AGENTS TO REDUCE LDL (AND FUTURE DEVELOPMENTS) - RAUL D. SANTOS MD, PHD HEART INSTITUTE-INCOR UNIVERSITY OF SAO PAULO BRAZIL

 
AGENTS TO REDUCE LDL (AND FUTURE DEVELOPMENTS) - RAUL D. SANTOS MD, PHD HEART INSTITUTE-INCOR UNIVERSITY OF SAO PAULO BRAZIL
Agents to reduce LDL
(and future developments)
      Raul D. Santos MD, PhD
       Heart Institute-InCor
      University of Sao Paulo
               Brazil
AGENTS TO REDUCE LDL (AND FUTURE DEVELOPMENTS) - RAUL D. SANTOS MD, PHD HEART INSTITUTE-INCOR UNIVERSITY OF SAO PAULO BRAZIL
AGENTS TO REDUCE LDL (AND FUTURE DEVELOPMENTS) - RAUL D. SANTOS MD, PHD HEART INSTITUTE-INCOR UNIVERSITY OF SAO PAULO BRAZIL
Disclosure
• Honoraria for consulting and speaker activities on the
  last year from
  – Amgen, Astra Zeneca, Akcea
  – Biolab, Merck, Novo-Nordisk
  – Pfizer,Kowa
  – Sanofi/Regeneron

                                                           3
AGENTS TO REDUCE LDL (AND FUTURE DEVELOPMENTS) - RAUL D. SANTOS MD, PHD HEART INSTITUTE-INCOR UNIVERSITY OF SAO PAULO BRAZIL
Agents do reduce LDL-C
• Current options
  – Statins
  – Ezetimibe
  – PCSK9 inhibitors
  – Niacin/Resins
  – Lomitapide
  – Mipomersen
• Future options?
  – ATP CL Inhibition

                                     4
AGENTS TO REDUCE LDL (AND FUTURE DEVELOPMENTS) - RAUL D. SANTOS MD, PHD HEART INSTITUTE-INCOR UNIVERSITY OF SAO PAULO BRAZIL
Statins
AGENTS TO REDUCE LDL (AND FUTURE DEVELOPMENTS) - RAUL D. SANTOS MD, PHD HEART INSTITUTE-INCOR UNIVERSITY OF SAO PAULO BRAZIL
Statins: Mechanism of Action
                                HMG-CoA reductase

                       Statins inhibit HMG-CoA reductase
                           Intrahepatic cholesteorl pool reduction

Increment on LDL receptor expression                  Reduction of VLDL production

   Incrementof LDL catabolsim                       Less VLDL particles available to become LDL

                      Reduction of : LDL-C, TC, non-HDL-C and TG
AGENTS TO REDUCE LDL (AND FUTURE DEVELOPMENTS) - RAUL D. SANTOS MD, PHD HEART INSTITUTE-INCOR UNIVERSITY OF SAO PAULO BRAZIL
STELLAR LDL-C
                         (% Changes vs. Baseline)
                           RSV                       ATV                     SIN                PRA

                    10    20     40      10    20     40   80     10   20     40    80    10    20    40
           0

         -10

         -20
                                                                                          -20
                                                                                                -24
         -30                                                     -28
                                                                                                      -30
    %                                                                  -35
         -40                             -37
                                                                              -39
                                               -43
         -50       -46                                                              -46
                     *                               -48
                         -52                               -51
         -60              ** -55
                             ***

                                 *P
AGENTS TO REDUCE LDL (AND FUTURE DEVELOPMENTS) - RAUL D. SANTOS MD, PHD HEART INSTITUTE-INCOR UNIVERSITY OF SAO PAULO BRAZIL
Pravastatin Increases the Removal
     From Plasma of Chylomicron Remnants
                in CHD patients

                     P = 0.01

D%

                 Santos RD et al. Am J Cardiol 2000; 85:1163-6
Impact of 1mmol/L reduction on LDL-C upon major
          cardiovascular events and mortality
                       CTT 2010
                                                Relative Risk (95% CI)

 All cause mortality                         0.90 (0.87-0.93), p
Non-Lipid Lowering Effects of Statins

                       Jain MK, Ridker PM. Nature Rev Drug Discov, 2005
in the rate of major vascular events (coronary deaths,

                                                                                                      Proportional reductio
                               myocardial infarctions, strokes, and coronary

