ueda2012 -incretin based therapy of type 2 diabetes mellitus_d.adel

Incretin Based Therapy of
Type 2 Diabetes Mellitus
BY
Prof. ADEL A EL-SAYED MD
Chairman Elect
Middle East and North Africa (MENA) Region
International Diabetes Federation (IDF)
Professor of Internal Medicine
Sohag Faculty of Medicine
Sohag-EGYPT

Pathophysiology of Type 2
Diabetes
• Insulin resistance.
• Beta cell dysfunction.

Pathophysiology of Type 2 Diabetes
Insulin Resistance
• Insulin Resistance starts very early in the
course of the disease.
• insulin resistance alone will not produce
diabetes. If beta-cell function is normal,
one can compensate for insulin resistance
by increasing insulin secretion.

Beta cell defect
• all type 2 patients have at least a relative defect in both
beta-cell function and mass.
• Function: in the (UKPDS), newly diagnosed people with
diabetes had, on average, only about 50% of normal
beta-cell function.[Diabetes. 1995;44:1249-1258 , Diab Res Clin
Pract. 1998;40(suppl):S21-S25. ]
• Mass: Autopsy studies comparing the volume of beta
cells in nondiabetic individuals with that of people with
diabetes found a 41% decrease in beta-cell mass among
people with type 2 diabetes

Beta cell defect
IV glucose infusion to a nondiabetic
individual results in a biphasic insulin
response:
- Immediate first-phase insulin response
in the first few minutes.
- Second-phase response, more
prolonged.

Beta cell defect
• This first-phase insulin response is absent
in type 2 diabetic patients contributing to
the excessive and prolonged glucose rise
after a meal in those with diabetes
Diabetologia. 2004;47(suppl 1):A279.
• Infusing insulin can only partially
improve this condition.

Other Factors
• Historically, hyperglycemia in diabetes has
been viewed as a failure of insulin-
mediated glucose disposal into muscle
and adipose tissue.
• This looks to be an over simplification of a
more complicated issue.

Other Factors
• Two other factors:
- Glucagon.
- Gastric emptying.

The Glucagon Factor
• In response to a carbohydrate-containing meal,
individuals without diabetes not only increase
insulin secretion but also simultaneously
decrease pancreatic alpha-cell glucagon
secretion.
• The decrease in glucagon is associated with a
decrease in hepatic glucose production, and
along with the insulin response, results in a very
modest increase in postprandial glucose.
N Engl J Med. 1971;285:443-449.

The Glucagon Factor
• In contrast, the glucagon secretion in type 2 diabetics is
not decreased, and may even be paradoxically
increased.
• These insulin and glucagon abnormalities produce an
excessive postprandial glucose excursion.
• more than 40 years ago, Roger Unger presciently stated,
"One wonders if the development of a pharmacologic
means of suppressing glucagon to appropriate levels
would increase the effectiveness of available treatments
for diabetes.
N Engl J Med. 1971;285:443-449.

The Gastric Emptying Factor
• Many factors can affect the rate of gastric
emptying.
• studies suggest that all other factors being
equal, most people with type 1 and type 2
diabetes have accelerated gastric emptying
compared to those without diabetes.
Gastroenterology. 1990;98:A378.

One last observation
• In healthy individuals, an oral glucose load is
associated with a greater insulin response than
administration of an isoglycemic IV glucose
infusion designed to mimic the plasma glucose
excursion achieved by the oral glucose load.
• Incretin hormones were discovered during
researchers trials to find out interpretation to this
phenomenon which has been called the incretin
effect.
J Clin Endocrinol Metab. 1986;63:492-498.

What are incretins?
• Hormones produced by the
gastrointestinal tract in response to
incoming nutrients, and have important
actions that contribute to glucose
homeostasis.
• Two hormones:
- Gastric inhibitory polypeptide (GIP)
. - Glucagon-like peptide-1 (GLP-1).

What are incretins?
Gastric Inhibitory Polypeptide
(GIP)
• Type 2 diabetes patients have a
resistance to GIP, making it a less
attractive therapeutic target.

