CKJ REVIEW
Old and new calcimime ics o ea men o seconda y
hype pa a hy oidism: impac on biochemical and
ele an clinical ou comes
Luciano Pe ei a
1,2,3,4
, Ca a ina Meng
1,2,3
, Daniela Ma ques
5
and
Jo~
ao M. F az~
ao
1,2,3,4
1
Ins i u e o In es iga ion and Inno a ion in Heal h, Uni e si y o Po o, Po o, Po ugal,
2
Neph ology and
In eciology g oup, INEB—Na ional Ins i u e o Biomedical Enginee , Uni e si y o Po o, Po o, Po ugal,
3
Depa men o Neph ology, S~
ao Jo~
ao Hospi al Cen e , Po o, Po ugal,
4
DaVi a Kidney Ca e, Po o, Po ugal
and
5
School o Medicine o Uni e si y o Po o, Po o, Po ugal
Co espondence and o p in eques s o: Jo~
ao M. F az~
ao; E-mail: [email p o ec ed]
Abs ac
Seconda y hype pa a hy oidism (SHPT) is associa ed wi h inc eased bone u no e , isk o ac u es, ascula calci ica ions,
and ca dio ascula and all-cause mo ali y. The classical ea men o SHPT includes ac i e i amin D compounds and
phospha e binde s. Howe e , achie ing he op imal labo a o y a ge s is o en di icul because i amin D s e ols supp ess
pa a hy oid ho mone (PTH) sec e ion, while also p omo ing calcium and phospha e in es inal abso p ion. Calcimime ics
inc ease he sensi i i y o he calcium-sensing ecep o , so ha e en wi h lowe le els o ex acellula calcium a signal can
s ill exis , leading o a dec ease o he se -poin o sys emic calcium homeos asis. This enables a dec ease in plasma PTH
le els and, consequen ly, o calcium le els. Cinacalce was he i s calcimime ic o be app o ed o clinical use. Mo e han 10
yea s since i s app o al, cinacalce has been demons a ed o e ec i ely educe PTH and imp o e biochemical con ol o
mine al and bone diso de s in ch onic kidney pa ien s. Th ee andomized con olled ials ha e analysed he e ec s o
ea men wi h cinacalce on ha d clinical ou comes such as ascula calci ica ion, bone his ology and ca dio ascula
mo ali y and mo bidi y. Howe e , a inal conclusion on he e ec o cinacalce on ha d ou comes emains elusi e.
E elcalce ide is a new second-gene a ion calcimime ic wi h a pha macokine ic p o ile ha allows h ice-weekly dosing a he
ime o haemodialysis. I was ecen ly app o ed in Eu ope, and is ega ded as a second oppo uni y o imp o e ou comes by
op imizing ea men o SHPT. In his e iew, we summa ize he impac o cinacalce wi h ega d o biochemical and clinical
ou comes. We also discuss he possible implica ions o he new calcimime ic e elcalce ide in he ques o imp o e ou comes.
Key wo ds: calcimime ic agen s, ch onic kidney disease, cinacalce , e elcalce ide, seconda y hype pa a hy oidism
In oduc ion
Ch onic kidney disease (CKD) is apidly becoming a public heal h
issue, wi h inc easing incidence and es ima ed wo ldwide
p e alence o 8–16% [1]. Du ing he cou se o CKD, he decline in
enal unc ion is accompanied by he de elopmen o diso de s
o calcium and phospha e me abolism, leading o he well-
known condi ion ‘Mine al Bone Disease associa ed wi h CKD’
Recei ed: July 6, 2017. Edi o ial decision: Augus 18, 2017
V
CThe Au ho 2017. Published by Ox o d Uni e si y P ess on behal o ERA-EDTA.
This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion Non-Comme cial License (h p://c ea i ecommons.o g/
licenses/by-nc/4.0/), which pe mi s non-comme cial e-use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
Fo comme cial e-use, please con ac [email p o ec ed]
80
Clinical Kidney Jou nal, 2018, ol. 11, no. 1, 80–88
doi: 10.1093/ckj/s x125
Ad ance Access Publica ion Da e: 8 Decembe 2017
CKJ Re iew
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(CKD-MBD) [2]. This condi ion de elops due o he inabili y o he
kidney o exc e e phospha e p ope ly, leading o i s e en ion and
accumula ion, which s imula es ib oblas g ow h ac o 23 (FGF-
23) and se um pa a hy oid ho mone (PTH) [3]. FGF-23, a pep ide
ho mone p oduced mainly in he os eocy es, is able o educe
phospha e le els using h ee di e en pa hways: inc eased enal
exc e ion, PTH s imula ion and calci iol syn hesis inhibi ion.
The la e p omo es dec eased gas oin es inal abso p ion o
phospha e and calcium, leading o hypocalcaemia. The low calci-
iol le els and hypocalcaemia also s imula e PTH sec e ion in
he pa a hy oid glands and induce he de elopmen o pa a hy-
oid gland hype plasia and seconda y hype pa a hy oidism
(SHPT).