                              Statins: Benefits and Risks
                               revascularisations) during each year (after the first) that it                                 10
                               continues to be taken. Consequently, lowering LDL
 ecause the                    cholesterol by 2 mmol/L reduces risk by about 45%.
surveillance        Panel 4: Known adverse effects of statin therapy
                      • Lowering LDL cholesterol by 2 mmol/L with an effective
   with other       • The  statin regimen
                               only  adverse forevents
                                                 about 5that
                                                          yearshave
                                                                in 10 been
                                                                      000 patients
                                                                            reliablywould
                                                                                     shown to           0
 simvastatin               typically prevent   major  vascular  events in about
                         be caused by statin therapy are myopathy (defined as                              0

gher rate (at              1000 (10%) patients at high risk of heart attacks and                                            M
                         muscle pain or weakness combined with large increases in
                           strokes (eg, secondary prevention) and 500 (5%) patients
 ated yearly)            creatine   kinase    blood   concentrations)     and new-onset
                           at lower  risk (eg, primary   prevention).                           Figure 3: Proportional ma
2
   about one             diabetes mellitus, along with a probable increase in                   cholesterol reductions in
 imen is no           •    Despite reports  based  largely on non-randomised
                         strokes   due to bleeding (ie, haemorrhagic strokes).
                           observational studies, there is not good evidence that statin
                                                                                                no routine statin use and
 f reports of                                                                                   Adapted from CTT Collabor
                    • Typically,      treatment     of  10 000   patients  for 5 years
                           therapy produces beneficial effects on other health outcomes  with a  against the average LDL cho
higher with              standard    statin
                           (eg, cancer,       regimen
                                        infections,       (suchdisease,
                                                    respiratory  as atorvastatin   40. mg
                                                                        arrhythmias)            routine statin therapy versu
pontaneous               daily) would be expected to cause about 5 cases of                     cholesterol reduction great
                                                                                                versus less intensive statin t
sks are still            myopathy, 50–100 new cases of diabetes, and                            cholesterol. The vertical axis
  The rate of       were    adverse    eff ects  on   non-vascular     causes  of death  and     because they represent redu
                         5–10 haemorrhagic         strokes.
n statins are       site-specific cancers. Consequently, data were sought for –log[0·9], –log[0·8], and –lo
                                                79

                    • Despite
                    each            reportstrials
                           of the eligible     basedabout
                                                       largely
                                                             theon  non-randomised
                                                                 baseline   characteristics average      effects on risk obse
  affect their Collins    observational
                    of Reach
                         et al.  Lancetand
                               patient      studies,
                                           2016;       there is good
                                                   388:2532-2561
                                               about   myocardial       evidence that
                                                                     infarctions,        statin treatment (when the risk re
                                                                                    strokes,
                                                                                                      11
Ezetimibe
NPC1L1 Transports Intestinal Cholesterol and
Phytosterols: Inhibition of NPC1L1 by Ezetimibe for
    Hypercholesterolemia and Sitosterolemia

   Cholesterol and
   Plant Sterols

              NPC1L1

        Sitosterolemia
Effects of ezetimibe, simvastatin and simvastatin/ezetimibe on
                pro-atherogenic lipids and apoB

     Farnier M et al. Atherosclerosis 2013; 229:415 - 422    14
Ezetimibe + Statin Trials: SHARP
                                                        and IMPROVE-IT
                                                                                                                IMPROVE-IT
                                                  SHARP
                              30%
                                                                       Statins vs. control
                                                    Intensive             (21 studies)
                              25%
of ischemic events (95% HF)

                                                hypolipidemia
   Relative risk reduction

                                                   treatment
                              20%                                           SHARP
                                                       vs.
                                                 Conventional
                                        (5 studies)                          17%
                              15%                                             risk
                                                                           reduction
                              10%                                    SHARP
                                                                     32mg/dL
                               5%

                               0%
                                    0           10              20   30            40

    Baigent et al. Lancet 2011; 377;2181–2192.
                                                                                             Cannon CP et al. N Engl J Med 2015;372:2387-2397.
                                                                                                                                                 15
Ezetimibe: Side Effects
• Gastro intestinal

                                       16
Antibodies against PCSK9
PCSK9 Promotes Degradation of LDLRs

                                                                                         LDLR
                                       PCSK9                                                       LDL-C
                                                                                         protein

                                       PCSK9 X                                           LDLR
                                                                                         protein
                                                                                                   LDL-C

     LDL-C=low-density lipoprotein cholesterol; LDLR=low-density lipoprotein receptor.