What are incretins?
Glucagon-like peptide-1 (GLP-1)
• a 30-amino acid peptide secreted in
response to the oral ingestion of nutrients
by L cells, primarily in the ileum and colon.
• There are GLP-1 receptors in islet cells
and in the central nervous system, among
other places.
• GLP-1 is metabolized by the enzyme
dipeptidyl peptidase-IV (DPP-IV) .

Actions of GLP-1
• It enhances glucose-dependent insulin
secretion.
• Inhibits glucagon secretion and therefore
hepatic glucose production.
• Slows gastric emptying.
• Increases satiety resulting in less food
intake.
• Stimulates insulin gene transcription and
insulin synthesis.

Actions of GLP-1
• In animal studies: it increases beta-cell
mass by decreasing apoptosis and
increasing both beta-cell replication and
neogenesis from pancreatic ductal cells.
Diabetes Care. 2003;26:2929-2940.

Actions of GLP-1
• Important, as glucose levels approach the
normal range, the GLP-1 effects on insulin
stimulation and glucagon inhibition
declined (glucose dependence - reduction
of hypoglycemia - therapeutic advantage)
Diabetologia. 1993;36:741-744.

Actions of GLP-1
The Problem
• Unfortunately, GLP-1 is rapidly broken
down by the DPP-IV enzyme (very short
half-life in plasma - requires continuous IV
infusion).

What to do?
• Incretin mimetics are glucagon-like
peptide-1 (GLP-1) agonists (Exenatide).
• Dipeptidyl peptidase-IV (DPP-IV) antagonists
inhibit the breakdown of GLP-1 (Sitagliptin).

Exenatide
• The first incretin-related therapy available
for patients with type 2 diabetes.
• Naturally occurring peptide from the saliva
of the Gila Monster.
• Has an approximate 50% amino acid
homology with GLP-1.
• Binds to GLP-1 receptors and behaves as
GLP-1.
• Resistant to DPP-IV inactivation.

Exenatide Problems
• It is measurably present in plasma for up
to 10 hours. Suitable for twice a day
administration by subcutaneous injection.
Regul Pept. 2004;117:77-88.
Am J Health Syst Pharm. 2005;62:173-181.

Exenatide Problems
• Nausea (sometimes accompanied with
vomiting) has uniformly been observed
across the clinical trials, although most
episodes were mild-to-moderate in
intensity and generally intermittent.
• Usually more frequent at the initiation of
treatment and decreased over the course
of several weeks.

Dipeptidyl Peptidase-IV
Antagonists
Sitagliptin
• The concept is to allow the endogenous GLP-1
to remain in circulation for a longer period.
• DPP-IV inhibitors are oral, rather than injectable.
• Weight neutral.
• associated with a low incidence of hypoglycemia
or gastrointestinal side effects. Diabetes Care.
2004;27:2874-2880.
• Long-term studies suggest a durable effect on
glycemia and improvement in of beta-cell
function. (www.glucagon.com).

Sitagliptin
• Sitagliptin, is the first agent in this class to
have received FDA approval.
• Incidence of adverse reactions with
sitagliptin in clinical trials was similar to
placebo.
• Sitagliptin is indicated as monotherapy
and in combination with metformin or
thiazolidinediones.
• The usual recommended dose is 100 mg
once daily.

Sitagliptin
• Efficacy
• Body weight
• ß-cell function
• Hypoglycemia
• CV risk and CV events
• Guidelines
• Summary

Sitagliptin
Efficacy: HbA1c reduction
• Nauck et al.2007
Non-inferiority of sitagliptin to glipizide
(on top of metformin)

