initiating treatment with oads

7/24/2019 Initiating Treatment With OADs

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Slide 1

Initiating Diabetes Treatment with OADs

Lecture:

Dr.dr.Agus Yuwono SpPD-KEMD,I!ASIM



Initiating Diabetes Treatment with OADs"e#ture

Main Learning Points

• Understand the different classes ofOADs and when to use which OADs –either as monotherapy or incombination with other OAD’s / Insulin

Slide 2



Factors to onsider when hoosing an Anti!h"#ergl"cemic agent

Slide $

%&&ecti'eness in lowering glucose

%(tragl"caemic e&&ects that ma" reduce long!term com#lications

Sa&et" #ro&ile

Tolerabilit"

ost

%&&ect on bod" weight

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.



Slide )

Treatment thera#ies &or T"#e 2 diabetes$hen and %ow to start treatment

Adated !r"# $a%%ah et al. Diabetes Metab $es $e& 2007;23:2'7.

Li&est"le *Met&ormin

*!other OADor +LP!1agonists

,bA1c -./0

asal

asalInsulin

Premi(Insulin

asal *olus

Insulin

STA&T T&EATME!T OAD T&EATME!T STA&T I!S'"I! I!S'"I! I!TE!SII(ATIO!



Slide 3

4#dated P%56%7I T"#e 2 Diabetes TreatmentAlgorithm

Diabetes ST%P 1 ST%P 2 ST%P $

Healthy life style Healthy life style

+

ono therapy

Healthy life style+

! OAD "ombination

Healthy life style

+

"ombination ! OAD

+

#asal insulin

InsulinIntensification$

$Intensi%e Insulin& use of basal insulin to'ether with insulin prandial

Healthy life style

+

( OAD "ombination

Alternati%e option) if &

• *o insulin is a%ailable

• he patient is ob,ectin' insulin

• #lood 'lucose is still not optimallycontrolled

7ote:

-. herapy failed iftar'et of HbA-c 01 is not achie%edwithin !2( monthsfor each step

!. In case of no HbA-ctest) the use of blood'lucose le%el is alsopermitted. A%era'eblood 'lucose le%elfor a few #3 test inone day can becon%erted to HbA-c4ref& ADA !5-56



Slide 8

Main #atho#h"siological de&ects in t"#e 2 DM

hepaticglucoseproduction

peripheral'lucoseupta7e

pancreaticinsulinsecretion

pancreatic'luca'onsecretion

'utcarbohydratedeli%ery andabsorption

incretinefect

Hyperglycemia

?

LiverMuscle

PancreasIntestines

Adipose

Brain

Kidney

Glucosereabsorpsion

Adated !r"#:n*%%hi +, +herin $+. Diabetes Mellit*s. n: /"ld#an A*siell" D eds. Ce%il etb"" "! Medi%ine. 23rd,dn. 4hiladelhia 4a: +a*nders ,lse&ier; 2007.



Slide .

urrent a'ailable OADs and non!Insulin in9ectables inIndonesia

• etformin

• 8ulfonylureas 48Us6 and 'linides

• 92'lucosidase inhibitors 4A3Is6

• 3luca'on2li7e peptide2- 43:;2-6 a'onists

• hia<olidinediones 4=Ds6

• Dipeptidyl peptidase2> inhibitors 4D;;2>

inhibitors6



Slide

Primar" sites o& action o& currentl" a'ailable oral anti!diabetic agents and non!insulin in9ectables

Chen5 A ant*s /. Can Med Ass"% 200';172:21326.. arnett A. nt Clin 4ra%t 2006;60:1'70. 4re <e / et al.Ne!r"l"5ia. 2010;30:6182'.

Liver

Muscle

PancreasIntestines

Circulatory System

Glucose

FFA

Metformin

TZG l u c o s e r e l e a s e

FFArelease

D e f e c t i v

e

i n s

u l i n

s e c

r e t i o

n

!LP"# agonist

Insulinrelease

A!I

Glucoseabsorption

Intestinallipase in$i%itor

F F A

a b s o

r p t i o

n

Carbohydrates

Fat

I m p a

i r e d g l u c

o s e

u p t a k e

T;D

Metformin

G l u

c o s e

u p t a k

e

Bloc&s

Promotes

PP"'in$i%itor

Adipose

A/: =-5l*%"sidase inhibit"rs; D44-: dietid>l etidase-; A: !ree !att> a%id; ?D: thia"lidinedi"ne



Slide <

Met&orminMode o) A#tion

The #rimar" e&&ects o& met&ormin are to decrease he#aticglucose #roduction and increase insulin!mediated #eri#heral

glucose u#ta=e

@rent A aile> C. Dr*5s 200';6':38'11.

