1104
KLINICKÁ341804001074588109168189242288347
FARMAKOLOGIE709804001074291138211265312372415474533554598
A13288040010753
FARMACIE1403804001074191138210265316336380
/18298040010732
Klin190680400107446583131
Farmakol2057804001074278105179220258305325
Farm.2402804001074178104179195
2025;39(1):14-212617804001074487128172185229271295335352367404443472511550
/32128040010732
www.klinickafarmakologie.cz4568804001076513320121425327329234035839843647950254457164568672477179183988990895196610061045
181878020012657111
PŮVODNÍ341200012660132201274348422456
PRÁCE818200012661124196256314
Lipid341360010629478199138
lowering49536001062968127158194212253293
with80336001065875107149
inclisiran:9673600106165791123141173190225267308324
a1306360010638
single-center13593600106314889128159192220256288329362394430
experience180436001063068103135171188220261296328
from214836001062864105159
Slovakia232336001063061100137174209227267
second,34362001093681123172222273292
and65562001094394145
subsequent82062001093585136172218269319365415445
doses,1284620010951101137183219238
as154262001094378
well1640620010966111133154
as181462001094479
for191362001092676106
sampling34376001093680155207229250300351
before71876001095298125175205250
further99376001092677106139189235264
approvals.128276001094395147177226269313334370389
The169676001094596141
prepared18627600109518112634390001095297127173226
application59690001094496149171193234279310331382434
was1056900010967112148
then123090001093181128180
sent143690001093683134164
by162690001095295
mail1748900010976120142164
or193890001095081
electronically,343104001094567113155187217267318339380424446467511526
and894104001094494146
the1066104001092980126
response1217104001093075112163214265300347
was15891040010967111147
mostly17611040010976126162193214258
recorded343118001092973114161191241285336
within694118001096687116165185235
a9441180010943
week.10021180010965109154196217
After1234118001095479112155185
approval1434118001094393144173221263306327
of1776118001094975
therapy1866118001093079123343132001092972121162
for520132001092674103
26381320010945
doses698132001095099133178212
and925132001094391141
scheduling1081132001093575123168218266287307355405
the1501132001092977122
patient1638132001095093121142186235263
for1916132001092674103
the343146001093080126
administration494146001094394170191241262297328358402432453502553
date,1072146001095195124169187
the1284146001093080126
current1435146001094090120150195245275
dose17351460010951101137182
of1943146001094976
inclisiran343160001092171112133154190211240284334
was6951600010966110145
ordered858160001094979130176206251303
based1178160001095196131177229
on14241600010950100
the1541160001093080126
approval1684160001094495147177226269313335
code343174001094087137181
from539174001092555103176
any730174001094291131
pharmacy876174001095099141169243285325368
directly125917400109507098142182213233275
by1548174001095091
our1654174001094897125
office,1794174001094874102125164207225
as343188001094378
it436188001092150
is502188001092155
a5731880010943
category631188001094083112156207256285330
A9771880010954
drug.1047188001095079128178197
The1259188001094595140
invoice1414188001092170112160181220264
due1694188001095099143
date1853188001095093122166
for343202001092676105
the464202001093079125
pharmacy6042020010951102145174249293333377
is997202001092156
usually1069202001094984133176198219261
60–751346202001094693141183226
days,1588202001095093134170189
so1793202001093585
the1894202001092979124
office343216001094976106130170215
incurs579216001092171112162191228
no8292160010950100
costs950216001094089125156192
before1164216001095198125174205250
the1435216001093080126
payment1582216001095196137213259310339
of1943216001094976
health343230001095199144167198250
therapy620230001093183130162207261304
by951230001095397
the1075230001093183130
insurance1232230001092274111162193239291333379
company,1638230001094292171224270322365381
which3432440010966117138178228
is595244001092156
guaranteed6742440010951101144174218268297342388440
by1138244001095193
the1254244001093080126
issued140324400109215692141187239
approval.1665244001094495147177226269313335354
During3432580010959109138159209259
the617258001093079124
administration757258001094393168188238258293323352396425446495544
of1317258001094975
inclisiran,1407258001092171111132152187207236280329348
we17702580010966110
encountered1896258001094494343272001094088137186215259288332383
no741272001095099
problems.855272001095180129179201246320355374
While12442720010975125146166211
