagliptin 100 mg (n588)
47
All Current Treatments for Type 2 Diabetes Have
Limitations
48
Hypoglycaemia in UKPDS a problem, also in type 2
diabetes
Patients reporting hypo-glycaemia during
treatment with
) Requiring 3rd party help
1. UKPDS 16. Diabetes 19954412491258. 2.
Riddle et al. Diabetes Care 20032630803086. 1.
Alberti. Pract Diab Int 2002192224. 2.
Korytowski. Int J Obesity 200226(Suppl
3)1824.3. Hunt et al. Diabetes Care
199720292298. 4. Leslie et al. Diabetes
Spectrum 1994752.
49
DDP- Inhibitors

• Advantages
• Oral bioavailability
• Decreases Hba1c by 0.5- 1
• Minimal hypoglycemic
• events
• Weight neutrality
• Can be combined with
• metformin or a TZD.

• Disadvantages
• Durability of Glycemic
• control
• DPP-4 inhibitors do not
• lower the blood glucose to a greater extent as
  compared to existing therapies
• Cost
• Long term safety data

Diabetes Care, Volume 26, Number 10, October 2003.
50
Mean Efficacy of PharmacotherapeuticOptions in
Type 2 Diabetes
51
Who might benefit most from incretin based
therapy

• Overweight or obese patients rather than add
• an agent which may cause additional weight
• gain
• Uncontrolled on current therapy especially
• those close to AIC goal
• ? Early in disease to preserve beta cells

52
Incretin Agents in Glucose Control
GIP gastric inhibitory peptide
Trujillo J. Formulary. 200641130-41.
53
Future of Incretins
? Type 2 diabetes Preserving B cell function
and mass ? Prevention of Type 2 diabetes ?
Treatment of IFG , IGT and Obesity ? Type 1
diabetes Benefits of glucagon suppression ?
Cardiology
54
GLP1 analogues with prolonged action
Liraglutide once daily injection
55
GLP 1 once weekly injection analogue
Taspoglutide investigational ? once
monthly injection