A: att> A%ids



Slide 10

Met&ormin(*ini#a* O+er+iew and (ontraindi#ations

Met&ormin

?fficacy$

8afety)olerability andAdherence

"ontraindications Ad%anta'es

• HbA-c reduction

of -2!1

• @;3 reduction of>5205 m'/dl

• Associated with

diarrhea and

abdominaldiscomfort

• :actic acidosis if

improperly

prescribed

• enal

insufficiency

• :i%er failure• Heart failure• 8e%ere

'astrointestinal

disease

• Do not cause

hypo'lycaemia

when used asmono2therapy

• Do not cause

wei'ht 'ainB may

contribute towei'ht loss

@rent A aile> C. Dr*5s 200';6':38'11.

,!!i%a%> deends "n eistin5 bl""d 5l*%"se le&els



Slide 11

Met&orminTitration

MET-XRMET-IR

1. Nathan DM et. al. Diabetes Care 2009;32:193203. 2. abb"*r + ?irin5 . 4"st5rad*ate Medi%ine 2011;123:1'23.

id: ti%e dail>; 4/: !astin5 las#a 5l*%"se; /: 5astr"intestinal; M,-$: i##ediate release #et!"r#in; M,-B$:etended release #et!"r#in; d: "n%e dail>.



Slide 12

Met&ormin"itt*e bene)it i) an - to go abo+e ./// mg

Fasting Plasma +lucose ,bA1c

h a n g e

' s / P l a c e b o > m g ? d l @

2300mg2000mg1300mg1000mg300mg

/arber A A# Med 1997;102:91-7.

Met)ormin Dose

h a n g

e ' s / P l a c e b o > 1 @

2300mg2000mg1300mg1000mg300mg

Met)ormin Dose



Slide 1$

S4s and +linidesMode o) A#tion

• 8ulfonylureas 48Us6 and'linides increaseendo'enous insulin secretionby bindin' to pancreatic C2cells and tri''erin' a

cascade of intracellulare%ents-–(

• he mode of action of 8Usand 'linides is similar) butstimulation of insulinsecretion is more rapid and

short2actin' with 'linides• 8U receptors are also found

on other cells) includin' thecardiac myocytes

1. /allit arin5 -E. Diabetes Fbes Metab 2010;12:111. 2. +%h*it C et al. Diabetes 2001;'0:111. 3. @rent A aile> C. Dr*5s 200';6':38'11.

+E: s*l!"n>l*rea; /E: 5l*%"se trans"rter.

Pancreatic ("cell

!lucoseupta&e

Insulin release

Voltage-gatedcalcium channel

ATP-sensitivepotassium channel

S)s *glinides

!lycolysisrespiration

e p o

l a r

i + a

t i o

n

!luco&inase

ATP

Ca,-

ATP = orangeCa! = light green



Slide 1)

S4s and +linides(*ini#a* O+er+iew

Sul#hon"lurea

?fficacy$


• HbA-c reductionof -2!1

• @;3 reduction of

>5205 m'/dl

• Associated withhypo'lycaemia

and wei'ht 'ain

@rent A aile> C. Dr*5s 200';6':38'11. Nathan DM et al. Diabet"l"5ia. 2009;'2:1730. $"senst"% et al. DiabetesCare. 200;27:126'70.


+linides

?fficacy$


• HbA-c reductionof 5.2-.1

• @;3 reduction of

!52E5 m'/dl• ;;3 reduction of

02-55 m'/dl

• Associated withhypo'lycaemia

and wei'ht 'ain• @reFuent

administration

4with e%erymeal6 is

reFuired.



Slide 13

Al#ha glucosidase inhibitorsMode o) A#tion

• 8low di'estion of sucroseand starch and thereforedelay absorption

• 8low post2meal rise in blood'lucose

• 8ide effects

• @latulence) abdominaldiscomfort ) diarrhoea

• As mono2therapy will notcause hypo'lycaemia

• Hypo'lycaemia when usedwith other medicine 4e.'. asulphonylurea6

1. /allit arin5 -E. Diabetes Fbes Metab 2010;12:111. 2. +%h*it C et al. Diabetes 2001;'0:111. 3. @rent A aile> C. Dr*5s 200';6':38'11.



