acp sglt2 slidecast 220

8/9/2019 Acp Sglt2 Slidecast 220

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Please Take A Moment to Complete the Pre-Program ClinicalPerformance and Knowledge Gap Assessment Survey


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CM%-certi/ed symposium 0ointly sponsored #y the.niversity of Massachusetts

Medical School andCM%ducation 1esources ''C

Commercial Support2 This

CM% activity is supported #yan educational grant fromAstra3eneca

4elcome and Program5verview4elcome and Program5verview


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"istinguished $aculty

VIVIAN A. FONSECA, MD,FRCP Program ChairProfessor of Medicine andPharmacology , Tullis TulaneAlumni Chair in "ia#etes ,

Chief Section of%ndocrinology , Tulane.niversity ealth SciencesCenter , Past PresidentScience and Medicine

American "ia#etesAssociation

CHARLES F. SHAEFER JR.,MD, FACP

Assistant Clinical Professor ofMedicine Medical Colle e of

GEORGE BAKRIS, MD

Professor of Medicine , "irectorypertension Center , .niversityof Chicago Medical Center ,Chicago (llinois

MUHAMMAD ABDUL-GHANI,MD, PHDAssistant Professor , "ia#etes"ivision , School of Medicine ,

.TSCSA Graduate School of+iomedical Sciences , SanAntonio Te7as


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C5( "isclosures

Fa!"#$ M%m&%r R%"a#io'(hi) Cor)ora#io'*Ma'!+a#!r%r

Viia' Fo'(%a, MD 1esearch Support 8to Tulane92

onoraria for Consultingand 'ectures2

Grants from %li 'illy A##ott 1eataAsahi

Gla7o Smith Kline Takeda *ovo*ordisksano/-aventis %li 'illy Pamla#sAstra-3eneca A##ott +ristol-Myers

S:ui## Merck+oehringer (ngelheim

Char"%( F. Sha%+%r,MD, FACP

Consultant2

Speaker;s +ureau2

Sano/-aventis +MS-A3

Sano/-Aventis Amylin +(


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VIVIAN A. FONSECA, MD, FRCPProgram ChairProfessor of Medicine and Pharmacology , Tullis TulaneAlumni Chair in "ia#etes , Chief Section of

%ndocrinology , Tulane .niversity ealth SciencesCenter , (mmediate Past President Science and

The Challenges of Achieving A"AGlycemic Target Goals and 5ptimi)ingCardiometa#olic Status in Patients

with T!".nmet Therapeutic *eeds on the 'andscape of 5ralAntidia#etic "rugs2 4hat are the *ew $rontiers and

Paradigms?

An %vidence-to-Strategy .pdate for Type ! "ia#etes


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$act @2 4e still need #etter control of#Ac levels

$act @!2 This is an unmet therapeutic need

$act @B2 There are new oral antidia#eticdrugs worthy of our attention analysis andconsideration

%volving $rontiers of Antidia#etic Therapy


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1eproduced with permission from the +M> Pu#lishing Group Khaw K-T et al BMJ!DDEB!!2-F

EPIC 0 E!ro)%a' Pro()%#i% I'%(#iga#io' o+ Ca'%r a' N!#ri#io'

P12.223 ag%-a4!(#% %a#h ra#%( +or "i'%ar #r%'

EPIC-Nor+o"/5 6778 Pa#i%'#( Fo""o9% +or 6 :%ar(

C= Mortality (ncreases with (ncreasingAC 'evel

R % " a # i - % R

i ( / o +

C V M o r # a

" i # $

A3C ;


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.K Prospective "ia#etes Study 8.KP"S9 Group Lancet HEBI!2HIJ-HFI!olman 11 et al N Engl J Med !DDHEBI2I-IHB The "ia#etes Control and Complications Trial 1esearch GroupN Engl J Med. BEB!E-HF J*athan "M et al N Engl J Med !DDIEBIB2!FJB-!FIB

IGerstein C et al N Engl J Med. !DDHEBIH2!IJI-!II FPatel A et al N Engl J Med. !DDHEBIH2!IFD-!I!"uckworth 4 et al N Engl J Med. !DDEBFD2!-B

S#!$Miroa(!"a

r CVD Mor#a"i#$

.KP"S!

"CCT


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DHJ 8DI-DJ9 L 8LF to B9

>N, %# a". Ann Intern Med. E-)!& ah%a o+ )ri'#.

(n the overall analysis intensive glucose control had no signi/cante&ect on either2C= mortality 8relative risk D IN C( DF-!JO9orall-cause mortality 8relative risk DH IN C( DHJ-IO9

Pooled analysis of the .KP"S ACC51" A"=A*C% and =A"T trials yielded aFN overall reduction in nonfatal M( The a#solute overall risk reduction was events per DDD patients over I years of treatment

' 0 8?,@28 R%"a#i% Ri(/ ;< CI=DI D !D

*onfatal M(F


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ACC51" %ye2 Microvascular 1elative1isk 1eduction 4ith (ntensive Therapy

"uration of follow-up

J years

+aseline AC

Mean (nt2 H!DN

Mean Std2 HBDN

AC at yearaMedian (nt2 FJNa

Median Std2 INa

1etinopathy

1ate of progression of dia#eticretinopathy2

(ntensive2 BNStandard2 DJN

8PQDDDB9aSigni/cant #etween-group di&erence was maintained throughout the study

ACC51"QAction to Control Cardiovascular 1isk in "ia#etes

ACC51" %ye Glycemia Arm

ACCORD S#!$ Gro!) a' ACCORD E$% S#!$ Gro!). N Engl J Med .-


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'ong-term %&ects of (ntensive Glucosein *ewly "iagnosed T!"M Patients

HR (95%CI)HR (95%CI)

Intensive (SU/Ins) vs. Conventional glucose control

HR (95%CI) HR (95%CI)

Intensive (metformin) vs. Conventional glucose control

Holman RR, et al . N Engl J Med 2008;!8"2!#!$!%.


13/169"el Prato S et al. Int J Clin Pract !DDEFJ2!ILBDJ

FI

FD

D

I

HD

I

D

HI

! B J I F H D ! JB I F

>im% (i'% iag'o(i(;$%ar(=

+efore entering =A"T intensivetreatment arm After entering =A"T intensivetreatment arm

H & A 3

; < =

G%'%ra#io' o+ a&a g"$%mi"%ga$

Dri%( ri(/ o+om)"ia#io'(

Mo%""i'g #h%)rior hi(#or$ o+)a#i%'#(r%r!i#% i'VAD> i""!(#ra#%(#h% ra9&a/(o+ "a#%i'#%r%'#io'

So"i "i'%5 ha'g%( i' H&A3 i' r%()o'(% #o i'#%'(i% #r%a#m%'# i' VAD>

U))%r &ro/%' "i'%5 #h%or%#ia" r%o'(#r!#io' o+ )rior ia&%#%( )rogr%((io' &a(% o'UKPDS

Lo9%r &ro/%' "i'%5 #h% i%a" #im% o!r(% o+ g"$%mi o'#ro"

'egacy of R+ad Meta#olic Memory;


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Complications are (rreversi#le

ACC51" L +P and lipid normali)ation alsodid not result in event reduction

'55K A%A" L no #ene/t of lifestylechange and weight loss

A#ove interventions were started too late

Therefore early intervention is #etter

+.T L 4hen is disease reversi#le ? At

diagnosis?


