07. Prof. Eman Rushdy Sulphonylurea a Golden Therapy for Diabetes

7/23/2019 07. Prof. Eman Rushdy Sulphonylurea a Golden Therapy for Diabetes

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SulphonylureaSulphonylurea

A Golden Therapy ForA Golden Therapy For

DiabetesDiabetes

ByByEman RushdyEman Rushdy

Prof. Internal MedicineProf. Internal MedicineCairo UniversityCairo University


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The shoes storyThe shoes story

Many years ago two salesmen were sentMany years ago two salesmen were sentby a British shoe manufacturer to frica toby a British shoe manufacturer to frica to

investigate and re!ort bac" on mar"etinvestigate and re!ort bac" on mar"et!otential.!otential.

The #rst salesman re!orted bac"$ %There isThe #rst salesman re!orted bac"$ %There isno !otential here & nobody wears shoes.%no !otential here & nobody wears shoes.%

The second salesman re!orted bac"$The second salesman re!orted bac"$%There is massive !otential here & nobody%There is massive !otential here & nobodywears shoes.%wears shoes.%


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What is your concern about oralWhat is your concern about oral

hypoglycemic drughypoglycemic drug?!?! B cell exhaution.B cell exhaution.

Less effectiveLess effective

HypoglycemiaHypoglycemia ExpensiveExpensive


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10 m

~ 10,000

granules

Micrograph: Lelio Orci, Geneva

The normal beta-cellThe normal beta-cell

Presented by Pr Philippe Halban

at the 1st Amsterdam Diabetes Meeting, March 30-April 1,2006

Pancreas consists of

1 million islets ofLangerhans

Start to develop from

week 9-11 gestation


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Half-life of !" #aysHalf-life of !" #ays

$poptosis is the ma%or mechanism of #eath$poptosis is the ma%or mechanism of #eath

normal apoptotic

New beta-cells byNew beta-cells by

"eplication"eplication

NeogenesisNeogenesis


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-cellmass

#$%

&'($

)odified from *+tler ,. et al/ Diabetes 02;(01031/


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Factors for progressive loss of B-

cell function & mass

'lucoto(icity )i!oto(icity

l

ApoptosisInsulin

Secretion

Prentki M et al.Prentki M et al. Diabetes.Diabetes.2002;51(suppl 3):s405-s413.2002;51(suppl 3):s405-s413.

A!loi" "epositionIn#laator!$!tokines% &'S


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*-cell 4ha+stion- , physical depletionof *-cell ins+lin stores

secondary to prolonged chronic stim+lation

with gl+cose on non-gl+cose secretagog+es/

- No defect in ins+lin synthesis/

- 5he *-cell f+nction f+lly recovers as it rests/

4ha+stion is reversible


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6l+coto4icity

Non physiologicaland potentially

irreversible*-cell damage ca+sed by chronic

e4pos+re to s+pra-physiological gl+cose

concentration with characteristic decreases in

ins+lin synthesis and secretion ca+sed by

decreases ins+lin gene e4pression/

6l+coto4icity is irreversible


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7nterplay between *-cell e4ha+stion 8 gl+coto4icity

4cess ins+lin secretion

Prolonged hyperglycemia

7ns+lin depletion from *-cell #4ha+stion%

yperglycemia

)ore. prolonged hyperglycemia

" Stress ":S ;a


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Frequently prescribedFrequently prescribed

oral hypoglycemicoral hypoglycemic

medicationsmedications??


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Factors to onsider !henFactors to onsider !hen

hoosing "harmacologicalhoosing "harmacological

Agent#s$ for DiabetesAgent#s$ for Diabetes Current *CCurrent *C

+uration of diabetes+uration of diabetes

Body weight ,BMI$ abdominalBody weight ,BMI$ abdominalobesity-obesity-

EectivenessEectiveness

Co&morbiditiesCo&morbidities Cradiovascular ris"Cradiovascular ris"

Cost of medicationCost of medication

Com!liance.Com!liance.


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ADA%ASD'ADA%ASD'

onsiderations for the Guidelinesonsiderations for the Guidelines

*.*. Use of information fromUse of information from clinical trials that address the e/cacyclinical trials that address the e/cacyand safetyand safetyof dierent modalities of treatment ,of dierent modalities of treatment ,Evidence based-Evidence based-

0.0. Clinical 1udgment of the !anel !artici!ants ,Clinical 1udgment of the !anel !artici!ants ,Recogni2e that betaRecogni2e that betacell failure is !rogressive-cell failure is !rogressive-

3.3. E(tra!olation ofE(tra!olation of U4P+5 dataU4P+5 datathat glucose lowering of drugsthat glucose lowering of drugs,metformin$ sulfonylureas$ insulin- !redicted decrease in,metformin$ sulfonylureas$ insulin- !redicted decrease incom!lications.com!lications.