Slide 18

Al#ha glucosidase inhibitors(*ini#a* O+er+iew

Al#ha glucosidase inhibitors

?fficacy$8afety) olerability andAdherence

• HbA-c reduction of 5.2

-1• @;3 reduction of -52!5

m'/dl• ;;3 reduction of >525

m'/dl

• Associated with

flatulence) diarrhea andabdominal discomfort

• As mono2therapy will

n"t cause

hypo'lycaemia• @reFuent administration

4with e%ery meal6 is

reFuired.

@rent A aile> C. Dr*5s 200';6':38'11. Nathan DM et al. Diabet"l"5ia. 2009;'2:1730. $"senst"% et al. DiabetesCare. 200;27:126'70.




Slide 1.

Thiaolidinediones >T;Ds@Mode o) A#tion

Thiaolidinediones >T;Ds@ increase the sensiti'it" o& muscleand adi#ose cells to insulin and su##ressing he#atic glucose

#roduction

@rent A aile> C. Dr*5s 200';6':38'11.

?D: hia"lidinedi"nes



Slide 1

Thiaolidinediones(*ini#a* O+er+iew

@rent A aile> C. Dr*5s 200';6':38'11. Dr*5 Class $e&ie: hia"lidinedi"nes. A&ailable at:htt:GGhar#a%>."re5"nstate.ed*Gdr*5H"li%>Ga5esGd*rHb"ardGre&iesGarti%lesG?DHClass$e&ie.d! . $i" M et al. ,ert Fin4har#a%"ther. 2008;9:229'303.


Thiaolidinediones

?fficacy$


"ontraindications Ad%anta'es

• HbA-c reduction

of 5.2-.1

• @;3 reduction of!52 m'/dl

• Associated with

wei'ht 'ain and

edema• "ontraindicated

in patients with

abnormal li%er

function• Garnin's

re'ardin' ris7 of

fractures• ay eacerbate

or precipitate

con'esti%e heart

failure

• :i%er disease)

heart failure or

history of heartdisease

• ;re'nancy and

breast feedin'

• educed le%els of

:D:2cholesterol

and increasedle%el of HD:2

cholesterol



Slide 1<

DPP!) inhibitorsMode o) A#tion

Dr*%er D et al. Nat*re 2006;368:169670'. dris et al. Diabetes Fbes Metab 2007;9:1'36'. arnett A. nt Clin 4ra%t2006;60:1'70. /allit et al. Diabetes Fbes Metab 2010;12:111.

D44-: dietid>l etidase-; /: 5astr"intestinal; /4:5l*%"se-deendent ins*lin"tr"i% "l>etide; /4-1: 5l*%a5"n-lie etide

Increases and prolongs!LP"# e.ect on α"cells

Increases and prolongs !LP"#and !IP e.ects on ("cells

Food inta"e

Stomac$

G# tract

Intestine

α"cells

Pancreas

Glucose-dependent insulinsecretion

("cells

PP"'in$i%itor

Glucose-dependent glucagon secretion

#ncretins$G%P-&' G#P(

DPP!)/et e.ect0

%lood glucose

) G#P does not inhibit glucagon secretion by α-cells



Slide 20

DPP!) inhibitors(*ini#a* O+er+iew

DPP!) inhibitors


• HbA-c reduction of 5.2

-1• @;3 reduction of !5

m'/dl• ;;3 reduction of >2

m'/dl

• 3enerally well tolerated• :ow ris7 of

hypo'lycemia• *ot associated with

wei'ht 'ain• Upper respiratory tract

infection has beenreported in clinical

studies

• ost reFuire only oncedaily administration

AhrIn . ,ert Fin ,#er5 Dr*5s 2008;13:'93607. /allit et al. Diabetes Fbes Metab 2010;12:111. A#"ri $, etal. AMA 2007;298:19206. +aa5litin DAJs ,nd"%rin"l"5i% and Metab"li% Dr*5s Ad&is"r> C"##ittee rie!in5 D"%*#ent!"r Aril 2009 Meetin5: NDA 22-3'0. A&ailable at: htt:GG.!da.5"&GF$M+GDFC@,+Ga%G09Gbrie!in5G2009-22b1-02-rist"l.d!. (a%%essed N"& 2010). As%hner 4 et al. Diabetes Care 2006;29:26327.