submitting1470272001093684134209230259291311360410
the1895272001093079124
application343286001094395147169190230274304325375425
for794286001092676106
therapy925286001093080126156200251293
approval,1243286001094495147177227269313335354
516222860010946
requests1693286001093075127176222258289326
were3433000010967112143188
rejected,55730000109307698144186218264316335
due9183000010951102148
to1092300001093079
the1197300001093081127
non-utilization13503000010950101152181233264285307328368413443465515566
of1942300001095077
prescribed343314001095283129166208239261313361414
statin784314001093667113143165216
therapy1027314001093081128159204257300
by1353314001095296
the1475314001093082128
pharmacy16303140010952104148179256301343389
(for343328001092650100130
24923280010946
patients),556328001095196125146192242272309332349
due9233280010951101146
to1088328001092978
concurrent1185328001094089139180230260290335385415
titration161832800109305181111155185206256306
of1943328001094976
the343342001093080126
maximum4873420010975119162184259309384
tolerated890342001092978100146176220250294346
dose12553420010951101136182
of1456342001094976
statin1551342001093566110140161211
by1781342001095193
the1893342001093080126
general343356001095198149196227272294
practitioner663356001095283128170203224255277328380426457
(11146356001092670
patient),1242356001095297128149196247278303321
and1589356001094495148
due17633560010952102149
to1938356001093181
a3433700010943
one-week4113700010950100146176243288335377
pause813370001095196145181226
in1064370001092171
the1160370001093080126
prescription1310370001095182127163204233255306336357407458
of1792370001095076
the1893370001093080126
maximum3433840010974117159180254302376
tolerated73438400109307899144173216245289339
dose1089384001095099133178
of1282384001094975
statin1372384001093565109137158207
(21594384001092569
patients).1678384001095194123143188237266302324341
In483398001092272
terms572398001092974104180215
of804398001095076
therapy897398001093080126155200251293
efficacy,1207398001094572102126166210251296311
we15353980010966111
observed16633980010949101137183213259304356
similar343412001093657132153174218248
results615412001092974110160181211248
in887412001092172
our983412001094999129
cohort1136412001094189140190220253
of1413412001094976
patients1513412001095196125146192242272309
indicated1846412001092171122144343426001094083112156207
for566426001092675104
the686426001092978123
therapy825426001092978123153196247288
with1128426001096687117166
inclisiran1309426001092170111131152186207236279328
as1653426001094378
in1746426001092170
large183242600109216492142187
clinical34344000109406283133154194239260
studies621440001093667117168189235271
(10–13).910440001092668111159200241264281
We12094400010977120
recorded1348440001092974116164194245291343
a17094400010944
similar1771440001093657132153175218248
therapeutic343454001093183131162208262310363394417459
effect831454001094675106154197231
on10904540010951104
LDL-C12234540010943106151173231
levels,1483454001092269114161184221242
overall1754454001095095142173219242265
efficacy,343468001094572102126166210251296311
and678468001094394145
safety847468001093680106152182228
of1099468001094976
therapy.1199468001092979125155199251293308
However,15314680010959109175220263308338352
we19074680010967112
observed3434820010949100135180209255298349
interindividual70848200109207099142172193242292313356377428476519540
differences126348200109507197126171200245294334378413
in1691482001092170
the1777482001092978123
reduction1916482001092973343496001095098137168189237286
of644496001094874
LDL-C,7324960010942100142162216236
as982496001094377
well10744960010965109130150
as1239496001094276
in1330496001092169
other1414496001094977126170199
monitored16284960010973122171191220268297340391
parameters.343510001095195125169244290321365395432452
In812510001092172
this901510001093080101136
study,1054510001093667116168211226
we12975100010966111
found1426510001092676126176227
a16715100010943
median17315100010975121173194238288
LDL-C3435240010942100142161215
reduction573524001092972122170210241261309358
of945524001094974
57.5103352400109468998145
±11935240010952
7.51259524001094655102
%,1371524001097089
which14745240010965114134173222
is1710524001092155
higher1779524001094969118167211240
than343538001093080123173
the534538001093079125
reduction677538001092974126176217249270320370
reported1065538001092974126177207239284336
in1418538001092171
other1507538001094979129175205
studies,1729538001093667116168189234270290
where3435520010966117163193238
