2ndjanuvia-Janumet June 24 2010.Ppt Final

8/17/2019 2ndjanuvia-Janumet June 24 2010.Ppt Final

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The Modern Comprehensive Approach for

Treating Type 2 DiabetesJosephine Carlos-Raboca M.D.


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2

Table of Contents

–Diabetes athophysiology

–Comprehensive Approach is

athophysiology !ased

–Therapy "ith D-# $nhibitor


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%

HYPERGLYCEMIA

Islet cell

dysfunction

PancreaticBeta CellsDecreased

ins&lin secretion

PancreaticAlpha Cells'(cessive

gl&cagon secretion

PancreaticBeta CellsDecreased

ins&lin secretion

PancreaticAlpha Cells'(cessive

gl&cagon secretion

Insulin

resistance

Adapted "ith permission from $n)&cchi *'. JAMA 2++2,2/%0+–%2, orte D Jr1 ahn *'. Clin Invest Med 3445,3/2#–25#.

Liver $ncreased

6l&cose rod&ction

Liver $ncreased

6l&cose rod&ction

Peripheral Tissues

Peripheral TissuesDecreased

6l&cose 7pta8e$ncreased9ipolysis

Co!ined islet cell dysfunction and insulin resistance

The athophysiology of Type 2 Diabetes $nvolves

M&ltiple :rgan *ystems


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#

"ecreased #luca#on

$alpha cells%

Increased insulin$!eta cells%

PancreasPancreas

Liver Liver

MuscleMuscle

AdiposeAdipose

tissuetissue

$ncretins Mod&late $ns&lin and 6l&cagon to Decrease

!lood 6l&cose D&ring ;yperglycemia

Gut

Peripheral

#lucose

upta&e

Glucose

production

GIP

GLP'(

Glucose

"ependent

Glucose "ependent

Meal

Physiolo#icGlucoseControl

69-3


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0

Mana#eent of Type ) "ia!etes

Horones involved in #lucose re#ulation

@ Insulin

@ Gluca#on@ Incretins

Insulin Resistance

islet cell s&eletal uscle

adipose tissue

liver


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Tie* in

I R I n s u l i n * + , L n

o l , L

-./

-.0

-.1

-.2

-.)

-.(

-

3-

/-

1-

)-

-

(3-/- ()--

The $ncretin 'ffect $s Diminished

in $ndivid&als ith Type 2 Diabetes

Control 4u!5ects

$n63%

Patients 7ith Type ) "ia!etes

$n6(1%

Tie* in

I R I n s u l i n * + , L n

o l , L

-./

-.0

-.1

-.2

-.)

-.(

-

3-

/-

1-

)-

-

(3-/- ()- -

8ral #lucose load Intravenous $I9% #lucose infusion

:oral Incretin Effect "iinished Incretin Effect

$R < imm&noreactive

Adapted "ith permission from Ba&c8 M et al. Diabetologia 340,24/#0–52. Copyright 340 *pringer-erlag.

ilsbEll T1 ;olst JJ. Diabetologia 2++#,#/%5–%00.


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Characteristics of an $deal Therapy

Characteristics of an ideal oral antidiabetic agent – 9o"ers ;bA3c to normal levels

– Decreases ins&lin resistance and hepatic gl&cose prod&ction and

increases or preserves beta-cell mass "hile restoring first-phase ins&lin

response

– Does not ca&se "eight gain

– Does not increase ris8 of hypoglycemia

– Does not ca&se edema or congestive heart fail&re


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<

–Therapy "ith D-# $nhibitor


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Glucose dependent

Insulin from beta cells(GLP-1 and GIP)

Adapted from Brubaker PL, Drucker DJEndocrinology2004;145:2653–2659; Zander M et alLancet2002;359:824–830; Ahrén BCurr Diab Rep 2003;3:365–372; Buse JB et al. InWilliams Textbook of Endocrinology. 10th ed. Philadelphia, Saunders,2003:1427–1483.

