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DPP4-inhibitors therapy and cardiovascular outcomes

Achmad Rudijanto
Endocrine and Metabolic Division of Internal Medicine Department
Faculty of Medicine Brawijaya University !aiful Anwar "eneral #ospital
M a l a n $
%he incidence of type&' diabetes mellitus (DM) continues to $row
rapidly* Metformin+ sulfonylureas and insulin are the main dru$ for type&' DM
for many years* In the last several decade there are many new dru$s
developed and approved for the treatment of type ' DM* !ome dru$s are
dedicatin$ for insulin resistance or insulin deficiency and the others are
desi$nin$ for inhibits carbohydrate absorption or inhibits $luca$on action*
Many of diabetic patient have co&morbidity* %his co&morbidity must be
loo, in choosin$ of dru$s for hyper$lycemia since this conditions may
influences the outcome of treatment* Each diabetic patient may has his-her
own co&morbidity ma,e tailorin$ treatment for each patient is needed* (Riedel+
'./')* Alon$ with discovered of new dru$s that may be use for therapeutic
options+ still there is uncertainty how to use these dru$s safely and effectively*
0hich a$ent should be used as first line1* 0hich a$ents are choosin$ for
combination when first dru$s failed+ and safe in combination with insulin if
In healthy persons releases of insulin from &cells is not only
influenced by carbohydrate contents of meal+ it2s also influenced by incretine
hormone synthesi3e by $ut cells* %hese peptides are released and+ in turn+
stimulate insulin and suppress $luca$on release+ delay $astric emptyin$+ and
increase satiety* Incretins also showed to improve &cell function and
decreases cardiovascular ris, factors in %'DM* All activities have important
role on $lucose homeostasis process and may improve cardiovascular
outcome* %hese incretins are rapidly de$raded by dipeptidyl peptidase&4
(D55&4) en3yme* D55&4 inhibitors+ a novel class of oral anti&hyper$lycemic
a$ents (6#As) inhibits the activity of D55&4 en3yme* By slowin$ incretin
de$radation+ enhance meal&stimulated active "75&/ and "I5 levels* D55& 4
inhibitors demonstrate efficacy+ with decreased ris, of hypo$lycemia and
beneficial wei$ht effects* Many D55&4 inhibitors are used for diabetes
treatment+ vilda$liptin+ sa8a$liptin+ lina$liptin+ sita$liptine and alo$liptin (the
last one not available yet in Indonesia)*
9ardiovascular (9:) safety has recently emer$ed as a critical concern
in the development of new a$ents for type ' diabetes mellitus (%'DM)* %he
development a$ents that e8hibit novel mechanisms of action+ such as the
$luca$on&li,e peptide&/ ("75&/) receptor a$onists and analo$ues and
dipeptidyl peptidase&4 (D55&4) inhibitors have differ in their pharmaco,inetic
and pharmacodynamic properties as well as their off&tar$et effects* Many
studies showed the receptor of "75&/R is e8pressed many or$ans such as in
the pancreatic islet cell as well as in the brain+ heart+ ,idney+ and the $astro&
intestinal tract* It is lo$ical to consider the role of "75&/&li,e peptides in these
other or$an systems (9ampos R:+ /;;4< Bulloc, B5+ /;;=)*Endothelial
function modulation throu$h D55&4 inhibition and the potential role of this
a$ent in inflammatory endothelial responses has been reported (%a,asawa