it598552001092151
ranged666552001092973124174220272
from955552001092657106182
411154552001094687
%12525520010972
to1341552001092978
461436552001094794
%15425520010971
(or1630552001092572102
491749552001094792
%18525520010971
to1940552001093079
52343566001094690
%4455660010971
when5375660010966117162213
adjusted771566001094394116166201232277329
to1121566001092978
placebo).1220566001095173117158202254305328345
Overall,15865660010962107151181225247268287
the1893566001093080126
reduction343580001092975127176217249270320371
of734580001094976
LDL-C8305800010942102146167222
in1072580001092272
our1164580001094999129
study1313580001093667117168211
ranged1544580001093074124175221272
from1837580001092656106182
41.88343594001094687102150197
%5525940010971
to642594001093079
86.25740594001094693112161207
%.958594001097292
Recently,483608001095098141187240271293338354
several865608001093684129176207253276
observational11686080010951105142190221270316347369421474519542
studies1737608001093769121174197244282
have343622001095195138184
been553622001095299146198
published7776220010952103156178200236287334386
with1190622001096789120171
real1387622001093076121143
clinical155662200109416284135157198243265
data1847622001095296127172
regarding343636001092975126170199250271322372
the732636001093080125
efficacy874636001094572102126166210251296
and1187636001094393144
safety1348636001093580106152182228
of1592636001094976
inclisiran1685636001092171112133154189210240284334
administration.343650001094393166187236256290320349392420441489539557
Some915650001094493167211
of1141650001094975
them1231650001092978122196
pointed14426500010951100121170198242292
to1749650001093077
similar184265000109355512814934366400109216494
LDL-C4536640010942102145165220
reductions689664001093075126175216248269318369404
as1108664001094479
in1203664001092171
the1290664001092979124
ORION-9–10–1114306640010962111133196256285332380420463511552589
studies,343678001093666116167188233269288
while6476780010966116137158204
others867678001094979128174203240
indicated1123678001092171122143183227256301352
a14916780010944
lower1551678001092170136181210
decrease1777678001095196138167212343692001094379125
(14,489692001092567109127
15).637692001094687111128
The786692001094596142
authors949692001094393123173223253289
reported1259692001093075127177207240285337
a16166920010944
lower1681692001092171137182212
reduction1914692001092974343706001095099139171191240290
in648706001092171
LDL-C7347060010942101144164219
levels968706001092166109153174209
than1192706001093079122171
in1378706001092170
clinical146470600109406081130151191234255
studies,1735706001093565114165185230265284
with343720001096891123175
a5457200010945
median6177200010977125179201247299
of943720001095179
381049720001094896
%11577200010974
in1258720001092274
patients1359720001095399130152200252283322
without1708720001096891123175227279311
statin343734001093565108137157206
co-medication564734001093987116191236286307346389418438486536
and1115734001094291141
451271734001094589
%13707340010970
in1455734001092170
patients1540734001095093122142187236264300
with1855734001096586115164
statin343748001093566110139160210
co-medication.568748001094189119195240292313353397426447496546565
Another11497480010955105154184233279308
study1473748001093666115166209
from1698748001092656105180
the1894748001093079125
UK3437620010959110
described479762001095298135177208230282330383
an888762001094496
average1010762001094488133164209261308
decrease1344762001095299141172218263299346
of1716762001095178
491820762001094793
%,1926762001097293
with343776001096790120171
the541776001093081128
group695776001095181132183235
receiving956776001093076119164186231254305357
statin1339776001093668113143165216
co-medication1581776001094191122200247299321363408213862001093153105158
achieving232462001094587139162209255278330383
up2735620010951105
to286862001093182
56%297862001094896169
decrease,3176620010952100143174221267304352371
which3576620010968121143186238
represents213876001093078132164211249297350381419
similar258876001093659137160183228260
results287876001093077115167190222260
as316876001094583
in328176001092174
our3385760010951103135
cohort355076001094192145198229264
and213890001094495148
in231290001092172
clinical24119000109416284135157198244266
studies270390001093668118171193239276
(16).300590001092669112137155
A3186900010956
lower326890001092273140186217
efficacy351190001094673104128170215257303
was21381040010967111147
also2311104001094465101152
demonstrated2489104001095197173224275310342372416446491544