Slide 21

+LP 1 AgonistMode o) A#tion

1. D">le M, ,5an M. 4har#a%"l her 2007;113(3):'693.

/4-1: 5l*%a5"n-lie etide

+lucagon!li=e #e#tide!1 >+LP!1@ agonist acti'ates the +LPrece#tor in the #ancreas/ This increases insulin release &romthe #ancreatic B!cellsC while inhibiting glucagon release b"

the #ancreatic !cells

α-cell

Pancreas

• Glucose-dependent insulin biosynthesisand secretion

• β-cell proliferation

β-cells

• Glucagon secretion• β-cell apoptosis

GLP-1 agonistNet effect:

blood glucose



Slide 22

+LP 1 Agonist(*ini#a* O+er+iew

DPP!) inhibitors


• HbA-c reduction of -2!1• @;3 reduction of E2-!

m'/dl• ;;3 reduction of E2-

m'/dl

• Associated with

moderate and transient

nausea) %omitin' anddiarrhea

• :ow ris7 of

hypo'lycemia and no

e%idence of increased"J ris7

• Associated with wei'ht

reduction• Associated with

reduction in #;

/arber A. Diabetes Care 2011;3 (+*l 2):+2798. M"rett" et al. Clin her 2008;30:1860. Dr*%er D. Cell Metab2006;3:1'36'. A#"ri $, et al. AMA 2007;298:19206.




Slide 2$

The Princi#les o& OAD ombination Theor"

• wo 4or more6 oral blood 'lucose2lowerin'medicines that ha%e different mechanisms ofaction

• wo medications is better rather than increasein initial medicine to maimum dosa'e

• @ewer side effects than mono2therapy at hi'herdoses



Slide 2)

Diabetes in elderl" #eo#le

• Always start with the lowest doseof any blood 'lucose2lowerin'

medicine and increase 'radually

• Usin' shorter2actin' medicinesthat reduces the ris7 ofhypo'lycaemia

• Hypo'lycaemia may increase the

ris7 of falls and heart attac7 inolder people

emember the possibility of

• @or'etfulness• ;oor moti%ation

• Depression

• "o'niti%e deficits

• ;oly2pharmacy

• educed manual deterity

•hese factors impact on the ability tomaintain self2care and achie%emaimum benefits from blood'lucose2lowerin' medicines.



OADEs a Guic= summar" o& the di&&erent mechanism o&actions

!+lucosidase inhibitorsDelay intestinal carbohydrateabsorption

!+lucosidase inhibitorsDelay intestinal carbohydrateabsorption

ThiaolidinedionesIncrease 'lucose upta7e ins7eletal muscle anddecrease lipolysis inadipose tissue

ThiaolidinedionesIncrease 'lucose upta7e ins7eletal muscle anddecrease lipolysis inadipose tissue

Sul&on"lureasIncrease insulin secretionfrom pancreatic β2cells

Sul&on"lureasIncrease insulin secretionfrom pancreatic β2cells

GLP = glucagon-like peptide.

Adapted from heng and !antus. CMAJ . "##$%&'"("&)*""+.

MeglitinidesIncrease insulin secretion frompancreatic β2cells

MeglitinidesIncrease insulin secretion frompancreatic β2cells

2iguanide >met&ormin@Decreases hepatic 'lucose production and increasesupta7e

2iguanide >met&ormin@Decr eases hepatic 'lucoseproduction and increasesupta7e

Incretins :+LP!1 analogue>e(en!atide@?DPP!) inhibitors Im#ro'esglucose!de#endent insulinsecretion from pancreatic B!cells) suppresses g*u#agon se#retion )rom -#e**s) slows 'astric emptyin'

Incretins :+LP!1 analogue>e(en!

atide@?DPP!) inhibitors Im#ro'esglucose!de#endent insulinsecretion from pancreatic B!cells) suppresses g*u#agon se#retion )rom -#e**s) slows 'astric emptyin'

Slide 23

Slid 28



Pro#erties o& a'ailable glucose!lowering agentsthat ma" guide treatment choice in T"#e 2Diabetes

lass om#ounds>s@ ellularmechanism Primar"Ph"siologicalaction>s@

Ad'antages Disad'antages

iguanides Met&ormin Acti'atesAMP!=inase

,e#atic +lucoseProduction ↓

%(tensi'e%(#erience

7o weight gain

7o h"#ogl"cemia

Li=el" HD %'ents ↓

+astrointestinal sidee&&ects

Lactic acidosis ris=

>rare@

Hitamin 12de&icienc"

Multi#le

contraindications:

6DC acidosisCh"#o(iaC

deh"dration etc/

Sul&on"lureas +libenclamide ?