Hyperglycemia

D-# $nhibitors $mprove 6l&cose Control by

$ncreasing $ncretin 9evels in Type 2 Diabetes

Glucagon from alpha cells

(GLP-1)Glucosedependent

Release of

incretins fromthe gut

Pancreas

α-cells

β-cells

Insulin

increases

peripheral

glucose

uptake

Ingestionof food

GI tract

↑insulin and

↓glucagon

reduce hepatic

glucose

output

Inactive

incretins

ImprovedPhysiologic

Glucose Control

"PP'1

En;ye

"PP'1

Inhi!itor

<

DPP-4 = dipeptidyl peptidase4


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D-# $nhibitors

Chemical Class F-phenethylamines( Cyanopyrrolidines Aminopiperidine3

6eneric Bame *itagliptin ildagliptin1 *a(agliptin/ Alogliptin

Molec&lar *tr&ct&re

*electivity =.=/ > (.-2 nM2 0.)3 > (.-1 nM2 2.2? > -.=- nM2 /.= > (.0 nM4

;alf-life @().1 h%

@)2 h5

@)).3 h

().0)(.( h3+

8

:

:H)

: :

:

C2

: :

8

H2C

8 :

C:

:H)

:

8

HH

:CH8

:H)

H8

:H

8

:

:C

(. im D et al. J Med C"em# 2++5,#>3?/3#3–353.

). Mats&yama-Go8ono A et al. $ioc"em %"armacol . 2++,0>3?/4–3+.

2. Data on file1 M*D.

1. illha&er '! et al. J Med C"em. 2++%,#0>3%?/2#–24.

0. 'M'A approval and *C for 6alv&s. http/HH""".emea.e&ropa.e&Hh&mandocsH;&mansH'ARHgalv&sHgalv&s.htm. Accessed on J&ly 1 2++4.

/. A&geri DJ et al. J Med C"em# 2++5,#>35?/5+25–5+%.

?. I&ra A et al. Drug Metab Dispos. 2++4,%>0?/330#–333.

3. Ieng J et al. J Med C"em. 2++,5+>3+?/224–2%++.=. 9ee ! et al. Eur J %"armacol . 2++,54>3–%?/%+0–3#.

(-.Covington et al. Clin T"er . 2++,%+>%?/#44–532.


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*itagliptin

*itagliptin is a D-# inhibitor thatimproves glycemic control in patients "ith

type 2 diabetes.3

*itagliptin is a potent1 highly selective1once-daily oral therapy.3

– *itagliptin is 210++ times more selective for D-# in vitro than D-1 D-41 andother related en)ymes.2

*itagliptin 3++ mg once daily has sho"n near ma(imal and s&stained D-#inhibition >4K? over 2# ho&rs.%

D-#


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Sitagliptin Lowers Post-meal GlucoseExcursion and Enhances Insulin Secretion

Bona8a et al. A2+3. Abstract presented at/ American Diabetes Association, J&ne 3+1 2++0, ashington1 DC.

Insulinogenic index = ∆ I30 / ∆ G30

I n s u l i n o g e n i c I n d e x ( µ U / m g )

P


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*itagliptin Consistently and *ignificantly 9o"ers A3C ith :nce-Daily

Dosing in Monotherapy

L!et"een gro&p difference in 9* means. Ra) $ et al, B+2%, Aschner et al. B+23, Bona8a et al, A2+3. Abstracts presented at/ 00 th *cientific *essions of the American

Diabetes Association, J&ne 4-3%1 2++0, ashington1 DC.

hange s%lace'o

Place'o (n!4)

#i$agli%$in 100 mg (n1)

Time (.)

1*-ee. s$ud

0 12 1

1 ( 6 )

!"2

!"

"0

"4

*0"6(P 7"001)

Place'o (n244)

#i$agli%$in 100 mg (n22+)

24*-ee. s$ud

Time (.)0 5 10 15 20 25

*0"!+6(P 7"001)

1 ( 6 )

!"2

!"

"0

"4

Place'o (n!5)

#i$agli%$in 100 mg (n!5)

Time (.)

8a%anese s$ud

*1"056(P 7"001)

1 ( 6 )

!"2

!"

"0

"4

"

0 4 12


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4ita#liptin Iproved Mar&ers of Beta'Cell

unction 24-Week Monotherapy Study

Proinsulin/insulin ratio

Aschner P et al. P:-)(D A!stract presented at Aerican "ia!etes AssociationD une (-* )--/D 7ashin#ton* "C.

= 0.078

(95% I -!"##$ -!"!&'F P value for chan#e fro !aseline copared to place!o

)atched = *aselineSolid = +ee, &$

∆ from baseline vs

pbo

p !"!!#.

+.%

+.%2

+.%#

+.%0

+.%

+.#

+.#2

+.##

+.#0

+.#

lacebo *itagliptin

HOMA- β

∆ from baseline vs

pbo

= 13.2 +/- 3.3

(95% I '"9 "9

p !"!!#.

