Chapter 6. Long-Term Cardiovascular Outcomes with PCSK9 Inhibitors INTRODUCTION LIMITATIONS OF CURRENT MANAGEMENT OF DYSLIPIDAEMIA

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1 Chapter 6 Long-Term Cardiovascular Outcomes with PCSK9 Inhibitors PREMCHAND RAJENDRA KUMAR GEETESH MANIK INTRODUCTION Cardiovascular disease (CVD) is the leading cause of adult mortality and morbidity worldwide and it remains a substantial public health issue with enormous financial impact to global economy. Statins remain the cornerstone of lipid management for both primary and secondary prevention of CVD. A variety of other lipid-modifying therapies are available which can be added to statin therapy to further reduce CV risk. Nowadays, proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors (evolocumab and alirocumab recently approved) appear promising agents with multiple trials demonstrating that these agents in combination with statins or monotherapy can modify lipids substantially with an unprecedented optimal safety profile 1. LIMITATIONS OF CURRENT MANAGEMENT OF DYSLIPIDAEMIA 1. Familial hypercholesterolaemia (FH): Two important challenges in treating FH are underdiagnosis and undertreatment. Underdiagnosis: Familial hypercholesterolaemia is the most common genetic disorder in the world and yet.99% of patients worldwide never receive the diagnosis that would facilitate intensive therapy to reduce their LDL cholesterol; this is largely due to a lack of awareness of the disease and uncertainty about how best to screen for cases. Recent evidence that the prevalence of familial hypercholesterolaemia is more likely to be 1:200 rather than the previously quoted 1:500 exacerbates the magnitude of this problem 2. Undertreatment: Introduction of statins into clinical practice has shown reduction in LDL cholesterol in patients with FH but 79% of patients with heterozygous familial hypercholesterolaemia in the Netherlands did not achieve their goal for LDL cholesterol (,2.5 mmol/l [100 mg/dl]), despite 96% receiving a statin. A second study showed that 81% of patients with familial hypercholesterolaemia did not achieve LDL cholesterol,2.6 mmol/l (100 mg/dl) despite maximal statin treatment plus a second lipidmodifying agent. In general, monotherapy with a statin is not usually sufficient to get a patient with familial hypercholesterolaemia to goal LDL cholesterol and adding further therapies (ezetimibe, a bile acid sequestrant and possibly nicotinic acid or a fibrate) will provide an additional reduction in LDL cholesterol Patients with elevated cardiovascular risk without FH: Many patients with elevated LDL cholesterol (even when not due to familial hypercholesterolaemia) do not achieve LDL cholesterol goals with current treatments. A survey of 9950 high-risk patients with CHD showed that more than half did not achieve LDL cholesterol,1.8 mmol/l (70 mg/dl) either with a statin alone, or with a statin combined with other lipid-modifying agents (Fig. 6-1) Variable LDL response to current therapy: Although high-potency statins provide reductions in LDL cholesterol, there is considerable variation between individuals in response to statin treatment, even when a high-potency statin is prescribed. Poor adherence to statin therapy is common (the majority of patients stop taking their statin within a year) and this is an important cause of the variable therapeutic response. An analysis from the Treating to New Targets trial showed that visit-to-visit variability of LDL cholesterol in statin-treated patients was 45

2 46 SECTION II Preventive Cardiology % achieving LDL-C <70 mg/dl 50% 40% 30% 20% 10% 0% 36% 37% All Statin alone 41% Statin + Ezitimibe 46% Statin + Niacin 35% Statin + Fibrate 20% 20% No statin No lipid modifying therapy Figure 6-1. Low rates of low-density lipoprotein cholesterol goal achievement in patients with coronary artery disease on lipidmodifying therapy (LDL-C, low-density lipoprotein cholesterol). (Based on data presented in: Karalis et al. (2012). Use of lipidlowering medications and the likelihood of achieving optimal LDL cholesterol goals in coronary artery disease patients. Cholesterol, 2012, ) a significant predictor of subsequent events (16% increase in risk for each additional standard deviation increase in LDL cholesterol variability) 4. A number of reports have identified a possible genetic basis for this variable treatment response, although the magnitude of effect of common genetic variants has been questioned 5,6. 4. Intolerance to statins: The incidence of adverse events attributable to statins in randomized clinical trials is low. However, side effects in muscle occurred in up to 29% of statin-treated patients in observational studies, presenting a potential barrier to treatment. A switch to a different agent in the same class, or to a lower statin dose as part of a combination regimen, helps most patients to remain on statin-based therapy. Pharmacogenetic studies have detected a gene that may identify patients at risk of statin-induced myopathy (SLCO1B1, a member of the solute carrier organic anion transporter family) 7. PCSK9 AND PATHOPHYSIOLOGY OF CHOLESTEROL METABOLISM Most cells in the body have the capacity to synthesize cholesterol. However, the majority of circulating LDL cholesterol is synthesized in the liver, by HMG-CoA reductase and the principal means of removal of LDL cholesterol from the circulation is via a family of hepatic LDL receptors 8. Current therapies are targeted at reducing the rate of cholesterol biosynthesis (the main effect of statins) or reducing the rate of absorption of cholesterol into the circulation (ezetimibe, bile acid sequestrants or plant sterols/stanols) derived from food and/or from bile (Fig. 6-2). PCSK9 inhibition is a novel therapeutic concept based on reduction of plasma LDL cholesterol through increased hepatic clearance. The binding of the PCSK9 protein to the LDL receptor increases the probability of the LDL receptor then being diverted to a lysosome, where it is degraded, rather than being recycled to the cell membrane as usual. A number of mutations and polymorphisms of the PCSK9 gene have been identified, which support its importance in the regulation of LDL cholesterol (Table 1). Common loss-of-function mutations in PCSK9 in humans are associated with lower LDL cholesterol and a reduced frequency of adverse cardiovascular events as reported in various studies. About 2.6% of black subjects in the Atherosclerosis Risk in Communities (ARIC) study in the USA had a nonsense (loss of function) mutation in the PCSK9 gene (0.8% for the Y142X allele and 1.8% for the C679X allele). Their mean LDL cholesterol was reduced by 28% (P 5.008) versus noncarriers of these mutations, and this was associated with an 88% lower risk of coronary heart disease (age-and gender-adjusted hazard ratio [HR] 0.11 [95% CI, ]; P 5.03) 9. About 2.6% of 45,699 subjects pooled from three observational studies in Denmark had the R46L loss of function mutation of PCSK9; a reduction in LDL cholesterol of 11% 16% was associated with a 30% reduction in the risk of ischaemic heart disease for carriers versus noncarriers. The improvement in cardiovascular outcomes was larger than predicted by the reduction in LDL cholesterol, which the authors attributed to the PCSK9 genotype being a better predictor of lower