18
Effects of Alirocumab on Lipoptoein Kinetics in Healthy Subjects

Gissette Reyes-Soffer et al. Circulation. 2017;135:352-362
Monoclonal Antibodies: Immunogenicity
                  Potential
           18                                                                               The Journal of Clinical Pharmacology / Vol 57 No 1 2017

                                                                                                               Evolocumab
                                                                                                               Alirocumab
                                                                  Bococizumab

           Figure 4. Evolution of therapeutic monoclonal antibodies. Fully mouse antibodies developed with early hybridoma technology were highly
           immunogenic. Development of recombinant DNA technologies resulted in more humanized and less immunogenic antibodies: chimeric, humanized,
           and fully human.45,46,48

                                                                                                                                                       20
Adaptedconvenience
        from Ito       MK &whoSantos
                   to patients, do not needRD     J Clin
                                            to receive the Pharmacol.        2017;57:7-32
                                                            hypercholesterolemia or HeFH was evaluated     58,65            67,68
Percent Reduction from Baseline in Low-Density Lipoprotein (LDL) Cholesterol
  Levels in the Evolocumab Group, as Compared with the Placebo Group, at
     Weeks 12 and 52, According to Background Lipid-Lowering Therapy.

N=901

         Blom DJ et al. N Engl J Med 2014;370:1809-1819.
Alirocumab Reduces LDL-C in Familial
                            Hypercholesterolemia

John J.P. Kastelein et al. Eur Heart J. 2015;36:2996-3003
After ≥12 weeks of 420 mg           After 12 weeks of 420 mg                   mutations in the apheresis g
                                                                                        evolocumab every month              evolocumab every 2 weeks                   apheresis group) and fewer
                         Long-term                    treatment
                               Value at baseline, mmol/L
                                                                                with        evolocumab
                                                                                      9·35 (3·35)
                                                                                                                          added
                                                                                                                             9·35 (3·35)
                                                                                                                                          to                           LDLR mutations (12 [35%] v
                         conventional
                               Change from baseline, drug    mmol/L therapy,                with or without
                                                                                     –1·77 (2·05)                                   apheresis,
                                                                                                                            –2·57 (2·14)                               reductions in LDL cholestero
                               Percentage change from baseline                      –20·1% (21·7)                         –28·3%(21·1)                                 both at week 12 and 48, we
                         in patients with homozygous familial hypercholesterolaemia:                                                                                   significantly differ from th
                              Data are mean (SD). Data are for 47 patients who were not on apheresis who increased their dosing to every 2 weeks.
                         anp=0·0001
                                interim              subset
                                           for difference              analysis
                                                           between groups                 ofbaseline.
                                                                             in change from    the open-label TAUSSIG study patients who were not on ap
                                                                                                                                                                       testing; appendix). Four pati
                         Frederick
                              TableJ Raal, G Keesof
                                      3: Effect    Hovingh,  Dirk Blom,
                                                     evolocumab        Raul D Santos,
                                                                    uptitration    onMariko                                                                            the frequency of the procedu
                                                                                             Harada-Shiba, Eric Bruckert, Patrick Couture, Handrean Soran, Gerald F Watts,
                                                                                       LDL cholesterol
                         Christopher Kurtz, Narimon Honarpour, Lihua Tang, Sree Kasichayanula, Scott M Wasserman, Evan A Stein
                                                                                                                                                                       monthly or less often, and
                         Summary      60
                                                                                                                                                                       discontinued apheresis. One
                                                                                                                                      LDLR–/– (5%)
                         Background Homozygous familial hypercholesterolaemia is a genetic disorder characterised                                                      apheresis
                                                                                                                                                 by substantially raised                  forEndocrinol
                                                                                                                                                                             Lancet Diabetes     more2017    than 2 yea
                         LDL cholesterol,  †      reduced LDL receptor function, xanthomas, and cardiovascular disease                    *‡      before age 20 years. Published Online
                                      40   *
                         Conventional therapy is with statins, ezetimibe, and apheresis. We aimed to assess the long-term safety and efficacy February 15, 2017
                                                                                                                                                                       began apheresis: one who is
                                       Change from baseline in LDL cholesterol (%)