%+

%5

#+

#5

5+

55

0+

05

+

5

lacebo *itagliptin


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Assessment of Dr&g $nteractions

ith *itagliptin

$n vitro &nli8ely to ca&se interactions "ith other dr&gs – Bo inhibition of CG iso)ymes CG%A#1 2C1 2C41 2D01 3A21 2C341 or 2!0

– Bo ind&ction of CG%A#

– Bot e(tensively bo&nd to plasma proteins

$n vivo lo" potential of dr&g interactions "ith s&bstrates of CG%A#1 2C1 and 2C4 –

Bo meaningf&l alteration of the pharmaco8inetics of metformin1 glyb&ride1 simvastatin1rosiglita)one1 "arfarin1 or oral contraceptives

Digo(in – Bo dosage ad&stment of digo(in or sitagliptin is recommended

Data on file1 M*D.


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$nitial Combination Therapy "ith *itagliptin and

Metformin/ 'ffective and D&rable 6lycemic Control

:ver 3 Gear in atients ith T2DM

-ee. 54 om%le$ersPT

P r o % o r $ i o n o 9 % a $ i e n $ s ( 6 )

Pro%or$ion o9 %a$ien$sachieing an 1 $arge$ o9 7!6

#i$agli%$in 100 mg &d (n10/5)

:e$9ormin 500 mg 'id (n11!/!!)

:e$9ormin 1000 mg 'id (n134/101)

#i$agli%$in 50 mg ; me$9ormin 500 mg 'id (n14!/10)

#i$agli%$in 50 mg ; me$9ormin 1000 mg 'id (n153/124)

Pro%or$ion o9 %a$ien$s achieing an 1 $arge$o9 7!6 a$ -ee. 24 remaining a$ 7!6 a$ -ee. 54

P

r o % o r $ i o n o 9 % a $ i e n

$ s ( 6 )

#i$agli%$in 100 mg &d (n33)

:e$9ormin 500 mg 'id (n34)

:e$9ormin 1000 mg 'id (n3)

#i$agli%$in 50 mg ; me$9ormin 500 mg 'id (n5)

#i$agli%$in 50 mg ; me$9ormin 1000 mg 'id (n+)

illiams-;erman D et al. oster presented at 2++ ADA Ann&al Meeting, Chicago1 $9.


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34

*itagliptin Add-on to Metformin $mproved 2#-;o&r 6l&cose

rofile in atients ith Type 2 Diabetes

Post Prandial

astin#,Pre'Prandial


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2+

*itagliptin Added to :ngoing Metformin Therapy/ *&stained

6lycemic Control :ver

5#-"ee8s ith eight 9oss

"5

"!

"+

!"1

!"3

!"5

!"!

!"+

0 12 1 24 30 3 4 54

Phase In$erim Phase ,

-ee.s

: e a n 1 ( 6 )

Phase In$erim Phase ,

0 12 24 3 54*2"0

*1"0

0"0

1"0

2"0

-ee.s

L # m e a n c h a n c e 9 r o m '

a s e l i n e

i n ' o d 3 e i g h $ ( . g )

arasi8 A et al. oster presented at 2++ ADA Ann&al Meeting.

1 (6) -eigh$ (.g)

L# mean change 9rom 'aseline

a$ ee. 54*0"!6 (+56 I< *0"= *0")

L# mean change 9rom'aseline a$ ee. 54

*0" .g (+56 I< *1"5= *0"2)


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23

$nitial Combination Therapy "ith *itagliptin and Metformin/ Change

Irom !aseline in A3C at ee8 5# by !aseline A3C *&bgro&psL

106(mean 10"46)

+6 and 7106(mean +"46)

6 and 7+6(mean "46)

76(mean !"6)

> ' 1

h a n g e 9 r o m

' a

s e l i n e

a $ - e e . 5 4 ( 6 )

*3"5

*3"0

*2"5

*2"0

*1"5

*1"0

*0"5

0"0

*3"5

*3"0

*2"5

*2"0

*1"5

*1"0

*0"5

0"0

#itagli"tin 100 mg $2%/&3/1'/1()

*etformin 500 mg bid $32/3'/30/1()

*etformin 1000 mg bid $&0/53/33/%)

#itagli"tin 50 mg + metformin 500 mg bid $3'/&'/3%/21)

#itagli"tin 50 mg + metformin 1000 mg bid $33/(0/&3/1,)

*ean change ± # PT Po%ula$ion"illiams-;erman D et al. oster presented at 2++ ADA Ann&al Meeting, Chicago1 $9.