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+ene/t of "i&erent (nterventionsper!DD "ia#etic Patients Treated for I

ears

Sattar *E "ia#etologia !DB

C V % - % ' # ( ) r % - % ' # % P%r 6 mmHg "o9%rSBP

P%r 3 mmo"*" "o9%rLDL-C P%r 2.< "o9%rH&A3


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Primary 1isk $actors for C=" Treatment Goals

American "ia#etes Association "ia#etes Care !DB

yperglycemia

FPG / preprandial glucose

PPG

A1c

90–130 mg/dL


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"espite (mportant Advances in TherapyGlycemic Control is *ot 5ptimalChallenges2

Too many patients L +urden or preventionopportunity?

$ailure to attain and sustain optimal long-termglycemic control

ypoglycemia risk

(nade:uate postprandial glucose control

.npredicta#le glucose Uuctuations

4eight gain

%7cess C="


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D%r%a(%I'r%#i' E%#

D%r%a(% I'(!"i'S%r%#io'

I'r%a(%H%)a#i G"!o(%Pro!#io'

I("%#a %""

I'r%a(%

G"!ago'S%r%#io'

D%r%a(% G"!o(%

U)#a/%

I'r%a(%

Li)o"$(i(

I'r%a(%G"!o(%R%a&(or)#io'

ro'o R %# a". Diabetes. 822@5??-?.

5minous 5CT%T

H:PERGL:CEMIA

N%!ro#ra'(mi##%r

D$(+!'#io'

A tih l i Th i T!"M A"A


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Antihyperglycaemic Therapy in T!"M - A"AGuidelines !D!Healt&' eating, eig&t control, increase *&'sical activit'

+fficac' (

H-c)

H'*ogl'caemia

eig&t

Sie

effects...

Costs

..

Initial rug

monot&era*'

1etformin 1etformin 1etformin 1etformin 1etformin

3o4rug

cominations

If comination t&era*' t&at inclues asal insulin i not ac&ieve H-c target after 45

mont&s, *rocee to a more com*le6 insulin strateg' usuall' in comination it& one or to

non4insulin agents1ore com*le6

insulin

strategies Insulin (multi*le ail' oses)

If iniviualise H-c target not reac&e, *rocee to to4rug comination

If iniviualise H-c target not reac&e, *rocee to t&ree4rug comination

SU

Hig&1oerate ris7

ain

H'*ogl'cemia

9o

3:

Hig&9o ris7

ain

+ema, H


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So what do we do now?

Should we rethinktreatment strategies withnew targets?

A*S4%12 %S


* l " V T t i


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*ovel "rugs V Targets in"evelopment for "ia#etes

+romocriptine 'ong-acting G'P-

receptor agonists "PP (= inhi#itors 1anola)ine "ual PPA1α


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$ocus of This %vening;sSymposium

The unmet need for safe ande&ective oral agents that help meetA"A target goals and have optimal

cardiometa#olic risk pro/les

The kidney plays a central role in the

pathogenesis of T!" and glucosehomeostasis

The emerging clinical role for SG'T!inhi#ition as a foundation therapy for

A % id t St t . d t f


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*ovel Kidney-+asedMechanisms and Strategies

for Glycemic 1egulation inealth and "isease

G%org% L. Ba/ri(, MD, FASH, FASNProfessor of Medicine

"irector AS Comprehensive ypertension Center

.niversity of Chicago MedicineChicago ('



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Physiology of

Glucose andling#y the Kidney


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The Kidneys Play an (mportant 1ole in the andling of Glucose

Total glucose stored in #ody YJID g

Glucose utili)ation Y!ID g


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The Kidney andles Glucose +y Three Key Mechanisms!

FFA5ree a!!$ acid6

16 Geric# 6 Diabet Med 6 0107(:13;1*66 .or!ora G e! al6 =n: .or!ora G, -erricson ), eds6 +o"oen, >: o#n ?ile$ @ ons, =nc 009:97710;16

2

Renal Corte6" luconeogenesis

Bain energ$ source: oCida!ion oFFAs

on!ri"u!es D0%–4% o !o!al"od$ glucose released in !#e as!ings!a!e

Renal 1eulla

E"liga!e consumer o glucose,

insulinindependen!

10% o !o!al glucose up!ae in !#e

"od$, as!ed s!a!e

. lucose =rouction 8. G"!o(% U#i"ia#io'

M%!""a

lomerulus

3o ureter

Collecting

uct

istal

convolute

tuule=ro6imalconvolute

tuule

9oo* of Henle

omanDs

ca*sule

. lucose =rouction

Cor#%


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Glomerular $iltration

!I m' of /ltrate formed

!IDDD m%: of *aZ $iltered .rine *aZ e7cretion

DD m%:

D g

HD '

1ea#sorption

Mount "+ u AS' (n2 +renner +M ed Brenner and Rector’s The Kidney Hth ed Philadelphia PA2 %lsevier SaundersE!DD2Chapter I A#dul-Ghani M "e$ron)o 1 Endocr Pract !DDHEJ2H!-D

Artery

Aferent EferentFiltration

Tubular system

Secretion


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1enal Glucose andling

atic representation of the typical titration curve for renal glucose rea#sorption in man

ed from Silverman M Turner 1> and!oo" o# Physiology ndhager %% ed 57ford .niversity PressE !2!D-!DBH

722

622

822

22 822 622 722 @22

R a # % o + g " ! o ( %

K " # r a # i o ' * r % a & ( o r ) #

i o ' * % J r % # i o '

; m g * m i ' =

P"a(ma g"!o(% ;mg*L=

>m

R%a&(or&%

Fi"#%r% Er%#%

>hr%(ho"

>ma

ThresholdTm!lucose

re"resentsthe

ma#imalresor"ti$eca"acityo% the

"ro#imaltubule

i 8 9 d i 8 9


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*air S et al J Clin Endocrinol Meta! !DDEI2BJ-J!

Active 8SG'T!9 and Passive 8G'.T!9Glucose Transport in a 1enal Pro7imal

Tu#ule Cell

=n!ers!i!ium.u"ular lumen

Ba

lucose

S932

Ba /E -3=ase

=um*Ba

E

9U32lucose


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Sodium-GlucoseCotransporters

Lee 6 e! al6 Kidney Int Suppl. 0077:7346

SGL>3 SGL>8

SiteMostly intestine withsome in kidney

Almost e7clusivelykidney

Sugarspeci/city Glucose or galactose Glucose

A[nity forglucose

igh

KMQDJ Mm

'ow

KmQ! Mm

Capacity forglucosetransport

'ow igh

"ietary glucosea#sor tion 1enal lucose


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1enal Glucose 1ea#sorption

Chao %C enry 11 Nat Re$ %rug %isco$ !DDE892II-II1eprinted #y permission from Macmillan Pu#lishers 'td2 Nat Re$ %rug %isco$ -

SGL>3

SGL>8

32<

Glucose

NOGLUCOSE

S segmentofpro7imaltu#ule

"istal S!