SHPT is associa ed wi h inc eased bone u no e , isk o
ac u es, ascula calci ica ions and, mos impo an ly, isk o
ca dio ascula and all-cause mo ali y [4]. Recen obse a ional
da a indica e ha PTH >600 pg/mL is associa ed wi h a highe
isk o ca dio ascula mo ali y as well as all-cause ca dio as-
cula hospi aliza ion [5]. I is in e es ing o no e ha pa ien s
ha e be e ou comes he longe he ime ha hey ha e PTH
wi hin ecommended le els. Indeed, consis en con ol o bone
me abolism pa ame e s, including PTH, wi hin published ec-
ommended a ge s is a s ong p edic o o su i al in haemo-
dialysis pa ien s [6].
The classical ea men o SHPT includes ac i e i amin D
compounds and phospha e binde s ( o limi i s gas oin es inal
phospha e abso p ion) [7]. Howe e , achie emen o op imal
labo a o y a ge s is o en di icul because i amin D s e ols
supp ess PTH sec e ion, bu also p omo e calcium and phos-
pha e in es inal abso p ion.
Calcium-sensing ecep o (CaSR) is essen ial o he main e-
nance o sys emic calcium homeos asis, and has become an
excellen a ge o he ea men o bone and mine al diso -
de s. I s ligands a e called calcimime ics and can be classi ied
as Type 1 (agonis s), such as ionized calcium and o he di alen
anions ha di ec ly s imula e CaSR, o Type 2 (posi i e allos-
e ic modula o s), which bind o a si e ha is dis inc om he
physiological ligand and inc ease he sensi i i y o CaSR o ion-
ized calcium, leading o he dec ease o he se -poin o sys-
emic calcium homeos asis (homeos asis is achie ed wi h
lowe concen a ions o ionized calcium). [8]. This enables a
dec ease in plasma PTH le els, and consequen ly o calcium
le els (Table 1). Addi ionally, lowe le els o phospho us and
calcium phospho us a e also seen [9], demons a ing he
capabili y o calcimime ics o imp o e he ou c i ical disease
bioma ke s associa ed wi h SHPT ( he phospho us- and cal-
cium-lowe ing e ec dis inguishes calcimime ics om ac i e
i amin D) [10].
Fi s -gene a ion compounds include phenylalkylamines R-
567 and R-568, which we e es ed in haemodialysis pa ien s, bu
pha macokine ics issues hal ed u he clinical de elopmen
[7]. Second-gene a ion calcimime ic d ugs include cinacalce
and o he s ha ha e ne e achie ed clinical use, such as calin-
dol and AC-265347. Cinacalce hyd ochlo ide was he i s
Type 2 calcimime ic o be app o ed o clinical use [11].
T ea men wi h cinacalce e ec i ely educes PTH, calcium
and phospho us [12]. Mo e han 10 yea s since i s app o al,
cinacalce has been demons a ed o e ec i ely educe PTH and
imp o e biochemical con ol o CKD-MBD.
E elcalce ide is a new second-gene a ion calcimime ic. As a
no el in a enous o mula ion wi h a pha macokine ic p o ile
ha allows h ice-weekly dosing (a he ime o haemodialysis),
e elcalce ide was de eloped o imp o e e icacy and adhe ence,
and educe gas oin es inal ad e se e ec s ela i e o cinacalce .
I was ecen ly app o ed in Eu ope, and is ega ded as a second
oppo uni y o imp o e ou comes in CKD-MBD pa ien s by
op imizing ea men o SHPT using his p omising new
calcimime ic [13].
In his e iew, we summa ize he impac o cinacalce in bio-
chemical and ele an clinical ou comes such as ca dio ascula
mo ali y, ascula calci ica ions and ac u es. We also discuss
he possible implica ions o he new calcimime ic e elcalce ide
in he ques o imp o e ou comes o CKD pa ien s.
Cinacalce e ec i ely con ols SHPT
Cinacalce ’s e icacy and sa e y has been es ed in se e al
andomized con olled ials (RCTs) [11,12,14]. Cinacalce ea -
men in addi ion o ac i e i amin D in pa ien s wi h SHPT ha
is inadequa ely con olled despi e s anda d he apy e ec i ely
dec eases PTH le els, while also educing se um calcium and
phospho us. Pos hoc analysis has demons a ed ha ea men
wi h cinacalce imp o es he achie emen o biochemical a -
ge s ecomended by in e na ional socie ies [15]. In a me a-
analysis [16] in ol ing eigh ials (1429 pa ien s) compa ing
cinacalce ea men plus s anda d he apy wi h placebo plus
s anda d he apy, end-o - ea men alues o PTH [290.49 pg/
mL, 95% con idence in e al (CI) 359.91 o 221.07], calcium
(0.85 mg/dL, 95% CI 1.14 o 0.56), phospho us (0.29 mg/dL,
95% CI 0.50 o 0.08) and calcium phospho us p oduc
(7.90 mg
2
/dL
2
, 95% CI 10.25 o 5.54) we e signi ican ly lowe
wi h cinacalce compa ed wi h placebo.
