diabetes mellitus emerging therapies

8/14/2019 Diabetes Mellitus Emerging Therapies

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EMERGINGEMERGING

THERAPIESTHERAPIESININ

DIABETES MELLITUSDIABETES MELLITUS(TYPE II)(TYPE II)

BYBYSWAPNAJEET SAHOOSWAPNAJEET SAHOO

44thth yryr

VSS MEDICAL COLLEGE,BURLAVSS MEDICAL COLLEGE,BURLA


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INTRODUCTIONINTRODUCTION

Diabetes mellitus is a syndrome characterized by hyperglycemiaDiabetes mellitus is a syndrome characterized by hyperglycemia

due todue to

AbsoluteAbsolute insulin deficiencyinsulin deficiency --Type 1 DMType 1 DM

RelativeRelative insulin deficiencyinsulin deficiency Type 2 DMType 2 DM

One of leading causes of morbidity & mortality worldwide.One of leading causes of morbidity & mortality worldwide.

It has been estimated that overIt has been estimated that over 230230 million diabetics bymillion diabetics by 20102010 &&

300300 million bymillion by 20252025 (King et al 1998) ,(King et al 1998) , majority being T2DM.majority being T2DM.

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

prevent the emerging global epidemic of diabetes ( mainly T2DM)prevent the emerging global epidemic of diabetes ( mainly T2DM)


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-Cell function and g-Cell function and glucagonlucagon

in Type 2 diabetesin Type 2 diabetes

Loss of -cell function and glucagon over-Loss of -cell function and glucagon over-

secretion both play key roles in Type 2secretion both play key roles in Type 2

diabetes developmentdiabetes development

Progressive -cell decline is coupled withProgressive -cell decline is coupled withinadequate insulin secretioninadequate insulin secretion

Glucagon is not suppressed during theGlucagon is not suppressed during the

postprandial periodpostprandial period Hepatic glucose production is increasedHepatic glucose production is increased

during the fasting period and is notduring the fasting period and is not

suppressed during the postprandial periodsuppressed during the postprandial period


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-Cell mass in Type 2-Cell mass in Type 2

diabetesdiabetes

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

ND IFG T2DM ND T2DM

-Cellvolum

e(%)

Obese Lean

-50%

-63%

Butler et al. Diabetes. 2003ND=non-diabetic;IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitus


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xcess ve epa cxcess ve epa cglucose production inglucose production in

Type 2 diabetesType 2 diabetes

Plasma glucose

concentration

Fasting &Fasting &

postprandialpostprandial

hyperglycaemiahyperglycaemia

Insulin; IR

GlucagonHepaticglucose

output

IR=insulin resistance


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PRESENT ORALPRESENT ORAL

HYPOGLYCEMIC DRUGSHYPOGLYCEMIC DRUGS

SULFONYL UREASSULFONYL UREAS::

11STST GENERATION-GENERATION- TolbutamideTolbutamide

22ndnd GENERATION GENERATION Glimepiride,Glimepiride,

Glibenclamide,GlipizideGlibenclamide,Glipizide

BIGUANIDESBIGUANIDES MetforminMetformin

MEGLITINIDE ANALOGSMEGLITINIDE ANALOGS Repaglinide,Repaglinide,

NateglinideNateglinide

THIAZOLIDINEDIONESTHIAZOLIDINEDIONES

ORAL HYPOGLYCEMIC


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ORAL HYPOGLYCEMICORAL HYPOGLYCEMICDRUGSDRUGS


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ADVERSE EFFECTS OFADVERSE EFFECTS OF

OHASOHAS Sulfonyl ureas -Sulfonyl ureas - HypoglycemiaHypoglycemia

(most common)(most common)

MetforminMetformin lactic acidosis & GI lactic acidosis & GI

disturbancesdisturbances

Meglitinide analoguesMeglitinide analogues Hypoglycemia( Hypoglycemia(less) & wt. gainless) & wt. gain