3 Chapter 6 Long-Term Cardiovascular Outcomes with PCSK9 Inhibitors 47 By inhibitin HMG-CoA reductase and decreasing intracellular cholesterol, statins upregulate LDL receptors and LDL clearance Statin Cholesterol precursors HMG-CoA reductase Cholesterol Triglyceride B100 VLDL B100 LDL B100 PCSK9 PCSK9 tags LDL receptor, resulting in its degradation in the lysosome PCSK9 B100 PCSK9 B100 Without PCSK9 attached, the LDL receptor is recycled to the cell surface, and can continue to clear LDL particles Anti-PCSK9 antibody binds to PCSK9, preventing it from binding to the LDL receptor B100 apolipoprotein-b100 PCSK9 proprotein convertase subtilisin/kexin type 9 LDL low-density lipoprotein VLDL very low-density lipoprotein Figure 6-2. PCSK9 and pathophysiology of cholesterol metabolism (B100, apolipoprotein-b100; HMG-CoA reductase, 3-hydroxy- 3-methyl-glutaryl-coenzyme A reductase; LDL, low-density lipoprotein; PCSK9, proprotein convertase subtilisin kexin type 9; VLDL, very low density lipoprotein). (Reproduced from: Page, M. M., & Watts, G. F. (2016). PCSK9 inhibitors mechanisms of action. Australian Prescriber, 39, DOI: /austprescr ; National Prescribing Service Ltd., reproduced with permission.) TABLE 6-1 EXAMPLES OF POLYMORPHISMS OF PCSK9 THAT INFLUENCE CIRCULATING LEVELS OF LDL-C 11 Mutation S127R P216L D374Y D37Y 1 N157K (double mutation) C( 161)T Y142X L108R D35Y R46L C679X Effect on PCSK9 Activity Gain of function (resulting in fewer LDL receptors and higher LDL cholesterol) Loss of function (resulting in more LDL receptors and lower LDL cholesterol) lifetime LDL cholesterol levels than a point measurement of LDL cholesterol made in adulthood 10. These observations have fuelled considerable interest among researchers in cardiovascular medicine in the prospect of pharmacological inhibition of PCSK9 as a therapeutic strategy for the management of dyslipidaemia and cardiovascular risk. CLINICAL EXPERIENCE WITH PCSK9 INHIBITORS The most extensively studied of these PCSK9 inhibitors are the subcutaneously administered, either fully human or humanized, PCSK9 MoAbs. Multiple trials have been conducted with these agents, which principally involve alirocumab (Sanofi/Regeneron), bococizumab (Pfizer the SPIRE trial programme) and evolocumab (Amgen). Alirocumab and evolocumab are currently USFDA approved. One-year evaluation of evolocumab demonstrates the marked reductions in LDL-C that result from PCSK9 inhibition, irrespective of the nature of background lipid-modifying therapy (Fig. 6-3) 12. Mean reductions from baseline in LDL-C approaching 50%, or greater, were seen in patients on background diet therapy, low- or high-intensity statin treatment, or high-intensity statin plus ezetimibe. A reduction in