To allow an objec i e assessmen o he e ec o cinacalce
on lowe ing PTH, he i amin D ac i a o ecep o agonis
(VDRag) dose was kep cons an . Howe e , subsequen clinical
s udies ha e con i med he PTH-lowe ing e ec o cinacalce
used in a ying o cons an doses o VDRags. This is an impo -
an inding conside ing ha , in clinical p ac ice, cinacalce is
used o en wi h VDRags [17]. Ad e se e ec s o cinacalce a e
desc ibed in Table 2.
Besides i s supp essi e e ec on PTH le els, da a sugges
ha cinacalce ea men can induce a olume educ ion o he
enla ged pa a hy oid glands wi h nodula hype plasia seen in
SHPT pa ien s [18].
Cinacalce educes FGF-23 le els
FGF-23 le els ha e been associa ed wi h ad e se clinical ou -
comes [19–24] such as p og ession o CKD, a e ial calci ica ion,
le en icle hype ophy, ca dio ascula e en s and inc eased
mo ali y. Pha macologic in e en ion capable o educing FGF-
23 would hold he p omise o ha ing a bene icial e ec on hese
impo an clinical ou comes.
CUPID (Cinacalce S udy o Pe i oneal Dialysis Pa ien s in
Double A m On he Lowing E ec o iPTH le el), a p ospec i e
RCT ha e alua ed he e ec o cinacalce on FGF-23 le els [25],
en olled pa ien s ha had been on pe i oneal dialysis o >3
mon hs and had PTH >300 pg/mL. Pa ien s we e andomized o
Table 1. E ec o PTH-supp essi e he apies on biochemical
pa ame e s
PTH Calcium Phospho us FGF-23
Vi amin D analogues #" " "
Cinacalce ## # #
E elcalce ide ## ## # ##
Old and new calcimime ics |81
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cinacalce he apy o i amin D. The cinacalce g oup had a
educ ion in FGF-23 le els (3960–2325 RU/mL), whe eas he con-
ol g oup had an inc ease in FGF-23 concen a ion (2085–2415
RU/mL). ACHIEVE (ACHIEVE: Op imizing he T ea men o SHPT:
A Compa ison o Sensipa and Low Dose Vi amin D s
Escala ing Doses o Vi amin D Alone)—a Phase 4, open-label,
placebo-con olled, mul icen e, RCT—was designed o compa e
ea men esul s wi h escala ing doses o cinacalce plus ixed
low-dose calci iol (cinacalce -D g oup) e sus calci iol alone
(Flex-D g oup) [26]. Using he da a o 91 subjec s om his s udy,
We mo e e al. e i ied ha he pe cen age change o FGF-23
be ween he wo g oups di e ed signi ican ly (P ¼0.002) [27].
In he cinacalce -D g oup, he pe cen age change dec eased
(9.7 618.2; P ¼0.021), while an inc ease was ound in he Flex-
D g oup; howe e , he esul s we e no signi ican (4.1 616.5).
The mechanism unde lying he abili y o cinacalce o
dec ease FGF-23 le els emains o be cla i ied. The CUPID in es-
iga o s concluded ha cinacalce ea men was independen ly
associa ed wi h FGF-23 educ ion, and no ela ed o he d ug’s
e ec s on PTH, calcium and phospho us se um le els. O he s
ha e obse ed ha he dec ease o FGF-23 le els is concomi an
wi h he dec ease in phospho us le els (bu no o PTH o cal-
cium le els) [28]. We mo e e al. sugges ed ha calcium and
phospho us a e esponsible o cinacalce ’s e ec on FGF-23 le -
els [27]. Fu he in es iga ion is needed in o de o unde s and
exac ly how cinacalce he apy esul s in a g ea e educ ion o
se um FGF-23 when compa ed wi h adi ional d ugs.
Recen ly, a pos hoc e alua ion o he EVOLVE (E alua ion o
Cinacalce Hyd ochlo ide The apy oLowe Ca dio ascula E en s)
s udy added some mo e in o ma ion o he FGF-23 issue [29].
When analysing he esul s om he cinacalce - ea ed pa ien
g oup (n¼1338), a dec ease in FGF-23 le els was seen (5555–2255
pg/mL; P <0.001), in con as o he con ol g oup (n¼1264), whe e
le els emained unchanged (5600–5580 pg/mL). Mo eo e , when
compa ed wi h he con ol g oup, a la ge p opo ion o pa ien s in
he cinacalce g oup had a meaning ul decline (30%) o FGF-23
(28% e sus 64%; P <0.001). This inding is ele an because he
30% educ ion o FGF-23 le els was associa ed wi h a dec eased
isk o ca dio ascula mo ali y (P <0.001), sudden dea h (P <
0.001) and hea ailu e (P ¼0.04).
Cinacalce and ac u es
Pa ien s wi h CKD ha e inc eased isk o ac u es compa ed
wi h he gene al popula ion [30,31]. The e is also a high a e o
dea h and hospi aliza ion ollowing bone ac u e among hae-
modialysis pa ien s [32]. Abno mali ies in bone s uc u e, which
a ec bone quali y, a e obse ed in pa ien s wi h CKD-MBD.
Malluche e al. demons a ed ha bone wi h high u no e had
ma e ial and nanomechanical abno mali ies such as a educed
mine al o ma ix a io [33]. Such u no e - ela ed al e a ions in
bone quali y may con ibu e o he diminished mechanical
compe ence o bone in CKD.