ThiazolidinedionesThiazolidinediones- plasma volume- plasma volume

expansionexpansion

- edema & heart failure- edema & heart failure

- weight gain- weight gain

- mild anemia- mild anemia

Alfa glucosidase inhibitorsAlfa glucosidase inhibitors flatulence flatulence


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IncretinIncretin

TherapiesTherapies


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WHAT RWHAT R

INCRETINS ?INCRETINS ? IncretinsIncretins are gut peptides that potentiate insulin secretionare gut peptides that potentiate insulin secretion

during eating.during eating.

mainly 2 types mainly 2 types GIPGIP ( gastro inhibitory peptide)( gastro inhibitory peptide)

-- GLP-1GLP-1 ( glucagon like peptide )( glucagon like peptide )

GIPGIP- secreted from- secreted from KK cells of intestine (Duodenum)cells of intestine (Duodenum)doesnot delay gastric emptyingdoesnot delay gastric emptying

doesnot affect pancreatic alpha cells secretion ofdoesnot affect pancreatic alpha cells secretion of

glucagon.glucagon.

GLP-1GLP-1 secreted from secreted from LL cells of intestine ( ileum & colon)cells of intestine ( ileum & colon)stimulates glucose dependent insulin releasestimulates glucose dependent insulin release

delaysdelays gastric emptying.gastric emptying.

So, GLP-1 has been considered a viable therapeuticSo, GLP-1 has been considered a viable therapeutic

approach in management ofapproach in management ofT2DM.T2DM.


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Nauck et al. Diabetologia. 1986

Incretin effect on insulin secretionIncretin effect on insulin secretion

Oral glucose load

Intravenous glucose infusion

Time (min)

Insu

lin(mU/l)

80

60

40

20

0

18060 1200

Time (min)

Insu

lin(mU/l)

80

60

40

20

0

18060 1200

Incretin

effect

Control subjects (n=8) People with Type 2 diabetes (n=14)


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- : e ec s n- :humanshumans

GLP-1 is secreted from

L-cells of the jejunum

and ileum

That in turn

Stimulates glucose-

dependent insulin secretion

Suppresses glucagon

secretion

Slows gastric emptying

Long-term effectsin animal models:

Increase of -cell mass

and improved -cell function

Improves insulin sensitivity

Leads to a reduction of

food intake

After food ingestion

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


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GLP-1 enhancementGLP-1 enhancement

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

GLP-1 secretion is impaired in Type 2 diabetes

Natural GLP-1 has extremely short half-life

Add GLP-1 analogueswith longer half-life:

exenatide

liraglutide

Injectables

Block DPP-4, the

enzyme that degrades

GLP-1:

sitagliptin vildagliptin

Oral agents


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Incretin-Based Therapies

Incretin Mimetics (GLP-1agonists/analogs)

Exenatide (Byetta)

Others: Liraglutide, LY307161 SR, CJC-1131,

ZP10, BIM51077 Incretin Enhancers (DPP-IV

inhibitors)

Sitagliptin


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GLP-1 RECEPTOR AGONISTSGLP-1 RECEPTOR AGONISTS

EXENATIDEEXENATIDE Approved by FDA April 2005 for T2DM withApproved by FDA April 2005 for T2DM with

SU/metforminSU/metformin

39 amino acid Synthetic peptide originally identified39 amino acid Synthetic peptide originally identified

in Gila lizard (in Gila lizard (Heloderma suspectumHeloderma suspectum))

ExhibitsExhibits incretinmimeticincretinmimetic activityactivity Significant 1 1.2% decrease in HbA1cSignificant 1 1.2% decrease in HbA1c

T1/2 2.4 hrsT1/2 2.4 hrs

Subcutaneously administeredSubcutaneously administered

Dose- 5 mcg start BD 10 mcg BDDose- 5 mcg start BD 10 mcg BD S/E nausea (most common), disappears after fewS/E nausea (most common), disappears after few

wkswks

diarrhoea,dizziness (less common)diarrhoea,dizziness (less common)

C/I hypersensitive ptsC/I hypersensitive pts

anti exenatide antibodies may develop in endanti exenatide antibodies may develop in end


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LIRAGLUTIDELIRAGLUTIDE GLP-1 analog with longer half life 10 -14 hrsGLP-1 analog with longer half life 10 -14 hrs

Once daily dose of 0.6 1.8 mg SCOnce daily dose of 0.6 1.8 mg SC Awaits FDA approval.Awaits FDA approval.