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Pathophysiology of

T!"M

( d % ti Th h ld d ( d


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(ncreased %7cretion Threshold and (ncreasedGlucose 1ea#sorption %7acer#atesyperglycemia in Type ! "ia#etes

Ccre!ed

Fil!ered

.m

ea"sor"ed

=ncreased.#res#old

u"Hec!s ?i!# .-+eal!#$ u"Hec!s

+eal!#$ u"Hec!s

.-5!$pe dia"e!es .m5!u"ular maCimum IG5urinar$ glucose eCcre!ion616 )a$s +6 Curr Med Res Opin6 00943(:;71;816 -iagram adap!ed i!# permission66 -eFron'o A e! al6 Diabetes Care6 01318 Jpu" a#ead o prin!K636 A"dulG#ani B e! al6 Curr Diab Rep6 01 un13(:3086 -iagram adap!ed i!# permission6

>ormal

.#res#old 1 a t e o f G l u c o s e

$ i l t r a t i o n <

1 e a # s o r p t i o n


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Meyer C et al A& J Physiol Endocrinol Meta! !DDJE!H2%DJ-%DIF

1enal and epatic Glucose 1elease AfterGlucose (ngestion in Patients 4ith "ia#etes

(ncreased #aselinegluconeogenesis

(nsulin resistancewith decreasedsuppression ofgluconeogenesis

(ncreased free fattyacids in "Mstimulates

gluconeogenesis inkidney V liver

-72 2 2 3@2 8?2

D

J

H

!

\ m o l ] k g - ] m i n -

D

B

F

\

m o l ] k g - ] m i n -

1enal Glucose 1elease

epatic Glucose 1elease

Minutes

i#h ia&%#%( ;' 0 32=

i#ho!# ia&%#%( ;' 0 32=


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Altered 1enal Glucose Control in"ia#etes

Gluconeogenesis is increased inpostprandial and posta#sorptive statesin patients with T!" 1enal contri#ution to hyperglycemia B-fold increase relative to patients

without dia#etes

Glucose rea#sorption (ncreased SG'T! e7pression and

activity in renal epithelial cells frompatients with dia#etes vsnormoglycemic individualsMarsenic 5 A& J Kidney %is !DDEIB2HI-HHB

+akris G' et al Kidney Int !DDEI2!!-!1ahmoune et al %ia!etes. !DDIEIJ2BJ!-BJBJ

1enal SG'T! 'evels


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1enal SG'T! 'evelsAre (ncreased in Type ! "ia#etes

1ahmoune et al %ia!etes. !DDIEIJ2BJ!-BJBJ

* o r m

a l i ) e d G l u c o

s e

T r a n s p o r t e r P r o t e

i n ' e v e l s

*GT T!"0

2

#

M

' P ^ DI #etween groups

1ationale for SG'T! (nhi#ition in


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1ationale for SG'T! (nhi#ition in"ia#etes $unctional "isorders

$amilial renal glucosuria "ue to SG'T! gene mutations 1are kidney disorder

• Benign• No corres(onding "idney co&(lications

.rinary glucose e7cretion of -D g


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1ationale for 1enal Sodium-GlucoseCotransporter ! 8SG'T!9 (nhi#itors

SG'T! is a low-a[nity high capacityglucose transporter located in the pro7imaltu#ule and is responsi#le for DN of glucoserea#sorption

Mutations in SG'T! transporter linked tohereditary renal glycosuria a #enigncondition in humans

Selective SG'T! inhi#itors could reduce#lood glucose levels due to increased renale7cretion of glucose

Selective SG'T! inhi#ition therefore would

cause urine loss of the calories from)roos AB, .#acer B6 Ann P#armaco!#er 009*3:18;


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Phlori)in2 The RPrototype; SG'T(nhi#itor

$irst descri#ed in the mid-th

century (solated from the root #ark of the

apple tree

.tili)ed in the e7ploration of SG'Tfunction

OH

OH

O

HO

OH

O

OHO

HO

HO

enkran) >1 %ia!etes Meta! Res Re$ !DDI

Treatment of "ia#etic 1ats 4ith


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Treatment of "ia#etic 1ats 4ithPhlori)in *ormali)es Plasma Glucose'evels

ssetti ' et al J Clin In$est H

P1.223 %r(!( gro!)( 3, , a'Group ( 8*QJ9 L sham-operated controlsGroup (( 8*Q9 L partial 8DN9 pancreatectomyGroup ((( 8*QD9 L DN pancreatectomy Z phlori)inGroup (= 8*Q9 L sham-operated Z phlori)inGroup = 8*QJ9 L DN pancreatectomy


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Mechanism of Action

=ncrease !#e remo&al o glucose &ia GL. in#i"i!ors

D%r%a(% g"!o(%r%a&(or)#io' i'#o($(#%mi ir!"a#io'Glucose SG'T-SG'T! SG'T!

inhi#itor

G"om%r!"!( Proima" Co'o"!#%>!&!"%

Ear"$ Di(#a"

G"!o(% i'!ri'%

1othen#erg P' et al Poster presented at2 JFth Annual Meeting of the%uropean Association for the Study of "ia#etesE Septem#er !D-!J !DDE

SG'T! (nhi#itors 'ower 1enal


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T!"M Z

SG'T!inhi#ition

SG'T! (nhi#itors 'ower 1enal Threshold for Glucose %7cretion 81TG9

dul-Ghani MA "e$ron)o 1A Endocr Pract. !DDHE *air S 4ilding >P J Clin Endocrinol Meta!

ealthyHDmgG

2

T!"M!JDmg


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SG'T! (nhi#itors

"apagliUo)in 8approved9

CanagliUo)in 8approved9

%mpagliUo)in 8+( DB9a

(pragliUo)in 8ASPJ9a

a These agents have not #een approved #y the $"A #ut they arein Phase B clinical trials


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Conclusions

The kidney contri#utes togluconeogenesis and hyperglycemia intype ! dia#etes

SG'T! inhi#itors act #y a novelmechanism and may #e useful inpatients who have not achieved goal#Ac levels

1ecent research reports that SG'T!inhi#itors lower #Ac levels and alsohave the #ene/t of weight reduction in

patients with T!"M

An %vidence-to-Strategy .pdate for


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1ationale for .se and %videncefrom 'andmark Clinical Studies

Safety and %[cacy 5f SG'T!(nhi#itors in T!"M

M!hamma A&!"-Gha'i, MD, PhDAssociate Professor of Medicine"ia#etes "ivision.TSCSA San Antonio T`

An %vidence to Strategy .pdate for Type ! "ia#etes

SG'T! Action (s (ndependent of


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SG'T! Action (s (ndependent of(nsulin Secretion and (nsulin Action

=lasma

lucose

=mpaired )e!aell Func!ion

Increase

He*atic lucose

=rouction

Insulin

Resistance

lucosuria

90 mg%

%&ect 5f "apagliUo in 5n #A


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%&ect 5f "apagliUo)in 5n #Ac

" e c

r e m e n t i n # A c

8 N 9

4

40.!

0

DAPA8.mg*

PLAC

ME>322mg*"

DAPAmg*

DAPA32mg*

DAPA2mg*

List J et al, Diabetes Care 32:650-657, 2009

8 l u c o s u r i a

( g r a m / 2 # & )

0

!

0

#!

50

F!