In hei single cen e coho s udy, Iimo i e al. [34] demon-
s a ed a U-shaped co ela ion be ween PTH le el and isk o
ac u e; only dec eased [PTH <150 pg/mL; haza d a io (HR)
3.27] o inc eased le els we e ela ed o a supe io haza d o
clinical ac u e (PTH >300 pg/mL; HR 2.69).
To da e, no RCT has been speci ically designed o e alua e
whe he any compounds used in he ea men o SHPT (phos-
pha e binde s, i amin D analogues o calcimime ics) dec ease
he isk o ac u e in CKD pa ien s. Howe e , ea men wi h
cinacalce has been associa ed wi h educed isk o ac u es. A
combined pos hoc analysis o sa e y da a om ou Phase 3
RCTs en olling 1184 pa ien s wi h end-s age enal disease
(ESRD) and uncon olled SHPT (de ined as PTH >300 pg/mL)
showed ha andomiza ion o cinacalce , in addi ion o con en-
ional ea men wi h ac i e i amin D, esul ed in a signi ican
educ ion in he isk o ac u e [ ela i e isk (RR) 0.46, 95% CI
0.22–0.95, P ¼0.04] compa ed wi h placebo and con en ional
ea men [35].
In he EVOLVE ial, in he in en ion- o- ea (ITT) analysis,
cinacalce did no signi ican ly educed he isk o ac u es [36].
Du ing he s udy, mo e han wo- hi ds o pa ien s in bo h
g oups discon inued he ea men , so a p ede e mined lag-
censo ing analysis (censo ing ime >6 mon hs a e s opping
he s udy d ug) was pe o med and a ela i e haza d o ac u e
Table 2. La e al e ec s o calcimime ic agen s and sugges ed ac ions o ake
Side e ec F equency P oposed ac ion
Gas oin es inal e en s
Nausea Ve y common Gi e cinacalce wi h main meal a e dialysis/in he e ening
Dec ease o ac iona e he dose i symp oms appea a e a dose
inc ease
Cau ion is ad ised wi h an i-eme ics, including me oclop amide
(QT p olonga ion)
Vomi ing Ve y common
Dia hoea and dyspepsia Uncommon
Ano exia Common
Hypocalcaemia and ne ous sys em
diso de s
Hypocalcaemia Common Wi hhold o educe cinacalce un il se um calcium le els each 8 mg/
dL o symp oms ha e esol ed
Use o calcium-based phospha e binde s, i amin D s e ols o adjus -
men s o dialysis luid calcium ha e been sugges ed by some
au ho s, acco ding o clinical judgemen
Dizziness and pa aes hesia Common
Seizu es Uncommon
O he s
Skin and cu aneous diso de s, ash Common Seek o he causes; conside discon inuing d ug
Musculoskele al, connec i e issue
and bone diso de s, myalgia
Common Seek o he causes; conside discon inuing d ug
Immune sys em diso de s,
hype sensi i i y eac ions
Uncommon Seek o he causes; conside discon inuing d ug
82 | L. Pe ei a e al.
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o 0.72 (95% CI 0.58–0.90; P ¼0.003) was ob ained. When pa ici-
pan s we e censo ed a he ime o co-in e en ions, such as
pa a hy oidec omy and kidney ansplan , he ela i e haza d
was 0.71 (95% CI 0.58–0.87; P ¼0.001). Mo eo e , when conside -
ing he isk o all clinical ac u es (no only he i s , bu also
subsequen ones) he mul i a iable-adjus ed ela i e haza d
was 0.83 (95% CI 0.72–0.98; P ¼0.02). They concluded ha , when
conside ing e en s p omp ing discon inua ion o he s udy
d ug, such as co-in e en ions and cumula i e clinical ac-
u es, cinacalce educed he a e o clinical ac u e by 17–29%
[36]. These da a p o ide sugges i e e idence ha cinacalce
educes he isk o ac u e in pa ien s wi h SHPT.
This e ec o cinacalce in educing ac u es is no a su -
p ising one conside ing wo epo s ha used bone his omo ph-
ome y om di e en g oups o desc ibe imp o ed his ology in
pa ien s ea ed wi h cinacalce [37,38]. In he BONAFIDE (Bone
Biopsy S udy o Dialysis Pa ien s wi h SHPT o End S age Renal
Disease) s udy [38], dialysis pa ien s wi h PTH >300 pg/mL and
biopsy-p o en high- u no e bone disease we e ea ed wi h
cinacalce and a second bone biopsy was pe o med a e 6–12
mon hs o cinacalce ea men . Bone o ma ion and bone eab-
so ion indices we e imp o ed; mos imp essi e was ha he
numbe o pa ien s wi h no mal bone his ology inc eased om
none a baseline o 20 a 12 mon hs.
The ole o bone mine al densi y (BMD) e alua ion in ch onic
kidney pa ien s is e ol ing. Unlike p e ious e sions, he cu -
en KDIGO (Kidney Disease: Imp o ing Global Ou comes)
guidelines sugges ha BMD es ing is unde aken in pa ien s
wi h CKD G3a-G5D wi h CKD-MBD and/o isk ac o s o os eo-
po osis i esul s will impac he apeu ic decisions [39].
