EMERGING

THERAPIES
IN
DIABETES MELLITUS
(TYPE II)
BY
SWAPNAJEET SAHOO
4th yr
VSS MEDICAL COLLEGE,BURLA
 INTRODUCTION
 Diabetes mellitus is a syndrome characterized by hyperglycemia

due to

 Absolute insulin deficiency - Type 1 DM

 Relative insulin deficiency – Type 2 DM

 One of leading causes of morbidity & mortality worldwide.

 It has been estimated that over 230 million diabetics by 2010 &

300 million by 2025 (King et al 1998) , majority being T2DM.

 So, there is urgent need for strategies to be implemented to

prevent the emerging global epidemic of diabetes ( mainly T2DM)

β-Cell function and glucagon
in Type 2 diabetes
 Loss of β-cell function and glucagon over-
secretion both play key roles in Type 2
diabetes development
 Progressive β-cell decline is coupled with
inadequate insulin secretion
 Glucagon is not suppressed during the
postprandial period
 Hepatic glucose production is increased
during the fasting period and is not
suppressed during the postprandial period
 β-Cell mass in Type 2
diabetes
3.5

3.0
-50%
β -Cell volume (%)

2.5

2.0 -63%
1.5

1.0

0.5

0.0
ND IFG T2DM ND T2DM
Obese Lean
ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitus
Butler et al. Diabetes. 2003
 Excessive hepatic
glucose production in
Type 2 diabetes

Insulin; IR
Hepatic
glucose Glucagon
output Fasting &
postprandial
hyperglycaemia

Plasma glucose
concentration
IR=insulin resistance
 PRESENT ORAL
HYPOGLYCEMIC DRUGS
SULFONYL UREAS:
 1ST GENERATION- Tolbutamide

 2nd GENERATION – Glimepiride,

Glibenclamide,Glipizide

BIGUANIDES – Metformin
MEGLITINIDE ANALOGS – Repaglinide,
Nateglinide
THIAZOLIDINEDIONES –
ORAL HYPOGLYCEMIC
DRUGS
 ADVERSE EFFECTS OF
 Sulfonyl ureas
OHAS
- Hypoglycemia
(most common)
 Metformin – lactic acidosis & GI
disturbances
 Meglitinide analogues – Hypoglycemia(
less) & wt. gain
 Thiazolidinediones- plasma volume
expansion
- edema & heart failure
- weight gain
- mild anemia
 Alfa glucosidase inhibitors – flatulence
 Incretin
Therapies
 WHAT R
INCRETINS ?
 Incretins are gut peptides that potentiate insulin secretion
Incretins are gut peptides that potentiate insulin secretion
during eating.
 mainly 2 types – GIP ( gastro inhibitory peptide)
- GLP-1 ( glucagon like peptide )
 GIP- secreted from K cells of intestine (Duodenum)
doesnot delay gastric emptying
doesnot affect pancreatic alpha cells secretion of
glucagon.
 GLP-1 – secreted from L cells of intestine ( ileum & colon)
stimulates glucose dependent insulin release
delays gastric emptying.
 So, GLP-1 has been considered a viable therapeutic
approach in management of T2DM.
 Incretin effect on insulin secretion
Control subjects (n=8) People with Type 2 diabetes (n=14)
80 80

60 60

Insulin (mU/l)
Insulin (mU/l)

40
Incretin 40
effect
20 20

0 0
0 60 120 180 0 60 120 180
Time (min) Time (min)

Oral glucose load

Intravenous glucose infusion

Nauck et al. Diabetologia. 1986

 GLP-1: effects in
humans
• Stimulates glucose-
After food ingestion… dependent insulin secretion
• Suppresses glucagon
secretion
• Slows gastric emptying

• Leads to a reduction of
GLP-1 is secreted from food intake
L-cells of the jejunum
and ileum • Improves insulin sensitivity

That in turn…
Drucker. Curr Pharm Des. 2001
Drucker. Mol Endocrinol. 2003
Long-term effects
in animal models:
• Increase of β-cell mass
and improved β-cell function
 GLP-1 enhancement
GLP-1 secretion is impaired in Type 2 diabetes
Natural GLP-1 has extremely short half-life

Add GLP-1 analogues Block DPP-4, the

with longer half-life: enzyme that degrades
• exenatide GLP-1:
• liraglutide • sitagliptin
• vildagliptin

Injectables Oral agents

Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003

Incretin-Based Therapies

• Incretin Mimetics (GLP-1

agonists/analogs)
– Exenatide (Byetta)
– Others: Liraglutide, LY307161 SR, CJC-
1131,
ZP10, BIM51077
• Incretin Enhancers (DPP-IV
inhibitors)
– Sitagliptin
 GLP-1 RECEPTOR AGONISTS
EXENATIDE
 Approved by FDA April 2005 for T2DM with
SU/metformin
 39 amino acid Synthetic peptide originally identified
in Gila lizard (Heloderma suspectum)
 Exhibits incretinmimetic activity
 Significant 1 – 1.2% decrease in HbA1c
 T1/2 – 2.4 hrs
 Subcutaneously administered
 Dose- 5 mcg start BD – 10 mcg BD
 S/E – nausea (most common), disappears after few
wks
diarrhoea,dizziness (less common)
 C/I – hypersensitive pts
anti exenatide antibodies may develop in end
LIRAGLUTIDE
 GLP-1 analog with longer half life – 10 -14 hrs
 Once daily dose of 0.6 – 1.8 mg SC
 Awaits FDA approval.