2.! ! 0 20 !0

;a*agliflo>in (mg)


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SG'T! (nhi#itors are%&ective in Com#ination

with All Anti-"ia#eticAgents (ncluding (nsulin

SG'T! (nhi#itors in Com#ination with


49/169

SG'T! (nhi#itors in Com#ination with5ther Antidia#etic Treatment

A"dulG#ani, Am Bed 01* in press(

; e c r e a s e I n H , - . c ( G )

4.0

40.8

40.5

40.#

40.2

0.0

-rug >ai&eBe!,ormin

AI

Piogli!a'one

=nsulin

Cana ;a*a +m*a

%&ect of "apagliUo)in Addition to (nsulin-


50/169

D

I

HD

HI

D

D J F H D !

=laceo-=-40mg

-=-420mg

AC 8N9

=laceo

-=-40mg

-=-420mg

-I-J

-B

-!-

D

! J F H D !

+ody 4eight 8kg9

4eeks

p gtreated T!"M Patients 8nQ9

Wilding et al, Diabetes Care 32:1656-62, 200


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SG'T! (nhi#itors are

%&ective in All Stages ofthe "isease

"apagliUo)in is %:ually %&ective in T!"M


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"apagliUo)in is %:ually %&ective in T!"MPatients with %arly and 'ate Stage"isease

Zhang et al, Diab Ob Metab 12:510-516, 2010 *p


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"apagliUo)in 8! 4eeks9 1educes AcSimilarly in T!"M Patients with %arly and

'ate Stage "isease

3han et al "ia# 5# Meta# !2ID-IF !DD

"apagliUo)in !Dmg

+

-

R

9

9

-

3

+

" %

C 1 % M % * T ( * A

c 8 N 9

"apagliUo)in Dmg

+

-

R

9

9

-

3

+

40.8

40.5

40.#

40.2

0

%igh# "o(( a' Ug"!V9%r% (imi"ar i' %ar"$a' "a#% (#ag% >8DM


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The Amount ofGlucosuria is Smallerthan %7pected fromSG'T! (nhi#ition

1enal andling 5f Glucose


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SGL>

8

1enal andling 5f Glucose;3@2 L*a$= ;2 mg*L= 0 3?2g*a$

32<

2<;32Gram(=

NOGLUCOSE

SS3

SGL>

3


56/169

SGL>

8

;3@2 L*a$= ;2 mg*L= 03?2 g*a$

82g*,82<O!)a'

$

32 g*,2<

O!)a'$

NO

GLUCOSE

SS3SGL>

3


57/169

S93 2

;3@2 L*a$= ;2 mg*L= 0 3?2g*a$

382g*,

322<2

S3S1

SGL>

3

2

g*

1elationship +etween .G% and


58/169

e a o s p e ee .G a dPlasma Glucose Concentration

-ul4&ani 1 - et al. iaetes 20;52"2#428

Plasma Glucose Concentration 8mg


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(mpact of +aseline #Ac on"apagliUo)in %[cacy

-ia"e!es are 33:17*, 010

C & a n g e

i n H , - . c ( G )

4.0

42.!

42.0

4.!

4.0

40.!

0.0

! 0 ! 0;a*a (mg)

H,-c (G) 8.0 0.8


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i et.al. Clin 3&era* 5"8#400, 20#

; e c

r e a s e i n H , - . c ( G )

4.5

4.2

40.8

40.#

0.0

H-cRange

J8G 84%K%G

aseline

2# ee7s

H-c F.F

5.F

8.#

F.2

%.!#

F.F5


61/169

"ura#ility of #Ac"ecrease #y SG'T!(nhi#itors

%&ect of "apagliUo)in Addition on Ac in (nade:uately


62/169

0 4

Controlled T!"M 8AcQHFN9 on (nsulin Therapy 8J-HDunits


63/169

Controlled T!"M 5* Metformin 5ne 5ther 5A"

Na$%& et al, Diabetes Care 3#:2015-22, 2011 C h a n g e i n

# A c

8 N 9

a*agliflo>in

(nL#00)

- - - - -

0-

-0.6 -

-0.4 -

-0.8 -

-1.0 -0 12 34 42

-0.2 -

5226 - -

186

4eeks

+aseline Ac

QN

-DI!N

-DI!N

3itration 1aintenance

li*i>ie (nL#0)


64/169

Meta#olic %&ects ofSG'T! (nhi#itors

Su#0ect Population


65/169

Su#0ect Population

Su#0ectPopulation "apagliUo)in Place#o

*um#er ! F

Se7 male Male

Age 8years9 JH ± J IJ ± J

+M( 8kg


66/169

(nsulin Sensitivity and +eta Cell $unction

m g


67/169

%&ect of "apagliUo)in on%ndogenous Glucose Production

"apagliUo)in

Place#o

- -

Day1

- - -

2.8-

3.2

2.0 -

2.4 -

1.6 - % G P 8 m g


68/169

Glucosuria8g

$PG8mg-!IZJI

g

1esponse to Glucosuria on +loodGlucose


69/169

The Com#ination ofSG'T! (nhi#itors plus

G'P-( Analogues has thePotential to CauseSynergistic "ecrease in+AC

%&ect of +ackground Therapy on


70/169

g pyCanagliUo)in %[cacy

1eininger et al. iaetologia !5 (su*l ) SF, 20

C & a n

g e i n H , - . c ( G )

4.00

40.F!

40.!0

40.2!

0.00

0.2!

=9-C C-B- C-B-=9-C

ac7groun 3&era*'

;==4IMIn&i,itor

9=4-nalogue

Summary of Glycemic Actions


71/169

of SG'T! (nhi#itors

SG'T! inhi#itors lower #Ac independent ofinsulin secretion and action %&ective in all stages of the disease

Can #e com#ined will all other therapies The e[cacy of SG'T! inhi#itors increases

with the increase in #aseline #Ac

SG'T! inhi#ition stimulates a compensatoryincrease in GP Potential com#ination with G'P- analogues


72/169

SG'T! (nhi#ition %7ertsMany *on-Glycemic

Meta#olic +ene/ts

%&ect of "apagliUo)in versus


73/169

Glipi)ideon +ody 4eight

Na$%& et al, Diabetes Care 3#:2015-22, 2011

0 -

a*agliflo>in

li*i>ie

- - - - -

-1-

1 -

-2 -

-

0 12 34 42

2 -

5226 - -

186

4eeks

+aseline 4eight QHHJ vsHFkg

-B!! kg

ZJJkg

Titration Maintenance

h a

n g e i n + o d y

4 e i g h t 8 k g 9

-3 -

-4 - =J0.000

%&ect of "apagliUo)in on +ody $at


74/169

%&ect of "apagliUo)in on +ody $atMass

Clin +nocrinol 1eta, 1arc& 202, %F ()"02040

Place#o ZMetformin*Q nQ

"apagliUo)in D mgZMetformin*QH nQH!

Place#o ZMetformin*QJ! nQB

"apagliUo)in D mgMetformin*QB nQBD

C h a n g e i n

# o d y m a s s c o m p o s i t i o n 8 k g

9

C h a n g e i n

a d i p o s e t i s s u e

v o l u m e 8 c m B

9

%&ect of "apagliUo)in on +lood Pressure( M f i T d T!"M P i


75/169

4!