E idence-based in o ma ion is sca ce abou he e ec o cina-
calce on BMD in CKD pa ien s. Some o he a ailable da a ha e
shown a posi i e e ec o cinacalce on BMD, namely on he
emo al neck [40] and p oximal emu [41]. Howe e , o he s
ha e e ealed ha cinacalce he apy shows no e ec on BMD
o he lumba spine [41] o has a de imen al e ec wi h associ-
a ed bone loss on he emo al neck and lumba spine [42]. The
e ec and signi icance o cinacalce on BMD emains o be
cla i ied.
Cinacalce and ascula calci ica ion
SHPT is associa ed wi h ascula calci ica ion. Once es ablished
in haemodialysis pa ien s, i gene ally p og esses much as e
han in he gene al popula ion, leading o inc eased isk o all-
cause and ca dio ascula mo ali y [2].
In a single-cen e p ospec i e coho s udy (n¼23),
Nakayama e al. [43] e alua ed he impac o cinacalce on
abdominal ao ic calci ica ion by calcula ing he ao ic calci ica-
ion a ea index (ACAI) be o e and a e ea men (12, 0, 12, 24
and 36 mon hs). The mean ACAI alues we e no dec eased du -
ing he obse a ion pe iod (21.4% a baseline, 23.9% a 12
mon hs, 23.7% a 24 mon hs and 24.3% a 36 mon hs). In addi-
ion, Tsu u a e al. [44] compa ed co ona y a e y calci ica ion
(CAC) in cinacalce (n¼8) and con ol (n¼60) g oups, e i ying
a dec ease (0.094/yea ) in he CAC sco e when cinacalce was
used, while opposi e was seen in he con ol g oup he (þ0.034/
yea ). Howe e , he esul s we e no s a is ically signi ican
(P ¼0.102).
The ADVANCE (A Randomized S udy o E alua e he E ec s
o Cinacalce Plus Low Dose Vi amin D on Vascula Calci ica ion
in Subjec s wi h CKD) s udy [45] compa ed ascula and ca diac
al e calci ica ion p og ession in 360 adul haemodialysis
pa ien s wi h SHPT, ea ed ei he wi h cinacalce plus low-dose
i amin D (n¼180) o lexible doses o i amin D alone
(n¼180). The p ima y endpoin was a change in he Aga s on
To al CAC sco e (which uses he concep o plaque densi y and
he e o e e lec s he amoun o calcium deposi ed wi hin a cal-
ci ied lesion). The median pe cen inc ease in Aga s on o al
CAC sco e was 24% o he cinacalce plus i amin D g oup and
31% o in he i amin D g oup (s a i ied median ea men di -
e ence ¼10.3%; 95% CI 22.6% o 0.8%; P ¼0.073). Simila ly,
Aga s on sco e changes in he ho acic ao a and mi al al e
we e no s a is ically signi ican . The ao ic al e, on he o he
hand, had a s a i ied median ea men di e ence o 44.7%
(95% CI 85.8% o 6.1%; P ¼0.014).
The ADVANCE s udy had some limi a ions. A subs an ial
numbe o pa ien s assigned o he cinacalce g oup ecei ed
doses o i amin D ha we e highe han speci ied in he p o o-
col. A pos hoc analysis [46] compa ing CAC p og ession among
p o ocol-adhe en pa ien s ea ed wi h cinacalce showed ha
he pe cen age inc ease in CAC and ao ic al e calci ica ion
was signi ican ly slowe in he cinacalce g oup. O he
limi a ions included he open-label design and sho pe iod o
ollow-up (12 mon hs, which is unlikely o be su icien o he
de ec ion o subs an ial changes in ascula calci ica ion).
Finally, he educed obse ed calci ica ion p og ession could
no be solely a ibu ed o cinacalce ; he lowe doses om i a-
min D s e ols in he cinacalce g oup also ha e o be conside ed.
Cinacalce , ca dio ascula disease and
all-cause mo ali y
Ele a ed se um le els o phospho us, calcium, PTH and FGF-23
ha e been linked o dea h and ca dio ascula ou comes [47–49].