31
Screening
Single-blind
placebo
Double-blind treatment period:
Sulfonylurea or sitagliptin 100 mg/day
Metformin monotherapy
Week 2:
Eligible if HbA1c
≥6.5% to ≤10%
If on an OHA, D/C
Continue/start
metformin
Day 1
Randomization Week 52
 Randomized, double-blind, parallel-group, active-controlled, non-
inferiority study in patients with T2DM (N = 1172)
 Treatment:
– Sitagliptin 100 mg/day with metformin ≥1500 mg/day
– Sulfonylureaa
up to 20 mg/day with metformin ≥1500 mg/day
a
Sitagliptin (100 mg/day) with metformin (≥1500 mg/day); b
glipizide 5 mg/day increased to 20 mg/day (dose not uptitrated if
finger stick <110 mg/dL or hypoglycemia).
OHA = oral antihyperglycemic agent; D/C = discontinued; T2DM = type 2 diabetes mellitus.
Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205.
Study Design
Metformin (stable dose ≥1500 mg/day)
Add-on Sitagliptin With Metformina
vs Glipizideb
With Metformin Study

32
Sulfonylurea + metformin (n=411)
Sitagliptin + metformin (n=382)
HbA1c(%±SE)
LS mean change from baseline
(for both groups): –0.67%
Weeks
5.8
6.0
6.2
6.4
6.6
6.8
7.0
7.2
7.4
7.6
7.8
0 6 12 18 24 30 36 42 52
a
Sitagliptin (100 mg/day) with metformin (≥1500 mg/day).
Per-protocol population; LS = least squares.
Sitagliptin With Metformin Showed Comparable
Efficacy to Sulfonylurea With Metformin (52
Weeks)
vs Glipizide With Metformin Study

Adapted from T. Secket al. Int J Clin Pract, April 2010, 64, 5, 562–576.
Two Years extension Data
HbA1c With Sitagliptin or Glipizide as Add-on Combination With Metformin:
Comparable Efficacy
Published Apr.
2010
HbA1C
FPG
a

34
Baseline HbA1C Category
ChangeFromBaselinein
HbA1c(%)
n=117
117 112 179 167 82 82 33 21
<7% ≥7 to <8% ≥8 to <9% ≥9%
-0.14
-0.59
-1.11
-1.76
-0.26
-0.53
-1.13
-1.68
-2.0
-1.8
-1.6
-1.4
-1.2
-1.0
-0.8
-0.6
-0.4
-0.2
0.0
Sitagliptin + metformin
Sulfonylurea + metformin
n =
Greater Reductions in HbA1c
Associated With Higher Baseline HbA1c
a
Per-protocol population.

Substantial Proportion of Patients Achieved
Goal on Sitagliptin With Metformin
n = 411
%PatientsatHbA1cGoal HbA1c < 7% at Week 52
20
30
40
50
60
70
n = 382
63%
Sitagliptin + metformin
59%
Sulfonylurea + metformin
a
Per-protocol population.

37
UKPDS 34. Lancet 1998:352:854–865. n=at baseline;
Changeinweight(kg)
Years from randomisation
*diet initially then sulphonylureas, insulin and/or metformin if FPG >15 mmol/l
0
1
5
0 3 6 9 12
8
7
6
4
3
2
Insulin (n=409)
Glibenclamide (n=277)
Metformin (n=342)
Conventional treatment (n=411)*
Insulin
SU
Conv.
Met
SU and weight gain (UPKPS 34)

Abdominal obesity is linked to a higher risk for
myocardial infarction
Yusuf S. et al. Lancet 2004; 364:937-52
INTERHEART-Study:
Case control study in 52 countries: 15152 cases vs 14820 controls
Abdominal obesity* leads to a significantly higher risk
for myocardial infarction:
OR (99%CI): 4.5 and 4.7 in W Eur and N Amer population
*waist/hip/ratio: upper tertile vs lowest tertile

39
Sitagliptin With Metformin Provided Weight Reduction
(vs Weight Gain)
a
All-patients-as-treated population.
Least squares mean between-group difference at Week 52 (95% CI): change in body weight = –2.5 kg [–3.1, –2.0] (P<0.001);
Least squares mean change from baseline at week 52: glipizide: +1.1 kg; sitagliptin: –1.5 kg (P<0.001).
BodyWeight(kg±SE) Sulfonylurea + metformin (n=416)
-3
-2
-1
0
1
2
3
Weeks
Least squares mean change over timeb
0 12 24 38 52