4#

4

42

4

0

(n Metformin-Treated T!"M Patients

'aile( CJ et al, )an%et 3*5:2223-33, 2010

∆

S y s t o

l i c + P

∆

" i a s t o l i c + P

4!

4#

4

42

4

0=9-C40.2

=9-C

40.

D A P A

8 . B m g

42.

4#.

4!.

D A P A

B m g

D A P A

3 2 m g

D A P A

8 . B m g

D A P A

B m g

D A P A

3 2 m g

%&ect of "apagliUo)in on Plasma 'ipidsd


76/169

and.ric Acid Concentration

D

DD -

D'"' C5'8mg


77/169

'ipid Pro/le in Phase ((( Trials

Har' et.al. iaetologia !5"SF%, 20

%&ect Place#o "apagliUo)in I mg

"apagliUo)in D mg

*um#er BB JI B

T Cholesterol -DJN ZN ZJN

"' ZBHN ZFIN ZIIN

'"' -N ZDFN Z!N

Triglycerides -DN -B!N -IJN

$$A -IN -DIN !N

SG'T ! (nhi#ition2 Meeting .nmet* d i "i # C


78/169

*eeds in "ia#etes Care

Lo9%r( >RIG

I'r%a(%( HDL

R%!%(H&A3

Promo#%(%igh# Lo((

Com)"%m%'#(A#io' o+ O#h%rA'#iia&%#iAg%'#(

R%!%(B"ooPr%((!r%

NoH$)og"$%mia

(mprovesGlycemicControland C=1$s

R%%r(a" o+ G"!o#oii#$

Summary of 5ngoing C= 5utcomesT i l


79/169

Trialswith SG'T! (nhi#itors

*ame Treatment Patients *um#er Completion

*CT-

DDB!F!

CanagliUo)i

n and

place#o

T!"M and

high C=

risk

JJDD !DH

*CT-

DBFF

%mpagliUo)i

n and

place#o

T!"M and

high C=

risk

DDD !DI

*CT-DBDIBJ

"apagliUo)in and

place#o

T!"M andhigh C=

risk

!!!DD !D

Safety (ssues


80/169

Safety (ssues

emodynamic Side %&ects

"apagliUo)in on emodynamic


81/169

Heers*in7 et.al. Diabetes, +besit( and Metabolis 15: 5362, 2013

Place#o Place#o "apagliUo)in

CT3

Age 8y9 IH IJ II

#Ac 8N9 I J

G$1 8ml


82/169

Phase ((( Trials of CanagliUo)in

(nfections Place#o DD mg BDD mg

Any .T( J I JB

Symptomatic

.T(!F BH B!

.pper .T( D D D

Serious .T( D D! D

Mycotic

(nfections$emales B! DJ J

Male DF J! B

Usis7in et.al. iaetologia !5"S80, 20

"apagliUo)in as *o %&ect on +one


83/169

"apagliUo)in as *o %&ect on +oneMarkers

An %vidence-to-Strategy .pdate forType ! "ia#etes


84/169

A Practical 1oadmap for(ndividuali)ing and 5ptimi)ing .se of

SG'T! (nhi#itors

in Clinical Practice

Char"%( F. Sha%+%r, Jr., MD, FACPSenior Partner.niversity Medical Group L Primary Care

.niversity ealth SystemsAssistant Clinical Professor of Medicine

Medical College of Georgia at Georgia 1egents.niversity

Augusta Georgia

Type ! "ia#etes

5minous 5ctet


85/169

$ron)o 1A %ia!etes. !DDEIH2B-I

Survival as a $unction of AC in Patientswith


86/169

urrie C> et al Lancet. !DDEF8BI92JH-

with Type ! "ia#etes2 A 1etrospective Cohort

Study

!HDDD patients ID years and older

Ora" Ag%'#( I'(!"i' *- Ora" Ag%'#(

Challenges in Type ! "ia#etes


87/169

g yp

'arge num#er of patients "ia#etes a&ects !IH million people 8HB N of the .S population9

• %IA+N)E%/ ,0.0 &illion (eo(le• 1N%IA+N)E%/ 2.3 &illion (eo(le• PRE%IABETE) 4 25 &illion (eo(le

Progressive worsening of insulin secretory de/cit

re:uiring increased num#er of antihyperglycemicmedications over time 1isk for hypoglycemia with some therapies 1isk for weight gain with some therapies

"i[culty controlling postprandial glucose and glucoseUuctuations Preventing and managing complications and co-

mor#idities "i[culty attaining and sustaining optimal long-term

l cemic controlDD *ational "ia#etes $act Sheet .S "epartment of ealth and uman Services

4T A& J Med !D!EBJB892!-!F

Many Patients 4ith T!"MAre *ot 1eaching #A ^N


88/169

Are *ot 1eaching #Ac ^N

*QBBJ"ata from *A*%S2 *ational ealth and *utrition %7amination Survey

N

P a t i e n

t s

4 i t h # A

c

^ K N

.nmet *eeds 4ith ConventionalAntihyperglycemic Therapies


89/169

Antihyperglycemic Therapies

Many therapies are associated with weightgain

(nsulin and non incretin oral insulinsecretagogue therapies are associated with

signi/cant risk for hypoglycemia 5ther A%s with some therapies include G( side

e&ects and edema Many therapies fail to ade:uately control

postprandial hyperglycemia Therapies often fail to maintain long-termglycemic control

+londe ' A& J Manag Care !DDEB2SBF-SJD

+londe ' et al J Manag Care Phar& !DDFE!8suppl92S!-S!

ow "o SG'T! (nhi#itors PotentiallyMeet These *eeds?


90/169

Meet These *eeds?

Associated with weight reduction generally ave no inherent propensity to cause

hypoglycemia 8unless used withsecretagogues or insulin9

=ery few side e&ects

Control postprandial hyperglycemia

Seem to o&er long-term glycemic dura#ility

.nmet *eeds


91/169

.nmet *eeds

mgarden 3T %ia!tes Care !DDEBD892J-HD

Type ! "M Control is *ot "ura#le

B F ! I H ! !J ! BD BB BF B J! JI

>im% ;mo'#h(=


92/169

4hat Shapes Clinical Consideration ofSG'T! (nhi#itors?


93/169

SG'T! (nhi#itors?

%[cacy "ura#ility

Collateral #ene/ts 4eight reduction +lood pressure reduction

Side e&ects Patient;s renal status

Meta-analysis for #Ac Change from+ li D " liU i


94/169

+aseline Dmg "apagliUo)in versusPlace#o

lar e! al6 )B Epen 01:e001007

N01 "$ )ri!is# Bedical ournal Pu"lis#ing Group

Meta-analysis for #Ac Change from+aseline D mg "apagliUo in ersus


95/169




Meta-analysis for #Ac Change from+aseline D mg "apagliUo)in versus


96/169




Meta-analysis for #Ac Change from+aseline D mg "apagliUo)in versus


97/169




CanagliUo)in


98/169

g

PDD vs place#o calculated using 'S measenstock > et al A#stract -51 A"A !DD

Metformin Z CanagliUo)in "ose-1anging Study

Mean +aselineAC 8N9

HD H I D F!