in3059104001092172
a31561040010944
German32261040010959106136212257307
cohort3559104001094190141192222255
of2138118001094976
1532232118001094687131
patients,2380118001095296126147192243272309328
which27261180010966117138179228
showed2972118001093686136202247299
a32881180010944
reduction3350118001092974126176217249270320370
of3738118001094976
322138132001094690
%22391320010972
in2331132001092272
non-statin2424132001094999150179215246291320341391
users2836132001095085131161198
and3055132001094393144
423220132001094690
%33211320010971
in3413132001092171
patients3505132001095296125147192242272309
with2138146001096891123174
statin2339146001093769115146169221
co-medication2587146001094192124203250304327369415446468520572
after3186146001094573107154185
a33981460010945
3-month3470146001094777157209261292344
follow-up.213816000109267495116164229256306356374
After2527160001095479111154183
9-month2725160001094675150199248276325
follow-up,306516000109267495116164229257306356374
reduction3453160001092973124172212243263312361
in2138174001092170
LDL-C22231740010942101143164218
levels2457174001092165108152173207
was26801740010965108143
observed28381740010949100135180209254298349
compared3202174001094088162213256285329380
to3598174001092977
the3690174001093079124
3-month2138188001094674149198248277326
follow-up248018800109267596117166231259309360
(17).2856188001092566105130147
Since3018188001094465114154198
we32311880010966110
did3356188001095171122
not3493188001095099128
have3636188001095093134178
data2138202001095194124168
from2322202001092657106182
patients2520202001095195125146191241271308
without2844202001096688118168217267298
statin3158202001093566110140161211
medication33852020010975121173194234278308329379429
after2138216001094370103148178
223402160010946
doses24112160010950100136182218
of2653216001095076
statins,2754216001093566111140161211247266
we30442160010967112
compared3180216001094089165216260290335387
LDL-C35922160010942102145166222
reduction2138230001093077130181223256278329381
based2546230001095298134181235
on28072300010951103
titrated293623000109315284114160190236290
statin3252230001093768114145167218
therapy.3497230001093081128159205258301317
We21382440010976120
found2276244001092676126176228
that2522244001093080123153
patients2693244001095296125146192242272309
who30202440010966117167
had3205244001095094145
a33692440010943
maximum34302440010975119162184259309384
statin2138258001093667112142164214
dose23782580010952102138185
experienced2589258001094589141188219241287338379424477
a30922580010944
higher3162258001095071123174220250
reduction3438258001093076128179220253274324376
in2138272001092171
LDL-C22262720010943103146167222
(61.52465272001092671112127175
±26572720010954
12.32728272001094686106155
%)2894272001097194
compared3005272001094189165217261290336387
to3409272001093079
patients3505272001095196125146192242272309
with2138286001096688118168
a23252860010943
reduced2388286001092974126176217261313
statin2720286001093667111140162212
dose29512860010950100136182
(31522860010926
53.23197286001094690108157
±33732860010954
5.93446286001094664109
%).3566286001097194112
Differential2278300001096081107135180209253303332352394415
efficacy2713300001094571100123162206245289
in3022300001092171
clinical311230000109416181130151190234254
studies3386300001093666114165185230265
and3671300001094392143
real-world2138314001093075119140169237286316338389
data2552314001095195125169
can2746314001094185135
be2906314001095298
explained3029314001094689141163206227278324376
by3429314001095295
several3548314001093682126170200244266
factors.2138328001092670110141189218254272
First,242632800109446492128158177
some2618328001093685160205
studies2839328001093565114165185230265
had3119328001095093144
follow-ups327832800109277697117166231259309360395
lasting368932800109216398213834200109305099149
223053420010947
months23703420010975124174202251286
instead2674342001092170105134178221271
of2964342001094975
3,3057342001094663
while31393420010966116136156201
in3358342001092171
our3447342001094998127
study,3592342001093666115165208222
we21383560010967111
compared2273356001094189165216260289334385
LDL-C26833560010942102145165221
values2928356001094387108157202238
one31903560010950100145
month33593560010976126176205255
after3638356001094470102146176
the2138370001093079124
third228037000109297899127177
dose,24753700010951100135180197
which26903700010966116136176225
represents2932370001093074125154198233278328357392
the3342370001093079124
standard3484370001093565109158208251280330