gl"buride+li#iide

+liclaide

+lime#iride

loses 6ATP

channels onbeta cell

#lasme

membranes

Insulin secretion %(tensi'e

e(#erienceMicro'ascular 5is= ↓

>46PDS@

,"#ogl"cemia

eight gainlunts m"ocardial

ischaemic

#reconditioning J

Low durabilit"

Meglitinides 5e#aglinide

7ateglinide

loses 6ATP

channels onbeta cell

#lasme

membranes

Insulin secretion Post#randial

glucose e(cursions ↓

Dosing &le(ibilit"

,"#ogl"cemia

eight gainlunts m"ocardial

ischaemic

#reconditioning JFreGuent dosing

schedule

n*%%i +, et al. Diabet"l"5ia. 2012

Slide 28

I n c l u d

e d i n t

h e

2 i n d e r

Slid 2.



Pro#erties o& a'ailable glucose!lowering agentsthat ma" guide treatment choice in T"#e 2Diabetes cont/

lass om#ounds>s@ ellular

mechanism

Primar"

Ph"siologicalaction>s@


Thiaolidinedi

ones

Pioglitaone

5osiglitaone

Acti'ates the

nuclear

transcri#tion&actor PPA5!"

Insulin Sensiti'it" 7o h"#ogl"cemia

Durabilit"

,DL!

Triac"lgl"cerols ↓

>#ioglitaone@HD %'ents ↓J

eight +ain

Oedema ? ,eart

Failureone Fractures

LDL!

>rosiglitaone@

Mn >meta!

anal"sesCrosiglitaone@ladder ancer J

>#ioglitaone@

a!+lucosidaseInhibitors

AcarboseMigitol

Hoglibose

Inhibitsintestinal a!

glucosidase

Slows intestinalcarboh"drate

digestions ?

absor#tion

7o h"#ogl"cemiaPost#randial

glucose

e(cursions ↓

HD %'ents ↓

7on!s"stemic

Modest ,bA1ce&&icac"

+astrointestinal side

e&&ects >&latulenceCdiarrhoea@

FreGuent dosing

schedule

DPP!)

Inhibitors

Sitagli#tin

Hildagli#tinSa(agli#tin

Linagli#tin

Alogli#tin

Inhibits DPP!)

acti'it"Cincreasing

#ost#randial

acti'e incretin>+LP!1C +IP@

concentrations

Insulin secretion

>glucose!de#endent@

+lucagon secretion ↓

>glucose!de#endent@

7o h"#ogl"cemia

ell tolerated

Modest ,bA1c

e&&icac"4rticardia?Angio!

oedema

Pancreatitis J


Slide 2.

I n c l u d

e d i n t

h e

2 i n d e r

Slide 2



Pro#erties o& a'ailable glucose!lowering agentsthat ma" guide treatment choice in T"#e 2Diabetes cont/

lass om#ounds>s@ ellularmechanism

Primar"Ph"siologicalaction>s@


+LP!1

5ece#tor

Agents

%(enatide

Liraglutide

Acti'ates +LP!

1 rece#tors

Insulin secretion

>glucose!de#endent@

+lucagon secretion ↓

>glucose!de#endent@

Slows gastricem#t"ing

Satiet"

7o h"#ogl"cemia

eight reduction

Im#ro'ed betacell mass ?

&unction J

ardio'ascular

#rotecti'eactions J

+astrointestinal side

e&&ects >nausea ?

'omiting@Acute #ancreatitis J

cell h"#er#lasia ?

medullar" th"roid

tumoursIn9ectable

Training

5eGuirements

Insulin ,uman 7P,,uman 5egular

Lis#ro

As#art+luisine

+largine

Determir

Pre!mi(ed>se'eral t"#es@

Acti'atesinsulin

rece#tors

+lucose dis#osal

,e#atic glucose#roduction ↓

4ni'ersall"e&&ecti'e

Theoreticall"

unlimitede&&icac"

Micro'ascular

5is= ↓ >46PDS@

,"#ogl"cemiaeight gain

Mitogenic e&&ects J

In9ectableTraining

5eGuirements

KStigmaE &or #atients


Slide 2

I n c l u d

e d i n t

h e

2 i n d e r

Slide 2<



OADEs and Incretins$or0shop

Main Learning Points

• Understand the different classes ofOAD’s and when to use which OAD’s –either as monotherapy or incombination with other OAD’s / Insulin

Summar"

• Different start and intensificationoptions for OADs eist dependin' on theneed for the indi%idual patient

• etformin will 'enerally be the first

dru' of choice

Slide 2<

initiating treatment with oads

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