                                                                                                                                                     PCSK9             withhttp://dx.doi.org/10.1016/
                                                                                                                                                                                a heterozygous genoty
                         of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab in a subset of patients with
                                      20     **                                                                                                    GoF/LDLR                  S2213-8587(17)30044-X
                         homozygous familial hypercholesterolaemia enrolled in an open-label, non-randomised phase 3 trial.
                                                                                                                                                   negative            remained           above goal despite
                                                                                                                                                                             See Online/Comment
                                                        LDLR unclassified (–25%)                        LDLR defective (–20%)                *
                         Methods In                                                               *
                                                                                                                                                    (–65%)             with evolocumab treatment.
                                                                                                                                                                             http://dx.doi.org/10.1016/
                                       0 this interim subset analysis of the TAUSSIG study,              which was undertaken at 35 sites in 17 countries, we S2213-8587(17)30060-8
                         included patients aged     ** 12 years or older with homozygous familial hypercholesterolaemia who
                                                                                                                                                        **
                                                                                                                                                * were on stable LDL   included          in the no apheres
                                                                                                                                                                             Carbohydrate and Lipid
                                                      * *                                                 *                                      *
                         cholesterol-lowering
                                     –20              therapy
                                                         ** * for at least 4 weeks; all patients received
                                                                 *
                                                                                                               ** *evolocumab
                                                                                                                     *
                                                                                                                                   420 mg subcutaneously monthly,      purposes. Research Unit,
                                                                                                                                                                             Metabolism
                         or if on apheresis every 2 weeks. Dosing could be increased to every 2*weeks after 12 weeks in patients not on Faculty of Health Sciences,
                                                                       *                                                                                                  Reductions              in apolipoprotei
                                                                                                                                                                             University of Witwatersrand,
                         apheresis. The primary outcome *of *the TAUSSIG study was treatment-emergent                         *            adverse events; secondary Johannesburg, South Africa
                                    –40                                       * on LDL cholesterol and other lipids. We analysed patients onARH                        cholesterol,            with greater redu
                         outcomes were the effects of evolocumab                                                                                            an intention-     (Prof F J Raal MD); Department
                                                                                  *                                                  *
                         to-treat basis, and all statistical comparisons were done post hoc in this interim analysis. The TAUSSIG studyweek        *     (–15%)          is  of 12. We noted a small re
                                                                                                                                                                                Vascular  Medicine,
                         registered –60with ClinicalTrials.gov, number NCT01624142,    *            and is ongoing.                    *                                     Academisch Medisch Centrum,
                                                                                          *                                               *                            week     12,
                                                                                                                                                                             Amsterdam, with       some additiona
                                                                                                                                                                                             Netherlands
                                                                                                                                                      *
                         Findings–80  106 patients were included in this analysis, 34 receiving apheresis at study                  Apolipoprotein
                                                                                                                                          entry andB 14 younger than   (tableLipidology,
                                                                                                                                                                                 2; appendix).
                                                                                                                                                                             (G K Hovingh PhD); Division of
                                                                                                                                                                                           Department of
                                                                                                                                                                                                               These re
                                                                                                                                         (–47%)
                         18 years. The first patient was enrolled on June 28, 2012, and the cutoff date for the analysis was Aug* 13, 2015; mean                        were not significant in patie
                                                                                                                                                                             Medicine,   University  of Cape
                                                                                                                                                                             Town, Cape Town, South Africa
                         follow-up–100was 1·7 years (SD 0·63). After 12 weeks, mean LDL cholesterol decreased from baseline by 20·6%                                   either       week            12 Heart
                                                                                                                                                                                                           or 48 (po
                                                                                                                                                                             (D Blom   MD); Lipid Clinic
                         (SD 24·4; mean absolute decrease 1·50 mmol/L [SD 1·92]); these reductions were maintained at week 48. Institute (InCor), University of
                         47Figure
                              of 722: LDL
                                       patients     not onchange
                                             cholesterol       apheresis     at studytoentry
                                                                     from baseline        week increased     evolocumab
                                                                                                12, by underlying      geneticdosing     to every 2 weeks, with appendix).
                                                                                                                                 abnormality                            an Sao Paulo Medical   VerySchool
                                                                                                                                                                                                           small red
                         additional     mean     reduction    in  LDL    cholesterol   of 8·3%  (SD   13·0;  mean     absolute    decrease
                            Mean change in LDL cholesterol is shown in parentheses after each genetic abnormality category. GoF=gain of       0·77   mmol/L   [SD      occurred
                                                                                                                                                                    1·38];   Hospital andin      patients
                                                                                                                                                                                             Preventive         with L
                                                                                                                                                                             Medicine Center and
                         p=0·0001).      In  a  post-hoc    analysis,   mean    reductions   in LDL   cholesterol    in  patients   on
                            function. *Apheresis patient. †Patient missed apheresis before week 12 blood draw due to snowstorm. ‡Week 12apheresis     were signifi cant  at
                                                                                                                                                                       bothCardiology
                                                                                                                                                                               alleles,         butHospital
                                                                                                                                                                                                        median redu
                                                                                                                                                                                          Program,
                         week    12 (p=0·0012)
                            immediately                and week
                                             after vacation;        48indiscretion
                                                               dietary    (p=0·0032),    and didARH=autosomal
                                                                                      suspected.   not differ from        reductions
                                                                                                                      recessive         achieved in patients not on Israelita Albert Einstein,
                                                                                                                                  hypercholesterolaemia.
                         apheresis (p=0·38 at week 12 and p=0·09 at week 48). We noted a small reduction (median –7·7% [IQR –21·6 to 6·8])                             –41) Sao
                                                                                                                                                                              atPaulo,
                                                                                                                                                                                    week Brazil
                                                                                                                                                                                                  12 and 67% (–6
                         in lipoprotein(a) at week 12 (p=0·0015), with some additional reduction at week 48 (–11·9% [–28·0 to 0·0];                                    seen(Prof
                                                                                                                                                                               inRpatients
                                                                                                                                                                                     D Santos MD); with   23 PCSK9
Lancet Diabetes Endocrinol  2017 Published
                         p
Evolocumab Reduces Lp(a) in Heterozygous
                 FH
% Change From Baseline