6.6. 7onglycemic eects of medication7onglycemic eects of medication$ such as eect on C8 ris"$$ such as eect on C8 ris"$li!ids$ hy!ertension or insulin resistanceli!ids$ hy!ertension or insulin resistance

9.9. 5afety$ side eects$ ease of use and e(!ense5afety$ side eects$ ease of use and e(!ense


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CE: CE CriteriaCE: CE Criteria

ttem!ts to !rovide a !lace and recommendationttem!ts to !rovide a !lace and recommendationfor all ;+ a!!roved drugsfor all ;+ a!!roved drugs

'reater em!hasis on hy!oglycemia avoidance'reater em!hasis on hy!oglycemia avoidance Recogni2es that !eo!le may want choices$ soRecogni2es that !eo!le may want choices$ so

allows a wide variety of choices and combinationsallows a wide variety of choices and combinationsfor individual situationsfor individual situations


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,dd basal or

intensify ins+lin

Lifestyle intervention and metformin

,dd s+lfonyl+rea

#least e4pensive%

,dd basal ins+lin

#most effective%

,dd 5=>

,dd 5=>,dd basal

ins+lin

,dd

s+lfonyl+rea

7f b,1c@$

7f b,1c@$

7f b,1c@$

7ntensive ins+lin < metformin

atan *M et al.Diabetes Care200+;2,():1,+3-2.atan *M et al. Diabetlgia200;51(1):-11.

7ntensify

ins+lin

+:E5+ Management lgorithm+:E5+ Management lgorithm


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,>,A,S> ;onsens+s,>,A,S> ;onsens+sAlgorithm forAlgorithm for

(anagement of Diabetes(anagement of DiabetesDiabetes are) *++, .*'/,.-*+.Diabetes are) *++, .*'/,.-*+.

At "ia/nosis:

i#est!le

Met#orin

i#est!leMet#orin

Pio/litaone

!" hypglycemia, edema,

CH#, bne lss$

i#est!leMet#orin

S+lfonyl+rea

i#est!leMet#orin

Intensie insulin

i#est!leMet#orin

asal Insulin

i#est!leMet#orin

P1!" hypglycemia, %t lss,

"a&sea'(miting$

i#est!leMet#orin

Pio/litaone

Sul#on!lurea

i#est!leMet#orin

asal Insulin

6ier 2: less 7ell-ali"ate"

terapies

5ier 1 Cell-validated core therapies

Step 1Step 1 Step 2Step 2 Step 3Step 3

A!lin a/onists8 lini"es

*PP-4 ini9itors a! 9e

appropriate in selecte"

patients

se#ul 7en

!po/l!ceia is to 9e

aoi"e"


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1D

Life style modification

,,; consens+s,,; consens+s

,lgorithm #09%,lgorithm #09%


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Ale


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)eading +iabetes Medications)eading +iabetes Medicationsby Treatment Classby Treatment Class

Ale


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SulfonylureasSulfonylureas

Divided into First Second and ThirdDivided into First Second and Third

GenerationGeneration First Generation: rarely used todayFirst Generation: rarely used today

Second Generation'Second Generation' glipi1ide Glicla1ideglipi1ide Glicla1ide

Third Generation'Third Generation' glimepirideglimepiride

The duration of action depends on theThe duration of action depends on the

a2nity to S34 and !hich part of it thea2nity to S34 and !hich part of it therate of metabolism activity ofrate of metabolism activity of

metabolites and rate of e5cretionmetabolites and rate of e5cretion


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Pharma"o"inetics ofPharma"o"inetics ofsul!honylureasul!honylurea::

?'lime!iride?'lime!iridehas a lower a/nity to thehas a lower a/nity to the &&cellcell

membrane than othersmembrane than others

?The metabolites of?The metabolites of glibenclamide areglibenclamide are

activeactivewhile those ofwhile those of glimi!ride andglimi!ride andglicla2ide are inactive.glicla2ide are inactive.


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6limepiride ;ontrols 6lycemia6limepiride ;ontrols 6lycemia

with Less 7ns+lin Secretionwith Less 7ns+lin Secretion

(ean ratio bet!een increasedlevel of insulin and reduced

glycemia

6

/+

/6

+

/

*

.