0+ './.)*
!tudies in animals showed that D55&4 inhibitor treatment (i)
enhances vascular endothelial function+ indicated by improved rela8ation in
response to acetylcholine and increased e>6! production- phosphorylation<
(ii) decreases pro&inflammatory cyto,ine (interleu,in&/b+ interleu,in&=+ tumor
necrosis factor&a) production in response to lipopolysaccharide&inducedlevels
of the inflammatory biomar,er s9D4. and (iii) suppresses atherosclerotic
lesion formation (Mason R5+ './/< %erasa,i M+ './/< Matsubara ?+ './')*
Althou$h study in human aboutthe role or effect of D55&4 inhibitors on
cardiovascular outcome still in $oin$ on+ the data from animal studies may
support the benefit of D55&4 inhibitor on cardiovascular performance*
%he results ofa meta&analysis of @A R9%s included more '. thousand
patients treated with different D55&4 inhibitors and more than /A thousand
controls treated with placebo or active comparators for '4 wee,s or lon$er+
showed that the odds ratio for major adverse cardiovascular events in the
D55&4 inhibitor treated $roup was reduced by A/B compared with all other
treatment $roups (odds ratio+ .*=;< ;@B 9I+ .*@A.*;.< 5 /C4 .*..=) (Monami
M+ './/)*%he results of the different meta&analyses of D55&4 inhibitors are
not entirely comparable+ but all data support to the hypothesis that D55&4
inhibitor treatment may have a beneficial effect on 9: outcome compared
with other $lucose&lowerin$ treatments for type&' diabetes*
7ina$liptin is a novel+ orally active+ hi$hly specific+ and potent inhibitor
of D55&4 that is currently in clinical development for the treatment of %'DM
(Ec,hardt M+ '..D< Fuchs #+ '..;)* Early clinical studies with lina$liptin
su$$ested a reduction in the $lycated hemo$lobin levels in patients with
%'DM (#eise %+ '..;< Retlich !+ '..;)*A meta&analysis of AA/; patients
treated by lina$liptincompared with /;'. treated with placebo-other dru$s as
comparators to assess cardiovascular ris, showed that lina$liptin has .*A4B
ris,&ratio compare to all comparators (9I ;@B) (?ohansen 6E+ './')*
All meta&analysis data used was not primary addressed for
cardiovascular outcome so the real benefit effect of D55&4 inhibitor need to
be tested throu$h properly research* 6n$oin$ studies such as 9AR67I>A will
provide important new information on the cardiovascular safety of the D55&4
inhibitor lina$liptin versus the !U $limepiride and will contribute to the
decision&ma,in$ process for selectin$ the best evidence&based second&line
therapy for addition to metformin in type&' diabetes*
In summary+ metformin+ sulfonylureas and insulin are the dru$s
widely used for type&' DM therapy* In the last several decade there are many
new dru$s developed and approved for the treatment of type ' DM includin$
incretin based therapy* D55&4 inhibitors such as lina$liptin treatment
improves $lycemic control by lowerin$ fastin$ and postprandial plasma
$lucose+ inhibitin$ $luca$on activity+ and improvin$ insulin sensitivity and E&
cell sensin$ in response to $lucose without dose adjustment in type&'
diabetes patients with ,idney dysfunction and may also be favorable for
cardiovascular outcome* 6n$oin$ study of lina$liptin (9AR67I>A) will $ive us
a brief data accordin$ safety of D55&4 inhibitor on cardiovascular*