procedure2138384001095078125165207256304331374
for2525384001092674102
approving2640384001094291141169216256276324373
the3026384001092977120
continuation3159384001094086134162181229276317345364412460
of3632384001094873
inclisiran3718384001092168213839800109406080114134162205254
therapy2406398001092978122151194244285
in2705398001092069
Slovakia.2788398001094464113155197238260302320
The3122398001094594139
ORION-132753980010961109131192251280319
study3608398001093665114164206
indicated2138412001092169118137175217245288337
that2488412001093077119147
the2648412001092977120
average2781412001094383125153195244287
LDL-C30814120010942100141160213
reduction3307412001092972122169208238258305353
was36734120010966107141
approximately2138426001094392142170217256276349391419461481522
502674426001094589
%27714260010970
after285542600109426798141169
230374260010946
months30964260010974122170198246279
and3388426001094391140
453542426001094588
%36384260010970
after37224260010942672138440001093073101
322534400010946
months23134400010975123172201249283
of2610440001094974
inclisiran2698440001092170109129149183203231273322
administration.3034440001094393167187235255289319347389418438486535553
Given3601440001095879121164213
the2138454001093078122
pharmacokinetics22744540010951100142170244287326373415436484529558578617652
and2940454001094392142
effect309545400109457199143183214
of3323454001094974
inclisiran,3411454001092169109129148182202230273321339
it3764454001092150
is2138468001092155
assumed2207468001094378112160234279330
that2551468001092978121149
the2714468001093079123
most28514680010975124159188
relevant305346800109307495139181224273301
data3368468001095193122165
point35474680010951100121170198
is3759468001092155
the2138482001093079124
LDL-C22814820010943102144164219
value2519482001094386107156200
after2739482001094369101145174
the2932482001093079124
third307548200109307999128178
administration3272482001094494168189238258292322351394423443492542
of2138496001094975
therapy,2233496001093079124153196247288302
as2555496001094378
observed26534960010950100135180209255298349
in3023496001092170
the3113496001093079124
ORION32574960010962110132194253
studies.3530496001093666115165185230265284
Additionally,21385100010955104154175204224272322364384404446460
the2612510001093079123
aforementioned2750510001094368117146190264309358386406455504549600
British336451000109487798127147181230
study3608510001093565114164206
had2138524001095093143
a23015240010944
higher2365524001095070120169214243
percentage2628524001095197126165209258287330380425
of3073524001095075
patients3168524001095295124144188238267303
with3491524001096687116165
statin36765240010936661092138538001093050100
co-medication2262538001094089118194240291312352395424445494544
compared2830538001094089164215258287332383
to3237538001093079
the3340538001093079124
study3488538001093666115166209
by3721538001095193
Mulder21385520010972120140189233261
et2413552001094473
al.250055200109436380
(18)2594552001092566106129
(532736552001092568110
%28555520010971
vs.293955200109437795
373048552001094587
%),3144552001097092108
which32655520010966114134173221
may35005520010974116156
also366955200109436396145
have2138566001095093134178
played2339566001095173115156200251
a26135660010943
role,268056600109297899144161
as2865566001094378
demonstrated2966566001095196170220269304334362405434478529
in3518566001092271
other3612566001095079128173202
studies2138580001093665114165185230265
with2417580001096687116165
PCSK9-mAbs25965800010948100144192237267343397448482
(mAb3093580001092597152202
–33105800010944
monoclonal33695800010975124174223263283332382424445
antibodies),2138594001094393121141192242293313357392414431
and2587594001094392143
which27485940010966116136176225
we29915940010966110
also312059400109436398147
demonstrated3285594001095196170220269304333362405434478529
in2138608001092169
our2221608001094998126
study2361608001093565113163204
in2579608001092170
the2662608001093078123
group2798608001095079127175225
with3037608001096586115163
maximum32146080010974117158178252300374
doses3601608001095199133178212
of2138622001094975
high2230622001095070120170
intensity241762200109217099142192226246276320
statins2754622001093666109138158207242
(18).3013622001092667108131147
The2278636001094596142
cohort2446636001094089140190220253
of2725636001094976
most28276360010975125161192
real-world3045636001092974118140169237286316338390
studies3460636001093667117168190235272
is3757636001092157
highly2138650001095173124176198242
heterogeneous2406650001095198129175205256309355407454505557593