*+

+

Glimepiride

Glibenclamide

Glipi1ide

Glicla1ide

+)++

+)+6

+)/+

+)/6

+)*+n7/8

n7/.

n7/9

n7/8

4atio

Muller '$ et al. +iabetes Res Clin Pract *


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)ess weight gain)ess weight gain::

Aeight gain is seen with allAeight gain is seen with all

agents$ glime!ride has beenagents$ glime!ride has beenre!orted to be the most weight&re!orted to be the most weight&neutral sul!honylureaneutral sul!honylurea


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ormal GT Type *

I75U)I7RE5I5T7CE

;P' : PP'@b*C

I75U)I75ECRETIK7

Glimepiride DualGlimepiride Dual

(echanism for Dual(echanism for Dual

"roblem"roblem

'ra!hic inter!retation based onTy!e 0 +iabetes B5IC5. Minnea!olis$ M7 International +iabetes Center 0===Muller '$ et al. +iabetes Res Clin Pract *


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E(!ected @b*c reductionE(!ected @b*c reductionaccordingaccording

to interventionto interventionnterventionntervention 5pected in HbA5pected in HbA/c/c#$%#$%)ifestyle interventions)ifestyle interventions 11 toto 2>2>

MetforminMetformin 11 toto 2>2>

5ulfonylureas5ulfonylureas 11 toto 2>2>

InsulinInsulin 1.51.5 toto 3.5>3.5>

'linides'linides 11 toto 1.5>1.5>11

Thia2olidinedionesThia2olidinediones 0.50.5 toto 1.4>1.4>

&'lucosidase inhibitors&'lucosidase inhibitors 0.50.5 toto 0.>0.>

')P&* agonist')P&* agonist 0.50.5 toto 1.0>1.0>

PramlintidePramlintide 0.50.5 toto 1.0>1.0>

+PP&I8 inhibitors+PP&I8 inhibitors 0.50.5 toto 0.>0.>

1. &epa/lini"e is ore e##ectie tan nate/lini"eA"apte" #ro atan *M8 et al.Diabetes Care200,;32:1,3-203.


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GlycemicGlycemic

ontrolontrol

In Monothera!yIn Monothera!y


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Glimepiride 2cacy "roven inGlimepiride 2cacy "roven in

(onotherapy(onotherapy

5chade +5 et al. L Clin Pharmacol *


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Glimepiride (etformin ombinationGlimepiride (etformin ombination

4educes nsulin 4esistance (ore than4educes nsulin 4esistance (ore than

(etformin (onotherapy(etformin (onotherapy

Bermde2&Pirela 8L$ et al. m L Thera!eutics 0==> *6 *


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2 li i id li


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2cacy' Glimepiride nsulin2cacy' Glimepiride nsulin

ombinationombination Reduced insulin reFuirement and fasterReduced insulin reFuirement and faster

glycemic controlglycemic control

Riddle et al. +iabetes Care *


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AdditionnalAdditionnal

Bene0ts for theBene0ts for the"atient"atient BeyondBeyond

Blood GlucoseBlood Glucoseontrolontrol


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(ode of action'(ode of action'DiJerentDiJerent

S34s in diJerent tissuesS34s in diJerent tissues Pancreatic beta&cellPancreatic beta&cell 5UR*:4irG.05UR*:4irG.0 Cardiac and s"eletal muscleCardiac and s"eletal muscle 5UR0:4irG.05UR0:4irG.0

8ascular smooth muscle8ascular smooth muscle

5UR0B:4irG.*5UR0B:4irG.*

7on&vascular smooth muscle7on&vascular smooth muscle 5UR0B:4irG.05UR0B:4irG.0 BrainBrain 5UR*&0B:4irG.05UR*&0B:4irG.0

Proks P et al/. >iabetes 00 (1 S2'D-S2@'/

Glimepride 2cient in reducing Q ris<


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Glimepiride accompanied by a better Q ris< mar


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dvantages of 'lime!iridedvantages of 'lime!iride 5ingle daily dosing5ingle daily dosing

Com!arable hy!oglycaemic side eect !ro#lCom!arable hy!oglycaemic side eect !ro#l

to other 5Uto other 5U 5afer in the !resence of cardiac disease5afer in the !resence of cardiac disease Peri!heral action conserves endogenousPeri!heral action conserves endogenous

insulininsulin

5afer to use in the !hysically active5afer to use in the !hysically active


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Review

Annals o# Internal Me"icine

Systematic Reie!" #omparatie $%%ectieness and

Sa%ety o% &ral Medications %or Type ' (iabetes

MellitusShari )olen, M(, M*+ eonard .eldman, M( /ason assy, M(, M*+ isa Wilson, )S, ScM +sin-#hieh eh, *h(Spyridon Marinopoulos, M(, M)2 #rystal Wiley, M(, M*+ $li3abeth Selin, *h( Renee Wilson, MS $ric )4 )ass,

M(, M*+ and .rederic5 4 )rancati, M(, M+S

#onclusions" *ompare# +ith ne+er, more expensive agents ol#er

agents secon#-generation sulfonylureas an# metformin have

similar or superior effects on glycemic control, lipi#s, an# other

interme#iate en# points. Large, long-term comparative stu#iesare nee#e# to #etermine the comparative effects of oral

#iaetes agents on har# clinical en# points.

%nn &ntern "e'. 0@1F@2D'-299


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07. Prof. Eman Rushdy Sulphonylurea a Golden Therapy for Diabetes