Changes from +aseline in ACin Phase B "apagliUo)in Studies


99/169

in Phase B "apagliUo)in Studies

4ilding >P et al A#stract H-51 A"A !DDE Stro0ek K et al A#stract HD %AS" !DDE

$errannini % et al %ia!etes Care. !DDEBB8D92!!-!!!JE +ailey C> et al Lancet.!DD BI BB 2!!!B-!!BB

Place#o "apa !Img "apa Img "apa Dmg

Collateral +ene/ts


100/169

4eight reduction

+P reduction

$+S reduction

CanagliUo)in


101/169

SG'T! (nhi#ition for Type ! "ia#etes2Metformin Z CanagliUo)in "ose-1anging Study

PDD vs place#o calculated using 'S mea1osenstock > et al A#stract -51 A"A !DD

Mean +aseline4eight 8kg9

HII HI H H HH HFB H

Changes from +aseline in +ody 4eightin Phase B "apagliUo)in Studies


102/169

in Phase B "apagliUo)in Studies

Place#o "apa !Img "apa Img "apa Dmg

4ilding >P et al A#stract H-51 A"A !DDE Stro0ek K et al A#stract HD %AS" !DDE

$errannini % et al %ia!etes Care. !DDEBB8D92!!-!!!JE +ailey C> et al Lancet.-

Meta-analysis for #Ac Change from+aseline


103/169

+aselineDmg "apagliUo)in versus Place#o



Meta-analysis for 4eight Change from+aseline


104/169

Dmg "apagliUo)in versus Place#o

Clar C et al. 1 N*en 202;2"e0000F


"apagliUo)in as Add-on to Metformin! ear %7tension Study


105/169

+rom BL;SE= P"a%&o

DAPA8.mg DAPA mg

DAPA32mg

Ac N D! 8D9 -DJH 8-9 -DIH 8D9 -DH 8DD9

$PG mg et al A#stract HH-P A"A !D

O %vents suggestive of urinary tract infection – "apagliUo)in !I mg2 HDN I mg2 HHN D mg2 BBN

– Place#o2 HDN

O %vents suggestive of urinary tract infection – "apagliUo)in !I mg2 N I mg2 JFN D mg2 !FN

– Place#o2 INO %vents primarily mild or moderate in intensity and responded to standard treatment


106/169

+lood Pressure 1eduction

Changes from +aseline in $asting PlasmaGlucose in Phase B "apagliUo)in Studies


107/169

-I

I

D

-D

-I

-!D

-!I

-BD

mg


108/169

Genital mycotic infections

.rinary tract infections

+ladder cancer

Genital Mycotic (nfections"apagliUo)in


109/169

"apagliUo)in

G%'i#a"M$o#iI'+%#io'(;GMI=

P"a%&o Da)a mg Da)a 32 mg

Genital mycoticinfection overall

DN IN JHN

Patients withprior GM(

DDN !BN !IN

Patients without

prior GM( DHN IN IDN"iscontinuationdue to GM(

DDN - D!N

$ar7iga Package (nsert accessed March !DJ

Genital Mycotic (nfections 8GM(9CanagliUo)in


110/169

CanagliUo)in

G%'i#a" M$o#iI'+%#io'( ;GMI=

P"a%&oCa'ag"iQo

i' 322mg

Ca'ag"iQoi' 22

mg

$emale

GM( =ulvovaginal Pruritis

B!NDDN

DJNFN

JNBDN

Male GM( DFN J!N BN

(nvokana Package (nsert accessed March !DJ

+ladder Cancer 1isk


111/169

Ri(/ Da)ag"iQoi' Ca'ag"iQoi'

Place#o *um#er e7posed N incidence

BIFDDBN

-

Any e7posure todrug *um#er e7posed N incidence

IJHFN

-

%7posure to drug ! months *um#er e7posed incidence

J cases-

$ar7iga and (nvokana Package (nserts accessed March


112/169

ow "oes 1enal Status

(mpact SG'T! (nhi#itor.se?

Snapshot of "K" in the .nited States


113/169

"K" a&ects !DN-JDN of patients withdia#etes

"ia#etes accounts for JJN of new cases ofkidney failure

'eading cause of %S1"• 60-726 (eo(le 8ith dia!etes !egan treat&ent #or

E)R%

• 939-953 (eo(le 8ith E)R% due to dia!etes li$ingon chronic dialysis or ha$e undergone a "idney

trans(lant

!N 8or BBF #illion9 of e7cess medicale7penditures associated with dia#etes carewas due to renal disease in !DD A-A6 Diabetes Care. 00831:49;;14 >a!ional =ns!i!u!e o -ia"e!es and -iges!i&e and idne$-iseases6 >a!ional -ia"e!es !a!is!ics, 0116

#!!p://dia"e!es6nidd6ni#6go&/dm/pu"s/s!a!is!ics/-BQ!a!is!ics6pd6 Accessed Fe"ruar$ *, 0136

113

-- 5 dia"e!ic idne$ disease

- 5 end s!age renal disease

(mpact of G$1 and $+S on GlucoseClearance #y SG'T! (nhi#itors


114/169

y

(ndications for .sage ofSG'T! (nhi#itors +ased on G$1


115/169

G"om%r!"arFi"#ra#io'Ra#%(

1 2m"*mi'

16 m"*mi'6-72m"*mi'

72m"*mi'

CanagliUo)in *o *o DD mg only DD or BDDmg

"apagliUo)in *o *o *o I or D mg

$ar7iga and (nvokana Package (nserts accessed March !DJ

Glomerular $iltration 1ates

Summary2 $ocus on Clinical (mplications1egarding SG'T! (nhi#itor .se


116/169

4ho are #est candidates for SG'T!(nhi#itor therapy?

4hat role do cardiometa#olic

considerations play in selection of SG'T!(nhi#itors for therapy?

ow do SG'T! inhi#itors /t into the overall

spectrum of dia#etes care?

4ho Are the +est Candidates?


117/169

4here renal status is good 8usually earlyon in therapy9

4here weight reduction would #edesira#le

4here avoiding hypoglycemia is desira#le

4here few side e&ects are desira#le

4here AC reductions of up to N may #eneeded

4here #asal insulin has not achieved AC

goal and up to a#out N AC reduction is

ow "o C= 1isks and Cardiometa#olic $actorsShape the "ecision to .se SG'T! (nhi#itors?


118/169

5#esity is a risk factor !BF kg weight reduction seen over !

years

ypertension is a risk factor A#out I mm g reduction in S+P

%levation in AC is a risk factor A#out N reduction in AC 8relates to

a#out FN reduction in M( risk in .KP"S9 %levation in lipids are a risk factor

May increase '"' J L H mg


119/169

p py

Clearly well suited as initial monotherapydual com#ination therapy or add on tometformin therapy

Cardiovascular 5utcome Trials are inprogress and should report out in the ne7tfew years

Adds on well to insulin 8even some studies

with T"9

5nly limitation is decreased e&ectivenesswith decreasing G$1 8 ^ FD ml


120/169

(n treatment-nave patient with newly-

diagnosed Type ! "M dapagliUo)inmonotherapy resulted in2 Clinically meaningful decreased in AC and fasting

plasma glucose with a near a#sence ofhypoglycemia

$avora#le e&ects on weight and #lood pressure

(n the e7ploratory evening dose cohortchanges from #aseline in AC fasting plasma

glucose and #ody weight at week !J weresimilar to those seen in the main patientcohort

(n the hi h AC 8jAM9 e7 lorator cohorterrannini % et al%ia!etes Care.