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22

'ffect of IDC *itagliptinHMetformin on A3C Red&ction $s

;igher Than Monotherapy

#i$agli%$in100 mg &d

1 r e d u c $ i o n 9 r o m

' a s e

l i n e ( 6 )

Place'o*#u'$rac$ed ?a$a in 24*-ee. #$ud

IDC$DI? in *o&th Africa1 2++0.

#i$agli%$in100 mg &d

:e$9ormin500 mg 'id

om'ina$ion#i$a 50 mg/

:e$ 500 mg 'id:e$9ormin

1000 mg 'id

om'ina$ion#i$a 50 mg/

:e$ 1000 mg 'id

ddi$ie $o +61"/(0" ; 1"0)

≈

+6

ddi$ie $o 1006

2"1/(0" ; 1"3)1006

P 7"001

P 7"001

*2"5

*2"0

*1"5

*1"0

*0"5

*0


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2%

Complementary 'ffect of *itagliptin

N Metformin on Active 69-3

Place'o :e$9ormin #i$agli%$in #i$agli%$in ;me$9ormin

c $ i 0 e L P * 1 (

% : )

L% O.++3 vs placebo.Migoya 'M et al. resented at 2++ ADA Ann&al Meeting. Abstract P 20-:R.


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2#

$ncidence of ;ypoglycemia ith *itagliptin ith

Metformin as *imilar to lacebo ith Metformin

'()Wee Add)on T"erapy to Met!ormin *tudy

All-patients-as-treated pop&lationa*itagliptin 3++ mgHday, bMetformin Q35++ mgHday

Adapted from Charbonnel ! et al. Diabetes Care# 2++0,24/20%–20#%.

Patients ith at least one episode of hypo#lyceia over )1 ee&s

P a t i e n t s $ H %

Place!o etforin! $n6)2?%

4ita#liptina etforin! $n61/1%

).(

(.2

-.-

(.-

).-

2.-

1.-

0.-


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25

*itagliptin ith Metformin rovided eight 9oss

*imilar to lacebo ith Metformin at ee8 2#

'()Wee Add)on T"erapy to Met!ormin *tudy

a'(cl&ding data after initiation of glycemic resc&e therapy, bleast s&ares means,c*itagliptin 3++ mgHday, dMetformin Q35++ mgHday

Adapted from Charbonnel ! et al. Diabetes Care# 2++0,24/20%–20#%.

-./

%


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20

Combination Therapy :ffers Advantages

:ver Monotherapy

Combination therapy may provide more glycemic control than theindivid&al monotherapies

Combination therapy may provide more comprehensive coverage ofthe 8ey pathophysiologies of type 2 diabetes than monotherapy

An appropriately chosen combination therapy may help morepatients achieve their ;bA3c goal "itho&t increasing side effects3

Adapted from Del rato Int J Clin %ract 2++5,54/3%#5-3%55.


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2

JAB7$AS >sitagliptin? $ndications and Contraindications/ !ased on the

orld"ide rod&ct Circ&lar

$ndications – JAB7$A is indicated as an ad&nct to diet and e(ercise to improve glycemic control in patients "ith type 2

diabetes mellit&s as/@ Monotherapy

@ $nitial combination therapy "ith metformin

@ $nitial combination therapy "ith a AR agonist >T=D?

@ Combination therapy "ith metformin1 s&lfonyl&rea1 or AR1 "hen the single agent alone "ith diet and e(ercisedoes not provide ade&ate glycemic control

@ Combination therapy "ith metformin and a s&lfonyl&rea1 "hen d&al therapy "ith these agents "ith diet and e(ercisedoes not provide ade&ate glycemic control

@ Combination therapy "ith metformin and a AR agonist1 "hen d&al therapy "ith these agents "ith diet ande(ercise does not provide ade&ate glycemic control

Combination +it" Insulin

@ JAB7$A is indicated in patients "ith type 2 diabetes mellit&s as an ad&nct to diet and e(ercise to improveglycemic control in combination "ith ins&lin >"ith or "itho&t metformin?.