EXENATIDE LAREXENATIDE LAR Microsphere suspension of exenatide.Microsphere suspension of exenatide.

Once a weekly regimen in a dose of 0.8-2.0 mgOnce a weekly regimen in a dose of 0.8-2.0 mg

Significant decrease in HbA1c 1.4-1.7% has been seenSignificant decrease in HbA1c 1.4-1.7% has been seen

Offers potential of 24 hrs glycemic control & wt.Offers potential of 24 hrs glycemic control & wt.

reduction when combined with metformin &/or diet &reduction when combined with metformin &/or diet &

exercise in T2DMexercise in T2DM

Long term trials are underwayLong term trials are underway


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Active GLP-1

Inactive GLP-1

inhibition might be expectedinhibition might be expected

to improve blood glucoseto improve blood glucose

controlcontrolIncrease insulin secretion

Decrease glucagon release

Glucose control

DPP-4 DPP-4 inhibitorX

Increase insulin secretionDecrease glucagon release

Glucose controlimproved

Inactive GLP-1

Active GLP-1


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DPP IV INHIBITORSDPP IV INHIBITORS

SITAGLIPTIN(JANUVIA/JANUMET)SITAGLIPTIN(JANUVIA/JANUMET) Approved by FDA Oct 2006 for T2DM withApproved by FDA Oct 2006 for T2DM with

metformin/TZDs/ monotherapy.metformin/TZDs/ monotherapy.

Dose 100 200mg orally ODDose 100 200mg orally OD

Reduction in 0.74-0.94% HbA1cReduction in 0.74-0.94% HbA1c

Doesn't cause nausea or weight lossDoesn't cause nausea or weight loss

DPP-IV inhibition could affect other hormoneDPP-IV inhibition could affect other hormone

degradation like hGH.degradation like hGH.

Would not be used in transplant pts.Would not be used in transplant pts.


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VILDAGLIPTIN(GALVUS)VILDAGLIPTIN(GALVUS) Pending approval by FDA , in phase III trials.Pending approval by FDA , in phase III trials.

Dosage studied 50 -100 mg dailyDosage studied 50 -100 mg daily Has shown equally encouraging results bothHas shown equally encouraging results both

when used as monotherapy / in combination withwhen used as monotherapy / in combination with

metformin/TZDsmetformin/TZDs

Till date no A/E has been reported .Till date no A/E has been reported .

There is much possibility that one ofThere is much possibility that one of

the gliptins may emerge as a 1the gliptins may emerge as a 1stst linelinetreatment in combination with metformintreatment in combination with metformin

in newly diagnosed pts with T2DM mayin newly diagnosed pts with T2DM may

materialize into recommended futurematerialize into recommended future

I ti i ti V DPP IVIncretin mimetics Vs DPP IV


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Incretin mimetics Vs DPP-IVIncretin mimetics Vs DPP-IV

inhibitorsinhibitors

Properties/effectProperties/effect IncretinIncretin

mimeticsmimeticsDPP-4DPP-4

inhibitorsinhibitors

Mechanism of stimulation ofMechanism of stimulation ofinsulin secretion exclusivelyinsulin secretion exclusivelythrough GLP-1 effectthrough GLP-1 effect

YesYes UnknownUnknown

HypoglycaemiaHypoglycaemia NoNo NoNo

Maintained counter-regulationMaintained counter-regulation

by glucagon in hypoglycaemiaby glucagon in hypoglycaemiaYesYes Not testedNot tested

Inhibition of gastric emptyingInhibition of gastric emptying YesYes MarginalMarginal

Effect on body weightEffect on body weight Weight lossWeight loss Weight neutralWeight neutral

Side effectsSide effects NauseaNausea None observedNone observed

AdministrationAdministration SubcutaneousSubcutaneous OralOral


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AMYLIN/IAPPAMYLIN/IAPP 37 AA peptide co-secreted with insulin in response to37 AA peptide co-secreted with insulin in response to

nutrient ingestion.nutrient ingestion.