                         Raal F et al. Circulation 2012;126:2408-2417
                                                                        24
Clinical Impact
LDL Cholesterol
                               100                                 Placebo
                               90
                               80
     LDL Cholesterol (mg/dl)

                               70                        59% mean reduction (95%CI 58-60), P
30
                                          (0.3%), and development of neutralizing antibodies                                                          0

                                                                                                            Cu
                                                                                                                                       20                 0      6      12      18          24     30   36
                                          did not occur in any patient.
                                                                                                                                       10

                                                   FOURIER: Study Endpoints
                                                                                                                                        0
                                                          Discussion                                                                        0     6            12        18          24          30     36
                                                                                                                                                                       Months
                                          When added to statin therapy, the PCSK9 inhibi-
  with Cardiovascular Disease
                       tor evolocumab lowered LDL cholesterol levels                                 No. at Risk
                                                                                                     Placebo                           13,780   13,278        12,825   11,871        7610        3690   686
                                by 59% from baseline levels as compared with                            Evolocumab 13,784     13,351    12,939     12,070        7771     3746     689
                                placebo, from a median of 92 mg per deciliter
 d,
                                (2.4 mmol per liter) to 30 mg per deciliter (0.78 B Key Secondary Efficacy End Point
       A Primary Efficacy End Point
up                  100         mmol
                                  16      per liter). This effect was sustained         14.6 with-                  100           11                                               9.9
an                                      Hazard ratio, 0.85 (95% CI, 0.79–0.92)                                                         Hazard ratio, 0.80 (95% CI, 0.73–0.88)
                     90         out
                                  14   evidence     of    attenuation.        In   this   dedicated                  90           10
 ed                                     P
CTTC Regression for the Risk of Major CV Events by Reduction of
            LDL-C Considering Duration of Therapy in Statin and PCSK9i Trials
                                                50%

                                                                                                                          ≥4 years of treatment

              Proportional reduction in major
                                                40%
                                                                                                                          3 years of treatment
                                                                                                                  4S
                  vascular event (95% CI)                                                    HPS
                                                30%                                                                       2 years of treatment
                                                                         WOSCOPS
                                                                                                                          1 year of treatment
                                                                            CARE
                                                20%                                      LIPID
                                                                                                            SPIRE-2 (HR: 0.79, 95% CI: 0.65–0.97)

                                                                                                 FOURIER (HR: 0.79, 95% CI: 0.74–0.84)
                                                10%
                                                  IMPROVE-IT

                                                 0%
                                                                   0.5             1.0                1.5              2.0

                                                -10%
                                                               Reduction in LDL cholesterol (mmol/L)

Ference BA, et al; [published online ahead of print 2017]. European Heart Journal. doi:10.1093/eurheartj/ehx450.
ODYSSEY OUTCOMES:
                                                       Study Design

