diabetes mellitus emerging therapies by asluad

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									EMERGING THERAPIES IN DIABETES MELLITUS (TYPE II)
BY SWAPNAJEET SAHOO 4th yr VSS MEDICAL COLLEGE,BURLA

PUBLISHED BY www.medicalppt.blogspot.com
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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)
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β-Cell function and glucagon in Type 2 diabetes


Loss of β-cell function and glucagon oversecretion 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
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β-Cell mass in Type 2 diabetes
3.5 3.0

b -Cell volume (%)

2.5 2.0 1.5 1.0 0.5 0.0 ND

-50%

-63%

IFG

T2DM

ND

T2DM

Obese
www.medicalppt.blogspot.com ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitus for more lectures Butler et al. Diabetes. 2003

Lean

Excessive hepatic glucose production in Type 2 diabetes

Hepatic glucose output

Insulin; IR Glucagon
Fasting & postprandial hyperglycaemia

Plasma glucose concentration
IR=insulin resistance
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PRESENT ORAL HYPOGLYCEMIC DRUGS
SULFONYL UREAS:


1ST GENERATION- Tolbutamide
2nd GENERATION – Glimepiride,



Glibenclamide,Glipizide

BIGUANIDES – Metformin MEGLITINIDE ANALOGS – Repaglinide, Nateglinide
THIAZOLIDINEDIONES – Rosiglitazone,Piaglitazone

ALPHA GLUCOSIDASE INHIBITORS – Acarbose, Miglitol
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ORAL HYPOGLYCEMIC DRUGS

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ADVERSE EFFECTS OF OHAS
   

Sulfonyl ureas Metformin

- Hypoglycemia (most common) – 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 - loose stools.

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Incretin Therapies

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WHAT
 

R

INCRETINS ?
( gastro inhibitory peptide) ( glucagon like peptide )

Incretins are gut peptides that potentiate insulin secretion during eating. mainly 2 types – GIP - GLP-1



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. www.medicalppt.blogspot.com
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Incretin effect on insulin secretion
Control subjects (n=8)
80

People with Type 2 diabetes (n=14)
80

40

Incretin effect

Insulin (mU/l)

Insulin (mU/l)

60

60

40

20

20

0 0 60 120 180

0 0 60 120 180

Time (min) Oral glucose load Intravenous glucose infusion
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Time (min)

Nauck et al. Diabetologia. 1986

GLP-1: effects in humans
After food ingestion… • Stimulates glucosedependent insulin secretion • Suppresses glucagon secretion • Slows gastric emptying GLP-1 is secreted from L-cells of the jejunum and ileum • Leads to a reduction of food intake • Improves insulin sensitivity

That in turn…

Long-term effects in animal models:

• Increase of β-cell mass and improved β-cell function
Drucker. Curr Pharm Des. 2001 Drucker. Mol Endocrinol. 2003
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GLP-1 enhancement
GLP-1 secretion is impaired in Type 2 diabetes
Natural GLP-1 has extremely short half-life

Add GLP-1 analogues with longer half-life: • • exenatide liraglutide

Block DPP-4, the enzyme that degrades GLP-1: • sitagliptin • vildagliptin

Injectables
www.medicalppt.blogspot.com for more lectures Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003

Oral agents

Incretin-Based Therapies
• Incretin Mimetics (GLP-1 agonists/analogs) – Exenatide (Byetta) – Others: Liraglutide, LY307161 SR, CJC-1131, ZP10, BIM51077
• Incretin Enhancers – Sitagliptin – Vildagliptin – Saxagliptin

(DPP-IV inhibitors)

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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

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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 stage renal disease Not a substitute ofwww.medicalppt.blogspot.com be used in T1DM insulin ,so NOT to
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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
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

Diagram of how DPP-4 inhibition might be expected to improve blood glucose control
Active GLP-1 Active GLP-1

Increase insulin secretion Increase insulin Decrease glucagon release Decrease glucagon

DPP-4 X DPP-4 inhibitor Inactive GLP-1

Glucose control Glucose control improved

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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.

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VILDAGLIPTIN(GALVUS)

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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 guidelines in management of T2DM.
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Incretin mimetics Vs DPP-IV inhibitors
Properties/effect
Mechanism of stimulation of insulin secretion exclusively through GLP-1 effect

Incretin mimetics
Yes

DPP-4 inhibitors
Unknown

Hypoglycaemia Maintained counter-regulation by glucagon in hypoglycaemia

No Yes

No Not tested

Inhibition of gastric emptying
Effect on body weight

Yes
Weight loss

Marginal
Weight neutral

Side effects
Administration

Nausea
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None observed
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) C/I – gastroparesis Important to lower mealtime insulin dose 50% when starting in T1DM.
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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
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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 modifications alone or with metformin?

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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. ?? great promise for future.
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SITES:

Want to know more ???

www.hormone.org www.medscape.com www.medworm.com www.diabeteshealth.com www.dentocafe.com

BOOKS:
JOSLIN’S DIABETES MELLITUS KATZUNG PHARMACOLOGY LIPPINCOTT PHARMACOLOGY

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