Two Years extension Data- 2010
Sitagliptin With Metformin Provided Weight Reduction
(vs Weight Gain)
Published Apr.
2010
Adapted from T. Secket al. Int J Clin Pract, April 2010, 64, 5, 562–576.
a
Sitagliptin (100 mg/day) with metformin (≥1500 mg/day);

ADOPT: Progressive deterioration of
glucose control

Sitagliptin and β-cell Mass
Mu J. et al. Eur J Pharm 2009; 623: 148-154

380,000 Emergency Department visits per year
in the U.S (1993 -2005) were attributed to Hypoglycemia
• 5 million emergency department visitsa
between 1993
and 2005 for hypoglycemia1
– 25% resulted in hospital admission
– 72% of patients had hypoglycemia as the primary
(first-listed) diagnosis
– ~44% of reported cases occurred in adults
≥65 years of age
1. Ginde AA et al. Diabetes Care. 2008;31:511–513.
2. Matyka K et al. Diabetes Care. 1997;20(2):135–141.

Vicious circle of hypoglycemia awareness
Hypoglycemic
events
lead
hypoglycaemic
events
Frequent hypoglycemias
<60 mg/dl
Adapted from Hermanns et al. Diabetologie 2009; 4: R 93-R112
Symptoms of hypoglycemia:
- weaker
- appear later
- change
Awareness of hypoglycemia:
- more difficult
- less reliable

Asymptomatic Episodes of Hypoglycemia May Go
Unreported
• In a cohort of patients
with diabetes, more
than 50% had
asymptomatic
(unrecognized)
hypoglycemia, as
identified by continuous
glucose monitoring1
• Other researchers have
reported similar
findings2,3
1. Copyright © 2003 American Diabetes Association. Chico A et al. Diabetes Care. 2003;26(4):1153–1157.
Reprinted with permission from the American Diabetes Association.
2. Weber KK et al. Exp Clin Endocrinol Diabetes. 2007;115(8):491–494.
3. Zick R et al. Diab Technol Ther. 2007;9(6):483–492.
0
25
50
75
100
All patients
with diabetes
Type 1
diabetes
Patients,%
Type 2
diabetes
55.7
62.5
46.6
Patients With ≥1 Unrecognized
Hypoglycemic Event, %
n=70 n=40 n=30

Complications and Effects of Severe
Hypoglycemia
Plasma glucose level
10
20
30
40
50
60
70
80
90
100
110
1
2
3
4
5
6
mg/dL
mmol/L
1. Landstedt-Hallin L et al. J Intern Med. 1999;246:299–307.
2. Cryer PE. J Clin Invest. 2007;117(4):868–870.
Increased Risk of Cardiac
Arrhythmia1
Progressive
Neuroglycopenia2
 Abnormal prolonged cardiac
repolarization—
↑ QTc and QTd
 Sudden death
 Cognitive impairment
 Unusual behavior
 Seizure
 Coma
 Brain death

50
Low Blood sugar warning sounded by study!
A WARNING PUBLISHED October 7, 2010
Severe Hypoglycemia and Risks of Vascular Events and Death
Methods:
Examined the associations between severe hypoglycemia and the risks of macrovascular
or microvascular events and death among 11,140 patients with type 2 diabetes,
Risk Factors for Severe Hypoglycemia
•older age,
•longer duration of diabetes,
•higher creatinine levels,
•Lower body-mass index,
•lower cognitive function,
•use of two or more oral glucose-lowering drugs,
•History of smoking or microvascular disease, and
•Assignment to intensive glucose control (P<0.05 for all)
Sophia Zoungas, M.D., Ph.D.,N Engl J Med 2010; 363:1410-1418October 7, 2010

Sitagliptin With Metformin Provided Much Lower Incidence
of Hypoglycemia
a
All-patients-as-treated population.
Least squares mean between-group difference at Week 52 (95% CI): change in body weight = –2.5 kg [–3.1, –2.0] (P<0.001);
Least squares mean change from baseline at week 52: glipizide: +1.1 kg; sitagliptin: –1.5 kg (P<0.001).
Hypoglycemiab
P<0.001
32%
5%
0
10
20
30
40
50
Week 52
%ofPatientsWith≥OneEpisode
Sulfonylurea + metformin (n=584)
vs Glipizideb
With Metformin Study

