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SHJ Vol 5, No 1                                M Ibrahim, Putting PCSK9 Inhibitors into practice

                              (Table 2)  Clinical trials involving alirocumab and evolocumab
                              Alirocumab                       Evolocumab

                              ODYSSEY LONG TERM                DESCARTES
                              ODYSSEY COMBO II                 RUTHERFORD-2
                              ODYSSEY FH I                     TESLA

                              ODYSSEY FH II                    OSLER

                                                               LA PLACE-2

            The US Food and Drug Administration (FDA)             the  researchers  found  no  evidence  that  adding
            have  raised  concerns  regarding  the  possibility   the  PCSK9  inhibitor  evolocumab  on  top  of
            of  adverse  effects  on  cognition  with  PCSK9      statin  treatment  causes  memory  loss  or  other
            inhibitors.  It  was  not  clear  whether  these      cognitive issues (32).
            concerns  were  relevant  specifically  to  these
            agents  or  to  lowering  of  LDL-C  per  se,  as     Recent  findings  have  extended our knowledge
            previously    expressed   for    statins   (29).      about  the  safety  of  PCSK9  monoclonal
            Furthermore, it is important to bear in mind that     antibody therapy:
            these   monoclonal     antibodies   are   large
            molecules  and  therefore  are  unlikely  to  cross   •  Two  recent  meta-analyses,  each  involving
            the  blood-brain  barrier.  The  incidence  of  any   over 10,000 patients treated with alirocumab or
            neuro-cognitive  event  in  a  pooled  analysis  of   evolocumab, have provided further reassurance
            phase  2/3  trials  was  0.8%  for  alirocumab        on the safety of PCSK9 inhibition (33,34).
            (N=2,476)  and  0.7%  for  placebo  (N=1,276),
            when  added  to  a  statin  (30).  Similarly,  data   •  We  now  have  evidence  that  treatment  with
            from a pooled analysis of integrated data from        evolocumab  for  up  to  52  weeks  did  not
            phase  2/3  trials  showed  no  increase  in  the     influence  plasma  levels  of  gonadal  hormones
            incidence  of  neuro-cognitive  effects,  which       and  adreno-cortico-trophic  hormone  (ACTH),
            were  reported  as  0.1%  with  evolocumab  (n=       or  erythrocyte  vitamin  E  concentration  (35).
            3,946)  versus  0.3%  in  the  control  groups        This  is  pertinent  given  that  vitamin  transport
            (n=2,080)  (31).  However,  a  recent  study  that    and steroidogenesis are  closely  linked to  LDL
            addressed  this  issue;  ―Evaluating  PCSK9           cholesterol metabolism.
            Binding  Antibody  Influence  On  Cognitive
            Health  in  High  Cardiovascular  Risk  Subjects      • Importantly, the available data do not indicate
            EBBINGHAUS‖, a sub-study of the FOURIER               any  increase  in  the  risk  of  new-onset  type  2
            outcomes     study   with   evolocumab     was        diabetes with either alirocumab or evolocumab,
            presented  in  the  ACC  2017  earlier  in  March     highly  relevant  given  the  target  patient
            which  evaluated  change  over  time  in              population (36).
            neurocognitive  testing  in  subjects  receiving
            statin therapy in combination with evolocumab         •  Finally,  anti-drug  binding  or  neutralizing
            (AMG 145), compared with subjects receiving           antibodies to these agents do not appear to be
            statin therapy in combination with placebo; and       an  issue,  with  evidence  suggesting  that  these
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