                         Population                                             Lipid criteria at entry                                                 Primary endpoint
         ••Patients 4-52 weeks post-                                        ••LDL-C ≥70 mg/dL                                              ••Composite of
          ACS                                                               ••OR                                                            – CHD death
         ••Age ≥ 40                                                         ••ApoB ≥80 mg/dL                                                – Nonfatal MI
         ••Optimal statin treatment*                                        ••OR                                                            – Ischemic stroke
                                                                            ••Non-HDL-C ≥100 mg/dL                                          – UA requiring hospitalization

                   Run-in Period                                                             Double-Blind Treatment Period                                                            Post-treatment
                    (up to 16w)                                                                       (~2-5 years)                                                                      follow-up

       Optimize statin; practice self-                                                                                                                                               2 weeks after end
     injection with placebo; complete                                                       Alirocumab 75 mg Q2W until Month 2.                                                        of treatment
         planned revascularization                               n=9,000                    After Month 2, 75 mg or 150 mg Q2W,
                                                                                           adjusted based upon Month 1 LDL-C, in a
                                                                                         blinded fashion to achieve 15
PCSK9 Inhibitors Adverse Events
• Cold like symptoms (not different from placebo)
• Neurocognitive changes not detected in Ebbinghaus
• Diabetes ? (genetic studies suggest)

                                                      30
Other less used medications
Resins /Niacin
• Resins                            • Niacin
  – Colesevelam and colestiramine      –   Reduce FFA input to liver
  – Reduce cholesterol absorption      –   Increase Apo A-I synthesis
    (bile acid binding)                –   Reduce Apo B synthesis
  – Increase LDLR expression           –   Reduce LDL-25-30%
  – Reduce LDL-C 20-25%                –   Reduce TG 20-30%
  – Colestiramine (reduced MI)         –   Increase HDL-C 20-30%
  – Colesevelam (reduces glucose)      –   Isolated use reduce MI
  – Side effects:                      –   Side effects
     • GI                                   • Flushing
     • Reduce drug absorption               • Gout
                                            • Increase glucose

                                                                        32
Drugs for Homozygous FH

                          33
LDL Receptor and Effect of Lipid Lowering Therapies
                              Sridevi                   01/25/18           4 Color Fig: F1        17:42          Art: ATV310675

       2     Arterioscler Thromb Vasc Biol           March 2018

       Figure. Mechanisms involved with low-density lipoprotein cholesterol (LDL-C) lowering by medications approved for homozygous familial
       hypercholesterolemia and their possible associations with LDLR (LDL receptor) expression/function. apoB indicates apolipoprotein B;        AQ10
       HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme reductase; IDOL, inducible degrader of LDL receptor; MTP, microsomal triglyceride trans-
       Santos RD. ATVB 2018 in press
       fer protein; PCSK9, proprotein convertase subtilisin kexin type 9; SREBP2, steroid regulatory element binding protein-2; and VLDL, very-          34
AQ11   low-density lipoprotein.
Drugs Approved for Homozygous FH
 • Lomitapide                                         • Mipomersen
     – Inhibits MTP                                     – ASO inhibits Apo B synthesis
     – Reduces VLDL and LDL                             – Reduces VLDL, LDL and Lp(a)
       production                                         production
     – Reduces LDL-C by 40-50% on                       – Reduces LDL-C 25-30% on top
       top of statins                                     of statins
     – Side effects                                     – Reduces Lp(a) 25-30%
          • Steatosis                                   – Side effects
          • Steatorrhea                                    • Injection site reactions
          • CYP3A4 interaction                             • Flu-like symptoms
                                                           • Steatosis
Cuchel M et al. Lancet 2013; 381:40-46
Raal FJ, Santos RD et al. Lancet. 2010;375:998-1006
Santos RD et al. ATVB. 2015;35:689-99                                                    35
Future Treatments?

                     36
ATP Citrate Lyase Inhibition

      Bempedoic Acid

                               37
Use of Bempedoic acid to treat
       hypercholesterolemia in patients with
                statin intolerance

Thompson P et al. Journal of Clinical Lipidology, 9(3):295-304
Inclisiran Chemical Configuration and Mechanism of
                                    Action.

RNA inhibition
Reduce cholesterol
With 2-3 injections a year?

Khvorova A. N Engl J Med 2017;376:4-7.
Conclusions
• LDL-C is an independent risk factor for atherosclerosis
• There are many proven therapies that reduce LDL-C and
  prevent CVD
• Statins are the cornerstone of LDL-C lowering
• Other drugs should be added to control LDL-C
  adequately (ezetimibe, PCSK9 inhibitors)
  – Cost effectiveness
• Newer medications?
                                                        40
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