In a pos hoc analysis, Cunningham e al. [35] combined da a on
clinical ou comes om ou Phase 3 RCTs and showed ha
ea men wi h cinacalce esul ed in a signi ican educ ion in
he isk o ca dio ascula hospi aliza ion (HR 0.61; 95% CI 0.43–
0.86) and a non-signi ican endency o educe all-cause mo al-
i y. Ano he obse a ional s udy, including 19 186 haemodialy-
sis pa ien s om a la ge dialysis p o ide [50] ecei ing
in a enous i amin D analogues (as a su oga e o he diagno-
sis o SHPT), ound ha ea men wi h cinacalce was associ-
a ed wi h signi ican educ ions in all-cause and ca dio ascula
mo ali y, wi h mo e p onounced su i al bene i s ound in
pa ien s wi h SHPT o g ea e se e i y. In a p ospec i ely obse -
a ional s udy, Block e al.[50] desc ibed a signi ican su i al
bene i associa ed wi h cinacalce p esc ip ion. These obse a-
ions and hose o o he s [51,52] led o he de elopmen o a
p ospec i e RCT e alua ing he e ec o cinacalce ea men on
ca dio ascula mo ali y. The EVOLVE [53] s udy was an RCT
ha en olled 3883 haemodialysis pa ien s wi h mode a e o
se e e SHPT (median PTH 693 pg/mL) assigned o ecei e cina-
calce (n¼1948) o placebo (n¼1935). All pa ien s we e eligible
o ecei e con en ional ea men including phospha e binde s
and i amin D s e ols. The p ima y composi e endpoin was
ime un il dea h, myoca dial in a c ion, hospi aliza ion o
uns able angina, hea ailu e o a pe iphe al ascula e en . In
an unadjus ed ITT analysis, he p ima y endpoin was eached
in 48.2% o pa ien s in he cinacalce g oup and 49.2% in he pla-
cebo g oup ( ela i e HR in he cinacalce g oup 0.93; 95% CI 0.85–
1.02; P ¼0.11). A e adjus ing o baseline cha ac e is ics, he
ela i e HR o he p ima y composi e endpoin was 0.88 (95% CI
0.79–0.97; P ¼0.008). In ac , despi e andomiza ion, he e was
an unexpec ed 1-yea di e ence in age be ween g oups (median
age 55 yea s in he cinacalce g oup and 54 yea s in he placebo
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g oup). As age is one o he s onges p edic ions o dea h, his
di e ence may ha e a ec ed he esul s. Also, he s a is ical
powe o he EVOLVE s udy was a ec ed by high a es o ea -
men c osso e because o discon inua ion in he cinacalce
g oup (d opou ) and use o comme cially a ailable cinacalce in
he placebo g oup (d op-in). A p especi ied lag-censo ing analy-
sis, in which da a was censo ed 6 mon hs a e pa ien s s opped
cinacalce , was pe o med. This analysis ound a signi ican
educ ion in he isk o p ima y composi e endpoin (HR 0.85;
95% CI 0.76–0.95; P ¼0.003) and isk o dea h (HR 0.83; 95% CI
0.73–0.96; P ¼0.009) in he cinacalce g oup.
Ano he p ede e mined p o ocol analysis compa ed younge
(<65 yea s) and olde pa ien s (65 yea s) [54]. Cinacalce
educed he isk o dea h and majo ca dio ascula e en s in
olde bu no younge pa ien s (HR 0.70; 95% CI 0.60–0.81 o
olde subjec s and HR 0.97; 95% CI 0.86–1.09 o younge
subjec s).
Al hough he p ima y analysis o he EVOLVE ial was nega-
i e, p especi ied addi ional analysis showed signi ican educ-
ion o he isk o dea h o ca dio ascula ou comes, which
sugges s a po en ial bene i o cinacalce .
Palme e al. [55] ha e published a me a-analysis o andom-
ized ials ha e alua ed he e ec s o calcimime ic he apy on
mo ali y and ad e se e en s in adul s wi h CKD. Including 18
ials and a o al o 7446 pa ien s, hey ound ha cinacalce
had li le o no e ec on all-cause mo ali y (RR 0.97; 95% CI
0.89–1.05) and an imp ecise e ec on ca dio ascula mo ali y
(RR 0.67; 95% CI 0.16–2.87). The esul s o his me a-analysis
should be in e p e ed wi h cau ion. Mo e han hal o he
pa ien s we e de i ed om he EVOLVE ial and his me a-
analysis only included he esul s om p ima y analysis, wi h
he po en ial se backs discussed abo e. Also, all o ials
included, excep he EVOLVE ial, we e small and no speci i-
cally designed o assess clinically ele an ou comes such as
mo ali y o ca dio ascula e en s.
New calcimime ics: e elcalce ide, a s ep
o wa d
E elcalce ide is a no el second-gene a ion calcimime ic agen
ha was ecen ly app o ed o he ea men o SHPT [13].
E elcalce ide is a eigh amino acid pep ide agonis o CaSR,
which binds o CaSR by a co alen disulphide bond ha esul s
in he allos e ic ac i a ion o CaSR and consequen ly educes
he ci cula ing le els o PTH and calcium [56]. In con as o
cinacalce , e elcalce ide unc ions as a di ec agonis o CaSR,
sligh ly ac i a ing CaSR e en unde calcium- ee condi ions
(Table 3). Howe e , downs eam signalling is s onge in he
p esence o calcium; hus, he main ac ion o e elcalce ide is
media ed h ough i s e ec s as an allos e ic ac i a o [57].