regarding3025650001093077129174204256278329381
accompanying34336500010944851261762533053512138664001095194118170223
lipid-lowering238866400109214497120173204227279348395426449501554
therapy.2969664001093082130161207260304321
In3317664001092274
our34186640010951103134
study,3579664001093769121174219235
we21386780010967112
found2276678001092676127177229
that2531678001093080124154
patients2711678001095196126147193244274311
treated3048678001093060105149179224276
with3350678001096789119170
statins,3545678001093667112142163214249269
especially2138692001094581132179220241285306327370
at2533692001094373
maximum26316920010975118161183258308383
doses,30396920010951101136182218237
had3301692001095094145
significantly3471692001093556107157178205229269314213870600109497898141
greater2294706001094978122165194237266
LDL-C25757060010942101143163218
reduction2808706001092973124172212243264313362
than3185706001092978121170
patients3370706001095094122143187237265301
not3686706001095098127
using2138720001095086107157209
statins.2372720001093667112142163213249269
This2666720001094597118154
finding2845720001092751101153175225276
is3147720001092157
consistent3229720001094190141176198233264309360390
with3645720001096688118169
previous2138734001095181126170191241291327
publications24847340010952102153175196237281311332382432468
evaluating2971734001094588132154203247277298348399
inclisiran3389734001092171112133154190211240284334
in3743734001092171
a21387480010943
real-world2200748001093075119140169236286316337389
clinical260874800109406182132153194238260
practice2887748001095181125166198219259304
cohort.3210748001094089140190220252272
It2278762001092253
is2358762001092258
well24437620010968114137159
known2629762001094397148216269
that2924762001093182128158
statins3109762001093769114145167219256
induce3391762001092274127178220266
the3684762001093182130
expression2138776001094588140170215251287308357408
of2563776001094976
the2655776001093080126
sterol2797776001093667111141191213
regulatory3026776001093075126176198241271320350395
element3438776001094567113188234285314
–37697760010945
binding393462001095172121172193242293
protein424262001095180129159203224273
24531620010946
(SREBP-2),459262001092667115159207255282324347364
a4971620010943
process503062001095180129170214249284
leading533062001092166109160180230280
to393476001093182
increased404376001092174116147194240277325379
transcription444976001093062108160197239270293347378400452505
of498176001095179
LDL-R5087760010944106151173226
mRNA,5340760010977128190248270
as393490001094379
well4036900010966111133154
as421490001094379
PCSK9,4316900010948100145194241257
and459690001094393145
thus476490001093080129165
to495290001093079
increased505490001092171112142187230266312364
concentrations5441900010940891393934104001094085135165194238268289339390425
of4379104001094976
PCSK944751040010947100145194240
in4735104001092171
plasma4826104001095173117153228271
(19).5117104001092668109133151
Previous5287104001094877122166187237287323
studies3934118001093666116168189234270
have4225118001095094136181
also4427118001094365100150
shown4598118001093686136202252
that4872118001092979123153
a50461180010943
greater5110118001095180125169199243273
reduction5404118001093075127177393413200109407293143194
in4147132001092171
LDL-C42371320010943103146167222
in4478132001092272
response4569132001092974110161212263298344
to4932132001093079
statins5030132001093566110140161211247
is5296132001092156
positively537113200109511021381591892103934146001094388110153
associated4113146001094379115165207228271301346398
with4536146001096789119169
plasma4731146001095173117153228272
levels5028146001092167111155178213
of5266146001095077
PCSK953681460010948101146195242
(20).3934160001092674122149167
Moreover,41371600010975128160208261306353385402
the4575160001093083131
relationship4742160001093078102148180203256309346399422476
between52541600010953102134206254302356
statin3934174001093667111141162212
treatment4171174001093060105149179254300351380
and4576174001094494145
plasma4747174001095173117152228271
concentrations5044174001094089140181225276305335379409430480530566
of3934188001094976
PCSK940321880010948101146194241
may42951880010975119160
explain4478188001094588140162205226276
variations4777188001094387116138181211232282332368
in5167188001092171
LDL-C52601880010943103146167223
response55051880010929743934202001093687137187223268
to4218202001093079
statin4313202001093566110139160210
therapy4539202001093080125155199250292
and4847202001094493145