Presented
EASD 2010
BJ. Goldstein et al. Poster presented at EASD 2010
Sitagliptin With Metformin Provided Much Lower Incidence of Hypoglycemia
vs Glimepride With Metformin Study

2008 CDA Pharmacotherapy Algorithm
Clinical assessment
Lifestyle intervention (initiation of nutrition therapy and physical activity)
A1C < 9.0% A1C ≥ 9.0% Symptomatic hyperglycemia with
metabolic decompensation
Initiate pharmacotherapy immediately without waiting
for effect from lifestyle interventions:
• Consider initiating metformin concurrently with another agent from a different
class; or
• Initiate insulin
Initiate metformin
Initiate
insulin ±
metformin
Add an agent best suited to the individual:
• Alpha-glucosidase inhibitor
• Incretin agent: DPP-4 inhibitor
• Insulin
• Insulin secretagogue: meglitinide, sulfonylurea
• TZD
• Weight-loss agent
• Add another drug from a different class; or
• Add bedtime insulin to other agent(s); or
• Intensify insulin regimen
If not at target
If not at target
L
I
F
E
S
T
Y
L
E
Timely adjustments to and/or addition of antihyperglycemic agents should be made to attain target A1C within 6-12 months
CDA Clinical Practice Guidelines Expert Committee. Can J Diabetes 2008; 32(suppl 1):S1-S201.

58
Algorithm1,2
HbA1C 6.5%* after trial of lifestyle measures≥
SU
Where blood glucose
control remains or
becomes inadequate on
metformin
TZD (glitazones)†
Consider adding instead of an SU
where
• Patients are at significant risk of
hypoglycaemia
or its consequences
• Patients are intolerant of or contra-indicated
to SU
May be preferable to DPP-4 inhibitors
where
• The patient has marked insulin insensitivity
• DPP-4 inhibitors are contra-indicated
• Previous poor response or intolerance to a
DPP-4 inhibitor
Where either a DPP-4 inhibitor or a
TZD may be suitable, the choice of
treatment should be based on patient
preference
* Or individually agreed target. Monitor patient following initiation of a new therapy and continue only if beneficial metabolic response occurs (refer to guideline
for suggested metabolic responses). Discuss potential risks and benefits of treatments with patients so informed decision can be made.
† When selecting a TZD take into account up-to-date advice from the relevant regulatory bodies, cost, safety and prescribing issues. Do not commence or
continue a TZD in people who have heart failure, or who are at higher risk of fracture.
HbA1C 6.5%*≥
Usual approach
DPP-4 inhibitor
Consider adding instead of an SU
where
• Patients are at significant risk of
hypoglycaemia or its consequences
• Patients are intolerant of or contra-indicated
to SU
May be preferable to TZD where
• Further weight gain would cause or
exacerbate significant problems associated
with a high body weight
• TZDs are contra-indicated
• Previous poor response or intolerance to a
TZD
Where either a DPP-4 inhibitor or a
TZD may be suitable, the choice of
treatment should be based on patient
preference
Alternatives
Metformin
Consider SU in people who
• Are not overweight
• Require a rapid response due to hyperglycaemic symptoms
• Are unable to tolerate metformin or where metformin is contra-indicated

Summary
• DPP-IV inhibitors raise GLP-1 levels 2- to 3-fold.
• Sitagliptin is the first of the DPP-IV inhibitors to
receive FDA approval.
• Sitagliptin is effective in glycemic control and
HbA1c reduction.
• The incidence of hypoglycemia with Sitagliptin is
very low.
• Sitagliptin appears to be weight beneficial and
have an incidence of adverse reactions similar
to placebo in clinical trials.
• It preserves and may improve beta cell funcion.
• Recently it is recognized as safe and effective
therapy in most of the guidelines.

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