Key word: type-2 DM, DPP-4 inhibitors, linagliptin, cardiovascular
Riedel M9+ Farl DM*Individuali3in$ %ar$ets and %actics for #i$h&Ris, 5atients 0ith
%ype' Diabetes5ractical lessons from A996RD and other cardiovascular
trials* Diabetes 9are A@G'/..&'/.D+ './'
9ampos R:+ 7ee H9+ Druc,er D?*Diver$ent tissue&specific and devel& opmental
e8pression of receptors for $luca$on and $luca$on&li,e peptide&/ in the
mouse* Endocrinolo$y /;;4</A4G'/@='/=4*
Bulloc, B5+ #eller R!+ #abener ?F*%issue distribution of messen$er ribonucleic acid
encodin$ the rat $luca$on&li,e peptide&/ receptor* Endocrinolo$y
%a,asawa 0+ 6hnuma F+ #atano R+ Endo H+ Dan$ >#+ Morimoto 9* In& hibition of
dipeptidyl peptidase 4 re$ulates microvascular endothelial $rowth induced
by inflammatory cyto,ines* BiochemBiophys Res 9ommun './.<4./GD/'*
Matsubara ?+ !u$iyama !+ !u$amura F+ >a,amura %+ Fujiwara H+ A,iyama E+
Furo,awa #+ >o3a,i %+ 6hba F+ Fonishi M+ Maeda #+ I3umiya H+ Fai,ita F+
!umida #+ ?innouchi #+ Matsui F+ Fim&Mitsuyama !+ %a,eya M+ 6$awa #*
A dipeptidyl peptidase&4 in& hibitor+ des&fluoro&sita$liptin+ improves
endothelial function and reduces atherosclerotic lesion formation in
apolipoprotein E& deficient mice* ? Am 9oll9ardiol './'<@;G'=@'D=*
%erasa,i M+ >a$ashima M+ 0atanabe %+ >ohtomi F+ Mori H+ Miyaa3a,i A+ #irano %*
Effects of 5FF'D@&.@@+ a dipeptidyl peptidase&4 inhibitor+ on the
development of atherosclerotic lesions in apolipoprotein E&null mice*
Metabolism './/* doiG/.*/./=- j*metabol*'.//*//*.//*
Mason R5+ ?acob RF+ Fubant R+ 0alter MF+ Bellamine A+ ?acoby A+ Mi3uno H+
Malins,i %* Effect of enhanced $lycemic control with sa8a& $liptin on
endothelial nitric o8ide release and 9D4. levels in obese rats* ?
Atheroscler%hromb './/</IGDD4DIA*
Ec,hardt M+ 7an$,opf E+ Mar, M+ %adayyon M+ %homas 7+ >ar #+ 5fren$le 0+ "uth
B+ 7ot3 R+ !ie$er 5+ et al* ('..D) I&(A&(R)&Aminopiperidin&/&yl)&D&but&'&ynyl&
A&methyl&/&(4&methyl& Juina3onlin&'&ylmethyl)&A+D&dihydropurine&'+=&dione
(BI/A@=)+ a hi$hly potent+ selective+ lon$&actin$+ and orally bioavailable
D55&4 inhibitor for the treatment of type ' diabetes* J MedChem50:=4@.
Fuchs #+ Binder R+ and "reischel A ('..;) %issue distribution of the novel D55&4
inhibitor BI/A@= is dominated by saturable bindin$ to its tar$et in rats*
Biopharm Drug Dispos30:''; '4.
#eise %+ "raefe&Mody EU+ #u ttner !+ Rin$ A+ %rommeshauser D+ and Du$i FA
('..;) 5harmaco,inetics+ pharmacodynamics and tolerability of multiple oral
doses of lina$liptin+ a dipeptidyl peptidase&4 inhibitor in male type ' diabetes
patients* Diabetes ObesMetab:DI= D;4*
Retlich !+ 0ithopf B+ "reischel A+ !taab A+ ?aehde U+ and Fuchs # ('..;) Bindin$ to
dipeptidylpeptidase&4 determines the disposition of lina$liptin (BI/A@=)K
investi$ations in D55&4 deficient and wildtype rats* Biopharm Drug
Monami M+ Dicembrini I+ Martelli D+ Mannucci E* !afety of dipeptidyl peptidase&4
inhibitorsG a meta&analysis of randomi3ed clinical trials* 9urr Med Res 6pin
'.//<'D(!uppl A)G@D=4*
?ohansen 6E+ Eubacher >+ :on Eynatten M+ 5atel !+ 0oerle #?* 9ardiovascular ris,
with lina$liptin in patients with type ' diabetesG a pre&specified+ prospective+
and adjudicated meta&analysis from alar$e phase III pro$ram*
9ardiovascDiabetol './'<//GA*