E elcalce ide has a a ou able pha macokine ic p o ile, wi h
a longe elimina ion hal -li e han cinacalce , and hal -li e elim-
ina ion ha exceeds 7 days in ESRD pa ien s [58]. I is adminis-
e ed in a enously a he end o a haemodialysis session; he
plasma concen a ion o e elcalce ide dec eases o e ime bu
emains ela i ely cons an om 24 h pos -dose o he nex
dialysis session [13]. I is a molecule ha is dialysable du ing
haemodialysis and, wi h he doses o e elcalce ide eaching
Table 3. Compa ison be ween cinacalce and e elcalce ide
Cinacalce E elcalce ide
Class Calcimime ic Calcimime ic
Yea o app o al (Eu ope) 2004 2016
Mechanism o ac ion In e ac s wi h memb ane-spanning segmen s o
CaSR and enhances signal ansduc ion, he eby
educing PTH sec e ion
Pep ide agonis o he CaSR ha in e ac s wi h and
ac i a es he ecep o , he eby educing PTH
sec e ion
Mode o adminis a ion Daily o al IV a he end o dialysis
Hal -li e 30–40 h >7 days
Exc e ion Renal (80%), aecal (15%) Renal
In e ac ion wi h CYPs Me abolized by CYP3A4, and o a lesse ex en
CYP1A2; inhibi s CYP2D6 (cau ion is ad ised when
p esc ibing po en ially in e ac ing d ugs)
No signi ican in e ac ions
Daily dosing (s a ing; maximal) 30–180 mg 2.5–15 mg/dialysis
E icacy endpoin s
>30% educ ion om baseline in
mean se um PTH le el du ing
he EAP
63.9 77.9
>50% educ ion om baseline in
mean se um PTH du ing he EAP
40 52 (P ¼0.001)
Ad e se e ec s
Nausea 22.6 18.3
Vomi ing 13.8 13.3
Dia hoea 10.3 6.2
Headache 7.0 6.5
Hype ension 6.7 6.2
Hypo ension 2.9 6.8
Muscle spasms 5.9 6.5
Pain in ex emi y 4.1 5.0
Asymp oma ic hypocalcaemia 59.8 68.9
Symp oma ic hypocalcaemia 2.3 5.0
Values a e exp essed as pe cen age unless indica ed o he wise. EAP, e icacy assessmen phase.
84 | L. Pe ei a e al.
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be ween 2.5 and 5 mg a he end o a dialysis session, plasma
concen a ions o e elcalce ide each s eady-s a e by week 4.
Al hough clinical expe ience is o cou se cu en ly limi ed,
in i o da a show ha e elcalce ide is no an inhibi o , induce
o subs a e o hepa ic cy och ome (CYP) enzymes, no is i an
inhibi o o subs a e o common e lux and up ake human
anspo p o eins such as P-glycop o ein [59]. Thus, e elcalce-
ide is expec ed o ha e a low isk o CYP o anspo e -
media ed d ug in e ac ions.
The immunogenici y isk o e elcalce ide has been e alua ed
[60]. While bo h p eexis ing an i-e elcalce ide an ibodies and
hose ha de eloped a e ea men we e de ec ed, no conse-
quences ha e been epo ed ega ding he clinical exposu e,
e icacy o sa e y o e elcalce ide.
Pi o al ials es ing e elcalce ide in he ea men o SHPT
we e ecen ly published [61,62]. Two pa allel Phase 3 placebo-
con olled ials we e conduc ed in 1023 haemodialysis pa ien s
wi h mode a e o se e e hype pa a hy oidism. In a enous
adminis a ion o e elcalce ide (n¼503) o placebo (n¼513) a e
each haemodialysis session o 26 weeks was pe o med.
Pa ien s andomized o e elcalce ide we e signi ican ly mo e
likely o achie e he p ima y e icacy endpoin (a educ ion
>30% in baseline PTH: 74.0–75.3% in he e elcalce ide g oup e -
sus 8.3–9.6% in he placebo g oup). In addi ion, pa ien s
andomized o e elcalce ide we e signi ican ly mo e likely o
achie e a PTH le el o 300 pg/mL o lowe (49.6–53.3% in he
e elcalce ide g oup e sus 4.6–5.1% in he placebo g oup). The
median dose o e elcalce ide du ing he e icacy assessmen
phase was 5.0 and 7.1 mg, espec i ely. Pa ien s andomized o
e elcalce ide we e mo e likely o expe ience subs an ial lowe -
ing o FGF-23 despi e mo e equen p o ision o calcium and
i amin D. T ea men wi h e elcalce ide dec eased bone-
speci ic alkaline phospha ase and collagen Type 1 c oss-linked
C- elopep ide. Pa ien s andomized o e elcalce ide had mo e
muscle spasms, nausea and omi ing han he placebo g oup.
Hypocalcaemia occu ed in 63.8% o pa ien s, bu symp oma ic
hypocalcaemia was epo ed in only 7% o pa ien s assigned o
e elcalce ide. Simila esul s we e ob ained in a placebo-
con olled ial om Japan, which es ed he e icacy and sa e y
o e elcalce ide [63].
A andomized double-bind, double-dummy ac i e clinical
ial has been conduc ed ha compa ed in a enous e elcalce-
ide e sus o al placebo and o al cinacalce e sus in a enous
placebo in 683 haemodialysis pa ien s wi h PTH highe han 500
pg/mL [62]. The p ima y e icacy endpoin was non-in e io i y
o e elcalce ide a achie ing mo e han a 30% educ ion om
baseline in mean p edialysis PTH concen a ion, and seconda y
endpoin s included supe io i y in achie ing biochemical
Fig. 1. Pa a hy oid ho mone, calcium and phospha e concen a ions in pa ien s ecei ing cinacalce o e elcalce ide. Rep oduced wi h pe mission om Block e al. [62].