subsequently5008202001093584135171217268318363414443464507
to5531202001093079
inclisiran3934216001092171112133154190211240284334
response4287216001093075111162213263299344
(21,4650216001092671113128
22).4797216001094692116133
Interindividual4074230001092272101146176198248299320364386437487530552
differences464923000109517299129174204250300341385421
were50942300010966111141186
also5304230001094465100150
observed547823000109501013934244001093681111158202254
in4209244001092172
the4302244001092979125
HEYMANS44482440010959104154226282341385
registry4854244001093075126148183214244289
focusing5164244001092776118167203224274325
on55102440010949100
the3934258001093080126
real4079258001092975118140
analysis4238258001094394137159202237258294
of4551258001095076
evolocumab4647258001094588137159209250300375419470
PCSK9-mAb,51372580010948100145194240271348403455473
which39342720010966117138179229
demonstrated4189272001095196172222273308339369413443488540
substantial4754272001093686137173204249299328350393415
interindividual519427200109217210114617619824829932136538739342860010951100144165
variability4117286001094387117138182233255276297327372
in4507286001092171
LDL-C45952860010943103146167223
reduction4835286001092975126176217249270320370
(23).5223286001092570117140157
In5397286001092272
addition54862860010944953934300001095172102123173224
to4181300001092978
biochemical4283300001095172122164214259335356397441462
and4769300001094393144
molecular49363000010976126148193235284306349379
characteristics,53383000010940901341642082483934314001093074104126161192213254291310
there4264314001093080125155201
are4484314001094473119
also4622314001094465101151
other4793314001094979129175204
possible50173140010952102138174195246268314
factors5351314001092670111143192222259
explaining3934328001094691145168213236288310362415
these4376328001093082130167215
differences.4618328001095275103134181212259312354401438459
In5104328001092274
controlled5205328001094292145176207258281303351405
clinical393434200109406182131152192236257
studies,4207342001093565115166186231267286
patients4509342001095194124144189239268305
exhibit4830342001094487137158209230260
greater5105342001095080124167197241270
adherence53913420010943941441893934356001092974123163207
to4157356001092977
prescribed4250356001095080124160200229250301346397
medications46633560010974119170191231274303324373423457
compared5136356001094088162213256285330381
to5532356001093078
observational39343700010949101137183213259303333354404454498519
studies4473370001093667117168189235271
due47643700010951100146
to4930370001093079
more50293700010975125155200
thorough5249370001093080130160210260311361
supervision,3934384001093584135181211257279314334384434453
regular4402384001093074125175196239268
monitoring,46863840010975124175195225274304325375425444
and5146384001094392143
a53053840010943
higher5364384001095071121171216246
level3934398001092167111155177
of4137398001094976
engagement.4239398001094595146190241287363409460489509
Furthermore,4773398001094492122155205251281357407438483501
patients5300398001095196125147192243273310
admitted3934412001094395170191221254298350
to4303412001093079
special4401412001093687134175196239261
lipid468141200109214294115167
clinics486741200109406182132154194231
are5117412001094473118
characterized5255412001094090133163207248280324393442600109295189135186
by4136426001095193
multiple42454260010975125146176197248270315
drug4576426001095180130181
intolerances.4773426001092171100149171216246290340381425461480
Thus,5269426001094596145180200
the5485426001092979125
cohort3934440001094089140190220252
of4209440001095076
observational43084400010950102138183213260304333354404455498520
studies4851440001093566116167189234270
with5144440001096688118168
real5335440001093075119140
clinical5498440001094062833934454001095071111155176
data4126454001095093123167
may43094540010974118159
differ448445400109507198127172202
from4702454001092656105180
clinical489845400109406182132153193237258
studies5172454001093566115166187232268
(24).5456454001092570113137154
Some4074468001094596172219
studies4318468001093668118170192238274
also4618468001094466102152
described4796468001095198134176206228280327379
a52014680010944
slight527146800109365779130181211
increase55084680010921723934482001094172118163200247
in4208482001092173
LDL-C43084820010943105149171229
levels4563482001092269114160182219
after4809482001094471106152183
switching50184820010937106128160201252274326378
from5423482001092758109187
PCSK9-mAb39344960010948100146194241272348403455
administration4413496001094395170191241262298329358402432453503553
