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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
7/23/2019 07. Prof. Eman Rushdy Sulphonylurea a Golden Therapy for Diabetes
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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!$!tokines% &'S
7/23/2019 07. Prof. Eman Rushdy Sulphonylurea a Golden Therapy for Diabetes
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*-cell 4ha+stion- , physical depletionof *-cell ins+lin stores
secondary to prolonged chronic stim+lation
with gl+cose on non-gl+cose secretagog+es/
- No defect in ins+lin synthesis/
- 5he *-cell f+nction f+lly recovers as it rests/
4ha+stion is reversible
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6l+coto4icity
Non physiologicaland potentially
irreversible*-cell damage ca+sed by chronic
e4pos+re to s+pra-physiological gl+cose
concentration with characteristic decreases in
ins+lin synthesis and secretion ca+sed by
decreases ins+lin gene e4pression/
6l+coto4icity is irreversible
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7nterplay between *-cell e4ha+stion 8 gl+coto4icity
4cess ins+lin secretion
Prolonged hyperglycemia
7ns+lin depletion from *-cell #4ha+stion%
yperglycemia
)ore. prolonged hyperglycemia
" Stress ":S ;a
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7/23/2019 07. Prof. Eman Rushdy Sulphonylurea a Golden Therapy for Diabetes
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Frequently prescribedFrequently prescribed
oral hypoglycemicoral hypoglycemic
medicationsmedications??
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Factors to onsider !henFactors to onsider !hen
hoosing "harmacologicalhoosing "harmacological
Agent#s$ 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
7/23/2019 07. Prof. Eman Rushdy Sulphonylurea a Golden Therapy for Diabetes
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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"
7/23/2019 07. Prof. Eman Rushdy Sulphonylurea a Golden Therapy for Diabetes
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1D
Life style modification
,,; consens+s,,; consens+s
,lgorithm #09%,lgorithm #09%
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Ale
7/23/2019 07. Prof. Eman Rushdy Sulphonylurea a Golden Therapy for Diabetes
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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 *
7/23/2019 07. Prof. Eman Rushdy Sulphonylurea a Golden Therapy for Diabetes
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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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