!DDEBB8D92!!-!!!J

Monotherapy StudySummary and Conclusions


121/169

(ncreased incidence of urinary tract andgenital infections with dapagliUo)intreatment2 %vents suggestive of urinary tract infection were

JN JFN !IN and IN for place#odapagliUo)in !Img Img and Dmg groupsrespectively

%vents suggestive of genital infections wereBN N HN and !N for place#o

dapagliUo)in !Img Img and Dmg groupsrespectively

ypoglycemic events occurred in !N

IN DN and ! N in atients inannini % et al %ia!etes Care. !DDEBB8D92!!-!!!J

"apagliUo)in as Add-on TherapySummary and Conclusions


122/169

Add-on to metformin in patients inade:uately

controlled with metformin alone $avora#le safety parameters and

tolera#ility

(mproved glycemic control 'owers weight

*ot associated with risk for hypoglycemia

Adverse events occurred in similarproportions

+ailey C> et al Lancet.



123/169

Add-on to glimepiride in patients poorly

controlled sulfonylurea therapy Signi/cantly improved mean AC

1educed weight

4ell-tolerated

Adverse events were similar across alltreatment groups

Stro0ek K et al A#stract HD %AS" !DD



124/169

Add-on to insulin in patients poorly controlled

with insulin Sustained e&ectiveness and sta#le tolera#ility

'ess likely to "C or re:uire insulin up-titration dueto poor glycemic control versus place#o

(ncreased fre:uency of weight loss and reducedfre:uency of peripheral edema over time

Adverse events and discontinuations were #alanced

across groups Actively solicited signs and symptoms suggestive of

urinary tract 8.T(9 and genital infections 8G(9 werehigher with dapagliUo)in vs place#o

4ilding >P et al A#stract H-51

Take-ome Messages


125/169

SG'T! inhi#itors are a new class that areindependent of insulin activity for e&ect

They are among the most potent oralagents for T!"

5utside of possi#le GM(s this class has veryfew side e&ects

This class may have possi#le #ene/ts forC= protection #y means of weightreduction lowering of #lood pressure andother as yet unknown mechanisms

*ew $rontiers and %mergingParadigms


126/169

$rom Science "ata and%vidence to 5ptimal Practice inthe 1eal 4orld

Case Study Simulations .sing anAudience 1esponse System 8A1S9

Clinical "ecision Tree Analysis $ocused on%vidence-+ased "eployment of SG'T! (nhi#itorsin Patients with T!"

Paradigms

Case Study


127/169

J-year-old African American male presented

for #etter +P control and had a F year historyof Type ! "ia#etes is family history ispositive for dia#etes and hypertension in #othparents e denies smoking or drinking and

has no allergies PM unremarka#le other than a#ove 15S2 positive for polyuria and nocturia and

fatigue Current meds2 m%#+ormi' 3222mg BID

CT3 !Img


128/169

'a#s

Sodium-BH potassium-BI m%:


129/169

4hich of the following would you add tometformin to ma7imally improve glycemiccontrol and aid in alleviating co-mor#idconditions?

9 Sulfonylurea

!9 "PPJ inhi#itor

B9 SG'T! inhi#itor

J9 G'P- agonist

Please %nter our 1esponse 5n our Keypad

Case Study


130/169

Physician added e7enatide e7tended-release 8+ydureon9 ! mg once-weeklyin0ection

B-weeks later returned with +P BF


131/169

4hat would #e your ne7t step to ma7imallyimprove glycemic control and aid inalleviating co-mor#id conditions?

9 Sulfonylurea!9 "PPJ antagonist

B9 SG'T! inhi#itor

J9 +asal insulin


Case Study


132/169

Plan2 The patient was started on the SG'T!inhi#itor dapagliUo)in I mg


133/169

4hat would #e your ne7t step to ma7imallyimprove glycemic control and aid inalleviating co-mor#id conditions?

9 Start insulin!9 Add sulfonlyurea

B9 (ncrease dose of dapagliUo)in to D mg po

dailyJ9 Add a "PP-J inhi#itor


Case Study


134/169

4e increased dose of SG'T! inhi#itordapagliUo)in to D mg daily and told himto return in ! months for repeat la#s at !months

$asting glucose was DB mg


135/169

A JI-year-old male patient with a historyof polydipsia and polyuria

+M(QBJB and +PQJF


136/169

4hat would you start this patient on?

9 'ifestyle modi/cation only

!9 'ife style plus metformin

B9 SG'T! inhi#itor

J9 +asal insulin


Antihyperglycemic Therapy in Type ! "ia#etes2 A"A1ecommendations


137/169

Case Study ! L juestion !


138/169

The patient was referred for intensive lifestylemodi/cation and was started on metformin DDD mgdaily and lorcaserin D mg twice daily e returned inJ weeks with a BN weight loss and #Ac level wasN At this point you would2

9 Add dapagliUo)in D mg once daily anddiscontinue lorcaserin!9 Add dapagliUo)in D mg once daily andcontinue lorcaserinB9 +egin a #asal insulin and continuelorcaserin

J9 +egin a G'P agonist and discontinuePlease %nter our 1esponse 5n our Keypad



139/169

-ia"e!es are 33:17*, 010

C & a n

g e i n H , - . c ( G )

4.0

42.!

42.0

4.!

4.0

40.!

0.0

! 0 ! 0;a*a (mg)

H,-c (G) 8.0 0.8


140/169

*ew 5nset T!"M"apagliUo

)in Metformin "apaZMet*um#er F I HI

(nitial Ac 8N9 J J !

Ac at !J 4 8N9F B Ac 8N9 - -BI -!DI

N Ac ^DN !!I BJI I!J

(nitial AcDN

(nitial Ac DBB DH D!Ac at !J 4 HFI HJ B

Ac 8N9 -F -H! -BD

Int J Clin Pract, May 2012, 66. 5, 446-456

%&ect of "apagliUo)in on$PG Concentration


141/169

Case Study ! L juestion !


142/169

The patient returned H weeks later with a FNweight loss and a #Ac of HJN At thispoint you would2

9Add #asal insulin and continue lorcaserin!9Add G'P- agonist and continue lorcaserinB9(ncrease metformin dose to !DDD mg


143/169

A IF year-old woman with T!"M

+M(QB! #Ac Q HHN

Treated with metformin !DDD mg


144/169

ow would you treat this patient who isnot achieving A"A target goal on aregimen of metformin and #asal insulin

9(nitiate a short acting insulin

!9 Start an SG'T! inhi#itor

B9 Start a "PP-(= inhi#itor

J9 Start a G'P- analoguePlease %nter our 1esponse 5n our Keypad

%&ect of "apagliUo)in Addition to (nsulin-treated T!"M Patients 8nQ9


145/169

D

I

HD

HI

D

D J F H D !

=laceo

-=-40mg

-=-420mg

AC 8N9

=laceo

-=-40mg

-=-420mg

-I

-J

-B

-!

-

D

! J F H D !