Stimulated also by glucagon & GLP-1Stimulated also by glucagon & GLP-1

Main effect inhibition of gastric emptying & glucagonMain effect inhibition of gastric emptying & glucagon

secretion.secretion.

Leads to reduced food intake & weight loss.Leads to reduced food intake & weight loss.

PRAMLINTIDE(Symlin)PRAMLINTIDE(Symlin) Amylin analog ,differs from it by 3 AAsAmylin analog ,differs from it by 3 AAs Slows gastric emptying & suppresses post prandialSlows gastric emptying & suppresses post prandial

glucagon secretionglucagon secretion

Given SC prior major meals.Given SC prior major meals.

Indicated in T2DM adjunct T/t to meal time insulinIndicated in T2DM adjunct T/t to meal time insulin

with/without awith/without a

SU/metformin.SU/metformin.

Advantages - wt. loss of 1 1.5 kg over 6 monthsAdvantages - wt. loss of 1 1.5 kg over 6 months

- decreases HbA1c by 0.5 0.7%- decreases HbA1c by 0.5 0.7% A E nausea 50% cases headache h o l cemia rareA E nausea 50% cases headache h o l cemia rare


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WHO MIGHT BE BENEFITEDTHE MOST ?

Overweight or obese patient

without adding an agent which maycause additional weight gain Uncontrolled on current therapy

Especially those close to A1C goal ? Early in disease to preserve beta

cells

I ti C t lI ti C t l


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Incretins: CrystalIncretins: Crystal

GazingGazing Whether the early introduction of gliptins inWhether the early introduction of gliptins in

management schema will protect cellmanagement schema will protect cell

functions?functions?

Will the use of incretins prevent/ delay theWill the use of incretins prevent/ delay the

progression of the early stages to frank T2DM?progression of the early stages to frank T2DM?

In India , the present cost of sitsgliptin(100mg)In India , the present cost of sitsgliptin(100mg)

is Rs 250/dayis Rs 250/day

But , finally keeping in view the safety & costBut , finally keeping in view the safety & cost

effectiveness will such therapeuticeffectiveness will such therapeutic

interventions be superior to lifestyleinterventions be superior to lifestyle

modifications alone or with metformin?


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OTHER DEVELOPMENTSOTHER DEVELOPMENTS

ORAL INSULIN ????ORAL INSULIN ????

Oral insulin spray {Oral insulin spray {Oral- lynOral- lyn} for T1DM &} for T1DM &

T2DM approved in Ecuador.T2DM approved in Ecuador.

In India, TheIn India, The Thiruvanthapuram based SreeThiruvanthapuram based SreeChitra Tirunal Institute of Medical SciencesChitra Tirunal Institute of Medical Sciences

& Technology& Technology has successfully has successfully

demonstrated the an oral insulindemonstrated the an oral insulin

preparation in experiments on mice.preparation in experiments on mice.

Stem cell therapy byStem cell therapy by Volterelli et al (2007Volterelli et al (2007))

for T1DMfor T1DM

stem cells from bone marrow are morestem cells from bone marrow are more

likely to differentiate into insulin producinglikely to differentiate into insulin producing

cells.cells.


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Want to know more ???Want to know more ???SITES:SITES:

www.hormone.orgwww.hormone.org

www.medscape.comwww.medscape.com

www.medworm.comwww.medworm.com

www.diabeteshealth.comwww.diabeteshealth.com

www.dentocafe.comwww.dentocafe.com

BOOKS:BOOKS:JOSLINS DIABETES MELLITUSJOSLINS DIABETES MELLITUS

KATZUNG PHARMACOLOGYKATZUNG PHARMACOLOGY

LIPPINCOTTLIPPINCOTT

PHARMACOLOGYPHARMACOLOGY
http://www.hormone.org/http://www.hormone.org/http://www.medscape.com/http://www.medscape.com/http://www.medworm.com/http://www.medworm.com/http://www.diabeteshealth.com/http://www.diabeteshealth.com/http://www.dentocafe.com/http://www.dentocafe.com/http://www.dentocafe.com/http://www.diabeteshealth.com/http://www.medworm.com/http://www.medscape.com/http://www.hormone.org/

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