EXENATIDE LAR
 Microsphere suspension of exenatide.
 Once a weekly regimen in a dose of 0.8-2.0 mg
 Significant decrease in HbA1c – 1.4-1.7% has been seen
 Offers potential of 24 hrs glycemic control & wt.
reduction when combined with metformin &/or diet &
exercise in T2DM
 Long term trials are underway
 Diagram of how DPP-4
inhibition might be expected
to improve blood glucose
control
Increase
Increaseinsulin secretion
insulin secretion
Active GLP-1
Active GLP-1
Decrease
Decreaseglucagon release
glucagon release

DPP-4 XDPP-4 inhibitor

Inactive GLP-1 Glucose

Glucose control
control
improved
 DPP – IV INHIBITORS
SITAGLIPTIN(JANUVIA/JANUMET)
 Approved by FDA Oct 2006 for T2DM with
metformin/TZDs/ monotherapy.
 Dose – 100 – 200mg orally OD
 Reduction in 0.74-0.94% HbA1c
 Doesn't cause nausea or weight loss
 DPP-IV inhibition could affect other hormone
degradation like hGH.
 Would not be used in transplant pts.
VILDAGLIPTIN(GALVUS)
 Pending approval by FDA , in phase III trials.
 Dosage studied – 50 -100 mg daily
 Has shown equally encouraging results both
when used as monotherapy / in combination with
metformin/TZDs
 Till date no A/E has been reported .

There is much possibility that one of

the gliptins may emerge as a 1st line
treatment in combination with metformin
in newly diagnosed pts with T2DM may
materialize into recommended future
 Incretin mimetics Vs DPP-IV
inhibitors
Properties/effect Incretin DPP-4
mimetics inhibitors
Mechanism of stimulation of Yes Unknown
insulin secretion exclusively
through GLP-1 effect

Hypoglycaemia No No

Maintained counter-regulation Yes Not tested

by glucagon in hypoglycaemia
Inhibition of gastric emptying Yes Marginal

Effect on body weight Weight loss Weight neutral

Side effects Nausea None observed

Administration Subcutaneous Oral

AMYLIN/IAPP
 37 AA peptide co-secreted with insulin in response to
nutrient ingestion.
 Stimulated also by glucagon & GLP-1
 Main effect – inhibition of gastric emptying & glucagon
secretion.
 Leads to reduced food intake & weight loss.

PRAMLINTIDE(Symlin)
 Amylin analog ,differs from it by 3 AAs
 Slows gastric emptying & suppresses post prandial
glucagon secretion
 Given SC prior major meals.
 Indicated in T2DM – adjunct T/t to meal time insulin
with/without a
SU/metformin.
 Advantages - wt. loss of 1 – 1.5 kg over 6 months
- decreases HbA1c by 0.5 – 0.7%
 A/E – nausea(50% cases), headache ,hypoglycemia (rare)
 WHO MIGHT BE BENEFITED
THE MOST ?

 Overweight or obese patient

–without adding an agent which may
cause additional weight gain
 Uncontrolled on current therapy
– Especially those close to A1C goal
 ? Early in disease to preserve beta
cells
 Incretins: Crystal

Gazing
Whether the early introduction of gliptins in
management schema will protect β cell
functions?
 Will the use of incretins prevent/ delay the
progression of the early stages to frank T2DM?
 In India , the present cost of sitsgliptin(100mg)
is Rs 250/day
 But , finally keeping in view the safety & cost
effectiveness will such therapeutic
interventions be superior to lifestyle
 OTHER DEVELOPMENTS

ORAL INSULIN ????

 Oral insulin spray {Oral- lyn} for T1DM &
T2DM approved in Ecuador.
 In India, The Thiruvanthapuram based Sree
Chitra Tirunal Institute of Medical Sciences
& Technology – has successfully
demonstrated the an oral insulin
preparation in experiments on mice.
 Stem cell therapy by Volterelli et al (2007)
for T1DM
stem cells from bone marrow are more
likely to differentiate into insulin producing
cells.
 Want to know more ???
SITES:
www.hormone.org
www.medscape.com
www.medworm.com

www.diabeteshealth.com

www.dentocafe.com
BOOKS:
JOSLIN’S DIABETES MELLITUS
KATZUNG PHARMACOLOGY
LIPPINCOTT
PHARMACOLOGY