Old and new calcimime ics |85
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endpoin s (>50% and >30% educ ion in PTH) and sel - epo ed
nausea o omi ing. E elcalce ide was no in e io o cinacalce
in educing PTH concen a ion and also me supe io c i e ia.
The p opo ion o pa ien s who achie ed >30% PTH educ ion
was 68.2% in he e elcalce ide g oup and 57.7% in he cinacalce
g oup (Figu e 1). The e was also a signi ican di e ence in he
p opo ion o pa ien s who achie ed >50% educ ion o PTH.
Hypocalcaemia was mo e equen in e elcalce ide g oup (68.9%
e sus 59.8%) and he mean numbe o days o omi ing o nau-
sea we e no signi ican ly di e en . O e all sa e y and ole abil-
i y be ween e elcalce ide and cinacalce we e simila . The e
was a nume ically highe numbe o hea ailu e episodes in
he e elcalce ide g oup, bu o e all he e en a es we e e y
low and simila o hose obse ed in he EVOLVE ial.
The e ec o e elcalce ide on FGF-23 le els is also no ewo -
hy. E elcalce ide ea men yielded a mo e p onounced
educ ion in FGF-23 le els han cinacalce . As discussed abo e,
FGF-23 is ele a ed in CKD pa ien s and has been associa ed
wi h ad e se ou comes such as le en icula hype ophy and
ca diac ailu e. In he EVOLVE ial, a 30% educ ion o FGF-23
le els was associa ed wi h signi ican educ ion o he p ima y
composi e endpoin , hea ailu e and dea h [29]. This p omis-
ing inding in he e elcalce ide g oup aises he possibili y o a
mo e p onounced impac on ca dio ascula ou comes.
The e a e some impo an clinical aspec s conside ing he
esul s o he ials men ioned abo e ha we wan o highligh .
E elcalce ide is supe io o cinacalce in achie ing a educ ion o
PTH and FGF-23 concen a ions in ESRD pa ien s; howe e , i
also leads o mo e equen episodes o hypocalcaemia. Da a
sugges ha his hypocalcaemic e ec could be mo e p o-
nounced a he beginning o ea men when PTH is highes .
Indeed, in a mul ina ional placebo-con olled ial, he calcium-
lowe ing e ec o e elcalce ide was e iden ea ly a e ea -
men ini ia ion and eached a nadi by weeks 10–12. This
calcium-lowe ing e ec was obse ed despi e inc eased use o
o al calcium-con aining binde s and ac i e i amin D ana-
logues, and inc eases in dialysa e calcium concen a ion in an
impo an p opo ion o pa ien s. This obse a ion aises legi i-
ma e conce ns ega ding he possible cumula i e posi i e cal-
cium balance. E elcalce ide is gi en a he end o haemodialysis
sessions, which imp o es medica ion adhe ence and educes
pill bu den. E elcalce ide does no seem o esul in ewe gas-
oin es inal symp oms ela ed o calcimime ic ea men
despi e in a enous adminis a ion, in con as o wha was
p e iously an icipa ed. The nausea and omi ing induced by
cinacalce and e elcalce ide appea s o be a sys emic e ec
a he han a local gas oin es inal class e ec .
Finally, i is emp ing o specula e ha he longe elimina-
ion hal -li e o e elcalce ide could lead o mo e s able con ol o
biochemical pa ame e s like PTH and calcium phospha e, and
ha such a sus ained supp ession o PTH could ansla e in o
imp o ed bone u no e and me abolism, dec eased ascula
calci ica ion and, ul ima ely, imp o ed ca dio ascula pa ien
ou comes. Any impac on such impo an ou comes emains o
be iden i ied.
Conclusion
In conclusion, SHPT is associa ed wi h inc eased bone u no e ,
isk o ac u es, ascula calci ica ions, and ca dio ascula and
all-cause mo ali y. Cinacalce , he i s calcimime ic app o ed
o clinical use, e ec i ely educes PTH and imp o es biochemi-
cal con ol o mine al and bone diso de s in CKD pa ien s.
Howe e , he e ec o cinacalce on ha d ou comes emains o
be p o ed.
E elcalce ide, a new second-gene a ion calcimime ic, is
supe io o cinacalce in achie ing he educ ion o PTH and
FGF-23 concen a ions in ESRD pa ien s, bu also leads o mo e
equen episodes o hypocalcaemia ha could be mo e p o-
nounced a beginning o ea men . E elcalce ide is gi en a he
end o haemodialysis sessions, which imp o es medica ion
adhe ence and educes pill bu den. Howe e , e elcalce ide does
no seem o cause ewe gas oin es inal symp oms despi e
in a enous adminis a ion.
In ou iew, e elcalce ide ep esen s a signi ican ad ance in
he ea men o SHPT, ia be e con ol o PTH and FGF-23 le -
els and imp o ed adhe ence. Howe e , whe he his imp o ed
biochemical con ol ansla es in o imp o ed clinical ou comes
such as bone ac u e a e and ca dio ascula mo bidi y and
mo ali y emains o be elucida ed by p ospec i e andomized
ials.
Con lic s o in e es s a emen
None decla ed.
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