+ody 4eight 8kg9

4eeks

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%&ect of "apagliUo)in Addition on Ac in (nade:uatelyControlled T!"M 8AcQHFN9 on (nsulin Therapy 8J-HDunits


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%7enatide versus (nsulin 'ispro inSu#0ects Treated with +asal (nsulin


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EENA>IDE LISPRO P-Va"!%

N!m&%r BF B!

H&A3 ;


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JI year old female presents with a I year

history of T!" hypertension mildo#esity and hyperlipidemia

She has #een treated with ma7imum

dose metformin daily 8DDD mg +("9 fromdiagnosis and within year her AC fellfrom HFN to DN

owever in the ne7t year the AC wentup to HN and she was treated withglipi)ide D mg +(" She feels shakyfrom time to time and often ni##les to

avoid that sensation er AC is BN

Case Study J L juestion


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The main pro#lem with her currenttherapy is that2

9er AC is not under N

!9She has not optimi)ed her S. therapyyet

B9She is having mild hypoglycemia

J9She needs a G'P- 1A added to lowerglucose and decrease her weight


N


150/169

Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]

(Adapted with permission from: Ismail-Beigi F, et al. Ann Intern Med 2011;154:554)

Case Study J L juestion !


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She works as a school #us driver

and has a ma0or concern a#outadding an in0ection 4hich option#est suits her needs?

9 (ncrease her S. to lower AC!9 Add a T3"

B9 Add a "PP-J inhi#itor

J9 Add an SG'T! inhi#itor


Case Study J L juestion B


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4hich of the following is not ofma0or concern in planning hertherapy?

9$re:uency of dose administration

!9'ikelihood of causing pancreatitis

B9ypoglycemia riskJ9Potential for weight gain


Case Study J


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"ose fre:uency has #een shown to impactadherence

The $"A and %MA have issued statements

that there is not availa#le data toimplicate therapies in pancreatitis risk

ypoglycemia has #een associated withpoor patient response and de/nite

worsening of C= events Many antidia#etes therapies are

associated with e7pected weight gain

Case Study J er current AC Q BN


154/169

er current AC Q BN

Current medications are Metformin DDD mg +(" Glipi)ide D mg +("

'isinopril !D mg j"

Simvastatin !D mg j"

er vital signs are eight FJ inches

4eight Q l#

+P Q BI


155/169

4hat would you do ne7t for thispatient?

9 Add a "PP-J inhi#itor

!9 Add an SG'T! (nhi#itorB9 Add #asal analog insulin

J9 Add a T3"


Case Study J


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A "PP-J inhi#itor should get her toAC goal #ut will not help with herweight

+asal insulin is a reasona#le choice

#ut she has shown resistance toin0ections and will have a very hardtime getting a C"' on insulin

A T3" will increase her weight andmay contri#ute to a worsenedfracture risk

An SG'T! inhi#itor should reduce

wei ht and S+P as well as lowerin

Case Study J L juestion I


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Prior to starting an SG'T! (nhi#itorthere are ! features of her history youwant to e7plore 4hat are they?9er eG$1

!9Prior history of kidney diseaseB9er history of prior GM(;s

J9er history of liver disease

I9 and B

F9! and J


(mportant Concerns +eforeStarting An SG'T! (nhi#itor


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A#solute contraindication to SG'T!

(nhi#itor use %&ectiveness decreases dramatically with

decreasing eG$1 $unctioning nephrons re:uired for glucose

release• %a(agli:o;in re ?3 &l@&in #oruse

• Canagli:o;in contraindicated 73 &l@&in-discouraged 6 &l@&in- lo8 dose only e+=R6/?3 &l@&in and high dose only i# e+=R ?3

&l@&in

1elative increase for most commonside e&ect of SG'T! use $emales rior 7 GM(

Case Study J L juestion F


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1egarding hypoglycemic riskadding an SG'T! inhi#itor will notaugment risk

9 True

!9$alse


ypoglycemia and SG'T! .se


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ypoglycemic risk is essentiallynon-e7istent if not on asecreatagogue or insulin

.se of a secreatagogue or insulinin the presence of an SG'T!(nhi#itor will increase thelikelihood of hypoglycemia #yaugmenting the risk of the S. orinsulin

Case Study J L juestion


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ou decide to do which of thefollowing?

9(ncrease the S. to ma7imumdose

!9Add dapagliUo)in I mg daily

B9Add dapagliUo)in D mg dailyJ9Add sa7agliptin !I mg daily


Case Study J


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(ncreasing the S. is not a good choiceas she is already showing signs of mildhypoglycemia

"apagliUo)in should #e started at I

mg daily and increased to D mg dailyif additional e[cacy is ultimatelyneeded

'ow dose sa7agliptin has #een studiedand shown #ene/cial in end stagerenal disease and dialysis patients8 AC reduction DHN with no increase

in h o l cemia #ut it will not ive

Case Study J


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er S. is dropped due tohypoglycemia

"apagliUo)in is added at I mgj"

er metformin is continued

er Ac is now FN and she has

lost J l#

er +P is !H


164/169

VIVIAN A. FONSECA, MD, FRCPProgram ChairProfessor of Medicine and Pharmacology , Tullis TulaneAlumni Chair in "ia#etes , Chief Section of%ndocrinology , Tulane .niversity ealth Sciences

Center , (mmediate Past President Science and

Translating Scienti/c and Clinical

Advances in 1enal-Mediated Glucose1egulation and SG'T! (nhi#ition to the$ront 'ines of "ia#etes Care

The 1ole of SG'T! (nhi#ition for(ndividuali)ing and 5ptimi)ing MultimodalCare in T!"

The %merging 1ole of the Kidney in "ia#etes Treatment2 SG'T ! (nhi#itors Address .nmet*eeds


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Good e[cacy in lowering AC %:uivalent to metformin or sulfonylurea

*o increased risk of hypoglycemia

4eight loss

5nce daily dosing irrespective of meals

5ral

%&ective in the full spectrum of patients (ndependent of #ackground therapy (ndependent of duration of dia#etes

Safety


166/169

• )ac!erial urinar$ !rac!

inec!ions

• Fungal geni!al inec!ions

• Ba$ no! "e as eec!i&e in

pa!ien!s i!# renal impairmen!• .ransien! ini!ial period o

de#$dra!ion, pol$uria, !#irs!

• >o non long!erm eec!s on

idne$ and on ou!comes

• Added cos! !o dia"e!es !#erap$

• Ence dail$ adminis!ra!ion

• -ecreases FPG, PPG, A1c

• ?eig#! loss ;0g urine glucose

5 *0 cal/da$5 R l"/ee(

• >o/ Lo ris o #$pogl$cemia• Bodes! "lood pressure

loering

• ec! independen! o insulin

secre!ion or insulin resis!ance

• Ise complemen!ar$ i!# o!#er

.- C S.1-,S Predia"e!es

• Po!en!ial or use in .$pe 1

-ia"e!es

ConcernsPotential Advantages


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Clinical Studieswith SG'T! (nhi#itors

4here "o They $it in the Treatment Algorithm?

SG'T! (nhi#itors2 4here "o They $itin the Treatment Algorithm?


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Monotherapy Add-on to2 M%T S. P(5 "PPJi

Triple therapy with M%T "PPJi P(5

Add-on to insulin in T!"M Add-on to insulin in T"M

(GT


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our juestions from Today;s Symposium

acp sglt2 slidecast 220

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