to4990496001093079
inclisiran5093496001092171112134155190211240285335
(25).5452496001092570116141158
In3934510001092272
our40295100010949100129
cohort,4182510001094089139189219252271
we44765100010967112
did4611510001095172123
not47575100010950100130
monitor49115100010975125175196226275305
the5240510001093079125
effect5389510001094572101147188221
of3934524001094975
this402452400109307999134
transition;4173524001092958102151185206235256305355372
however,4560524001094998163207250294323337
it4913524001092050
is4978524001092156
known5049524001094292141206256
that5320524001093079122151
the5486524001092978123
inhibition3934538001092273125147200223254276328380
of4341538001095178
PCSK9-mAb44465380010949103150200249281359417470
increases4943538001092173115146193238275322360
plasma5329538001095376121158235281
concentrations3934552001094292145188234286317349395426448500552589
of4550552001095179
PCSK946565520010950104151202251
during49345520010952104135157210263
the5224552001093082130
first538155200109275283122154
355625520010948
months39345660010974124174203252287
after4236566001094369102146175
the4427566001092979124
injection456656600109217192137177209230279329
of4910566001094975
PCSK9-mAb5001566001094799144191237268343398449
due54655660010951100145
to3934580001092977
delayed4025580001095094115158198241291
plasma4331580001095071114148221263
clearance4609580001094060104146175217266305349
of4972580001094974
PCSK95061580001094798142189234
induced5310580001092069119167206249300
by3934594001095295
the4056594001093081128
PCSK9-mAb42115940010948102149198246278356412465
complex.4703594001094191168221243290334355
This5084594001094698120156
could5267594001094191142164217
be55105940010952100
a39346080010944
potential40056080010952104135181233263285330352
reason4383608001093077122158210262
why46716080010968120162
pre-treatment4860608001095283129161192222269314344421469520551
with5437608001096890122173
PCSK9-mAb39346220010948101147196243274351407459
was44196220010966111146
associated4591622001094480116166208229273303348400
with5017622001096789119170
a52126220010944
less5282622001092167103139
pronounced544762200109528213239346360010950100150200241286337
reduction4293636001092975126176217249270320371
in4685636001092171
LDL-C.47786360010942102145166222243
To5042636001094589
what51536360010966117160190
extent5364636001094588121166216246
this3934650001093081103139
may40996500010976121163
influence4288650001092273100124175221273314360
the4674650001093081128
magnitude48286500010976121173224245276327379426
of5280650001095077
LDL-C53836500010943105149170227
reduction3934664001092975127176217249270320371
in4328664001092171
response4423664001092975111162213263298344
to4791664001093079
inclisiran4893664001092171112133155190211240284334
and5251664001094494145
what54206640010966116160190
other3934678001095080131178208
pathways4168678001095297127178244289331367
may45616780010976121163
contribute4750678001094090141171201223275327357403
to5179678001093079
the5284678001093181128
relationship5438678001092975981423934692001093051102153188239260312
between4272692001095198129198244290341
PCSK946396920010948102147196243
protein4908692001095282132162207229280
and5214692001094394146
LDL-C53866920010942103146168224
reduction3934706001093077130181223256278329381
is4342706001092158
not44267060010951103134
fully4586706001092779101123168
known;4780706001094396148216268286
however,50937060010951102170216261307337353
it5473706001092152
is5552706001092158
assumed3934720001094378114163238283335
that4285720001092979122152
after4453720001094369102146176
switching46457200010935102123153193242263313363
to5024720001093079
inclisiran5119720001092170111132153188209238282331
and5466720001094393144
stabilizing3934734001093565109159180201221259280329379
levels,4328734001092166108152173208227
any4570734001094392132
increase4718734001092070110138183225260305
in5038734001092170
LDL-C51237340010942101144164218
should5357734001093584133182203253
not39347480010950100130
be4083748001095198
significant.4200748001093556107157178205229269314364393413
Large4074762001094287117167213
clinical430676200109406182132153194238260
studies4584762001093666116167189234270
have4872762001095094136181
demonstrated5071762001095197172222273308339369413442487539
a39347760010944
reduction4005776001093077131182225258280332384
in4416776001092173
Lp(a)4516776001094397124166191
levels4734776001092169114160183219
of4980776001095178
up50857760010951104
to5216776001093081
305324776001094795
%54327760010973
of5531776001095179