Contraindications – JAB7$A is contraindicated in patients "ho are hypersensitive to any components of this prod&ct


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2

JAB7$AS >sitagliptin? Recommended Dosing/ !ased on the orld"ide

rod&ct Circ&lar

Dosage – Recommended dosage of JAB7$A is 3++ mg once daily ta8en "ith or "itho&t

food

– hen JAB7$A is &sed in combination "ith a s&lfonyl&rea or "ith ins&lin1 a lo"erdose of the s&lfonyl&rea or ins&lin may be considered to red&ce the ris8 ofs&lfonyl&rea- or ins&lin-ind&ced hypoglycemia

– Ior patients "ith renal ins&fficiency@ Milda U no dosage ad&stment is re&ired@ Moderateb U JAB7$A 5+ mg once daily

@ *everec or end-stage renal diseased U JAB7$A 25 mg once daily – !eca&se there is a dosage ad&stment based &pon renal f&nction1 assessment of

renal f&nction is recommended prior to initiation of JAB7$A and periodicallythereafter

aMild6CrCl J0- L,in.!

Moderate6CrCl J2- to K0- L,in.c4evere6CrCl K2- L,in.dReuirin# heodialysis or peritoneal dialysis. A:+9IA ay !e adinistered ithout re#ard to the tiin# of heodialysis.


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24

JAB7M'TS >sitagliptinHmetformin1 M*D? $ndications/

!ased on the orld"ide rod&ct Circ&lar

$ndications – JAB7M'T is indicated in patients "ith type 2 diabetes mellit&s to improve

glycemic control

@ As initial therapy "hen diet and e(ercise do not provide ade&ateglycemic control

@ As an ad&nct to diet and e(ercise in patients "ho have inade&ate

glycemic control on metformin or sitagliptin alone or in patients alreadybeing treated "ith the combination of sitagliptin and metformin

@ $n combination "ith a s&lfonyl&rea >ie1 triple combination therapy? as anad&nct to diet and e(ercise in patients "ho have inade&ate glycemiccontrol "ith any 2 of the % agents/ metformin1 sitagliptin1 or a s&lfonyl&rea

@ $n combination "ith a AR agonist >ie1 triple combination therapy? asan ad&nct to diet and e(ercise in patients "ho have inade&ate glycemiccontrol "ith any 2 of the % agents/ metformin1 sitagliptin1 or a ARagonist >ie1 thia)olidinediones?

@ $n combination "ith ins&lin as an ad&nct to diet and e(ercise


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%+

Contraindications – JAB7M'T is contraindicated in patients "ith/

@ Renal disease or renal dysf&nction1 e.g.1 as s&ggested byser&m creatinine levels Q3.5 mgHd9 VmalesW1 Q3.# mgHd9VfemalesW1 or abnormal creatinine clearance1 "hich may also

res&lt from conditions s&ch as cardiovasc&lar collapse >shoc8?1ac&te myocardial infarction1 and septicemia.

@ no"n hypersensitivity to sitagliptin phosphate1 metforminhydrochloride or any other component of JAB7M'T

@ Ac&te or chronic metabolic acidosis1 incl&ding diabetic8etoacidosis1 "ith or "itho&t coma.

– JAB7M'T sho&ld be temporarily discontin&ed in patients&ndergoing radiologic st&dies involving intravasc&laradministration of iodinated contrast materials1 beca&se the &se ofs&ch prod&cts may res&lt in ac&te alteration of renal f&nction

JAB7M'TS >sitagliptinHmetformin1 M*D? Contraindications/ !ased on

the orld"ide rod&ct Circ&lar


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%3

$nitial Ii(ed-Dose Combination Therapy ith JAB7M'TS

vs Metformin Monotherapy/ Concl&sions

Compared "ith metformin alone1 in patients "ith

type 2 diabetes and moderate to severe hyperglycemia

on diet and e(ercise initial combination therapy "ith

sitagliptinHmetformin IDC >JAB7M'T? provided312

@ *&perior glycemic improvements res&lting in more patients

achieving ;bA3c goal

@ A similar incidence of hypoglycemia1 and lo"er incidences of

abdominal pain and diarrhea compared "ith metformin alone.

IDC


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%2

Concl&sions

Treatment to achieve glycemic control early is important to helpred&ce complications of type 2 diabetes3

Many patients on c&rrent monotherapies do not achieve glycemiccontrol2

Combination therapy "ith a D-# inhibitor and metformin offersopport&nity for improved glycemic efficacy1 complementarymechanisms of action1 and a lo" ris8 of hypoglycemia "itho&t "eight

gain

*itagliptinHmetformin provides a more comprehensive approach for

addressing the 8ey pathophysiologies of type 2 diabetes

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2ndjanuvia-Janumet June 24 2010.Ppt Final