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SHJ Vol 5, No 1                                M Ibrahim, Putting PCSK9 Inhibitors into practice
                                                          http://dx.doi.org/10.25239/SHJ/Vol5/No1/ReviewArticle
            therapy. On the other hand; many patients with        adherence  to  statin  therapy  is  common  (the
            elevated  LDL  cholesterol  not  due  to  familial    majority  of  patients  stop  taking  their  statin
            hypercholesterolemia  do  not  achieve  LDL           within a year) and this is an important cause of
            cholesterol  goals  with  current  treatments.  A     the variable therapeutic response. Indeed, these
            survey  of  9,950  high-risk  patients  with  CHD     phenomena      are   probably     linked,   as
            showed  that  more  than  half  did  not  achieve     pharmacokinetic and other factors may underlie
            LDL  cholesterol  <1.8  mmol/L  (70  mg/dL)           to some extent the inter-individual variability in
            either  with  a  single  lipid  modifying  drug,  or   the  response  to  a  statin  and  also  the  extent  to
            combination  therapy  (5).  Similarly,  about  half   which this treatment is tolerated (10).
            of  patients  with  CHD  did  not  achieve  LDL
            cholesterol  <2.5  mmol/L  in  the  pan-European      Another important aspect to address here; is the
            EUROASPIRE  III  survey  of  people  with  a          problem of intolerance to statins; where despite
            history  of  cardiovascular  disease  (6).  Recent    the  fact  that  the  incidence  of  adverse  events
            data  from  the  EUROASPIRE  IV  survey               attributable  to  statins  in  randomized  clinical
            confirm  and  extend  these  findings:  only  58%     trials  is  low  (11);  however,  side-effects  in
            and 21% achieved an LDL cholesterol level of          muscle occurred in up to 29% of statin-treated
            2.5 mmol/L or 1.8 mmol/L, respectively (7).           patients  in  observational  studies,  presenting  a
            Statins                                               potential  barrier  to  treatment  (12).  It  is
                                                                  important  that  patients  remain  on  a  statin
            By now you've heard of statins, also known as         whenever  possible,  in  order  to  reduce  their
            HMG-CoA reductase inhibitors. Statins are the         exposure to hypercholesterolemia and to reduce
            cornerstone  of  treatment  to  help  regulate        their risk of an adverse cardiovascular outcome.
            cholesterol production. Available since the late      A switch to a different agent in the same class,
            1980's,  statins  include  well-known  agents  like   or  to  a  lower  statin  dose  as  part  of  a
            atorvastatin (Lipitor), simvastatin (Zocor), and      combination  regimen,  helps  most  patients  to
            rosuvastatin  (Crestor).  Statins  work  so  well     remain on statin-based therapy (13). Pharmaco-
            because they inhibit an enzyme involved in the        genetic  studies  have  detected  a  gene  that  may
            making of cholesterol in the liver and boost the      identify  patients  at  risk  of  statin-induced
            number  of  low  density  lipoprotein  receptors      myopathy  (SLCO1B1,  a  member  of  the  solute
            (LDL-R) to help clear the body of LDL ("bad           carrier organic anion transporter family) (14).
            cholesterol).   However,    although    hugely
            successful  in  terms  of  sales  —  Pfizer‘s
            atorvastatin (Lipitor) is the bestselling drug of     Pcsk9 a promise to fulfill
            all time — for many, statins are ineffective or       However, a new class of drugs may change the
            the  side  effects  are  intolerable  (8).  Very  low   face  of  lowering  LDL  cholesterol.  Hoping  to
            levels  of  LDL-C  are  not  achievable  in  the      address this unmet need, the drug development
            majority of patients.                                 pipelines of some biopharmaceutical companies
                                                                  feature  novel  candidates  to  lower  LDL-C.
            There  are  a  number  of  problems  encountered      Perhaps  the  most  eagerly  anticipated  are  the
            clinically with the use of statins; although high-    PCSK9 inhibitors, several of which have been
            potency  statins  provide  reductions  in  LDL        shown to reduce LDL-C levels in clinical trials.
            cholesterol  there  is  considerable  variation
            between  individuals  in  the  response  to  statin
            treatment,  even  when  a  high-potency  statin  is   Cholesterol metabolism
            prescribed: one study estimated that it would be      Before proceeding into the story of PCSK9; we
            necessary to treat to a mean LDL cholesterol of       have  to  go  quickly  through  this  simplified
            1.5–1.6  mmol/L  to  maintain  LDL  cholesterol       review  of  the  main  sources  of  plasma  LDL
            continuously below 2.0 mmol/L (9). Also, poor         cholesterol;  most  cells  in  the  body  have  the
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