4 48 SECTION II Preventive Cardiology Mean placebo-subtracted treatment difference at 52 weeks % -62% -57% -49% Mean LDL-C (mg/dl) Placebo, baseline Placebo, 52 weeks Evolocumab, baseline Evolocumab, 52 weeks None Atorva 10 mg Atorva 80 mg Atorva 80 mg + Ezetimibe 10 mg Figure 6-3. Substantial reductions in low-density lipoprotein cholesterol with evolocumab irrespective of background intensity of lipid-modifying therapy (LDL-C, low-density lipoprotein cholesterol). (Based on data presented in: Blom et al. (2014). A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. New England Journal of Medicine, 370, ) LDL cholesterol of comparable magnitude was seen in a phase III study in which alirocumab was compared with ezetimibe in patients with hypercholesterolaemia (Fig. 6-4) 13. The results of other phase III studies with evolocumab and alirocumab, the most advanced agents in therapeutic development, are shown in Table 6-2. Other agents in development include MPSK3169A (Genentech), RG7652 (Genentech), ALN-PC502 (Alnylam), BMS (Bristol-Myers Squibb/Adnexus), ISIS (Isis), SPC 4061 (Santaris) and SX-PCK9 (Serometrix). Most are monoclonal antibodies or oligonucleotides and thus require subcutaneous injection by patients. Mean change in LDL-C (%) Alirocumab 47.2 Ezetimibe % (P <0.0001) Figure 6-4. Effects of 24 weeks of treatment with alirocumab versus ezetimibe on low-density lipoprotein cholesterol in patients with hypercholesterolaemia (LDL-C, low-density lipoprotein cholesterol). (Based on data presented in: Roth et al. (2014). Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. International Journal of Cardiology, 176, ) PCSK9 inhibition induced marked reductions in LDL cholesterol in people with familial hypercholesterolaemia or hypercholesterolaemia due to another cause. In addition, treatment with a PCSK9 inhibitor was effective in dyslipidaemic patients receiving background intensive lipid management with a statin, with or without other lipid-modifying therapies. The MENDEL-2 study also showed that PCSK9 inhibition was effective in reducing levels of ApoB and non-hdl cholesterol, and the ratio of ApoB to ApoAI, in addition to LDL cholesterol (Fig. 6-5) 18. Significant reductions in the level of the atherogenic lipoprotein Lp(a) also occurred. HDL cholesterol increased significantly, in parallel with modest decrease in levels of triglycerides and very low density lipoprotein (VLDL) cholesterol, depending on the dosing regimen. EFFECT OF PCSK9 INHIBITORS ON CARDIOVASCULAR OUTCOMES The substantial lowering of LDL-C by PCSK9 inhibitors holds considerable therapeutic promise for improving long-term cardiovascular prognosis in high-risk patients. Large, randomized outcomes studies with these agents are underway and results of few have been recently published Table 3. Recently published data from FOURIER trial showed that at 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per decilitre (2.4 mmol per litre) to 30 mg per decilitre (0.78 mmol per litre) (P,.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point

5 Chapter 6 Long-Term Cardiovascular Outcomes with PCSK9 Inhibitors 49 TABLE 6-2 IMPORTANT PHASE III STUDIES WITH PCSK9 INHIBITORS Drug (Study) Patient Population n, Duration Effect on LDL-C Evolocumab (DESCARTES) 12 Alirocumab 13 patients with a range of cardiovascular risks and a range of LDL-C lowering therapies patients at moderate cardiovascular risk not receiving statins or other lipid-lowering therapy 901, 52 weeks D 257.0% vs. placebo 103, 24 weeks D 247.0% with alirocumab vs % placebo Evolocumab (TESLA-B) 14 Homozygous FH 49, 12 weeks D 230.9% vs. placebo Evolocumab (RUTHER- FORD-2) 15 Heterozygous FH 331, 12 weeks D 259% to 266% vs. placebo for 2-weekly or monthly administration Evolocumab (LAPLACE-2) 16 HC 2067, 12 weeks D 263% to 275% vs. placebo for 2-weekly or monthly administration Evolocumab (GAUSS-2) 17 Statin-intolerant 307, 12 weeks D 263% to 275% vs. placebo, D 237% to 239% vs. ezetemibe, 2-weekly or monthly administration Evolocumab (MENDEL-2) 18 Alirocumab (each at ODYSSEY-COMBO II) 19 Alirocumab (ODYSSEY FH I and II) 20 HC not previously on drug treatment High CV risk on maximal statin therapy Heterozygous FH on maximal statin 614, 12 weeks D 255% to 257% vs. placebo, D 238% to 240% vs. ezetemibe, 2-weekly or monthly administration 707, 104 weeks D 251% vs. baseline, D 230% vs. ezetimibe 2-weekly or monthly administration 486, 78 weeks; D 258% vs. ezetimibe; D 251% vs. ezetimibe 249, 78 weeks P <0.001 P <0.001 % achieving LDL-C <70 mg/dl % P < % 71.3% 1.3% 0% 2.8% P < mg every 2 weeks 420 mg once every month Placebo (n=76) Ezetimibe (n=77) Evolocumab (n=153) Evolocumab dosing regimen Figure 6-5. Proportions of patients achieving low-density lipoprotein cholesterol,70 mg/dl in the MENDEL-2 study (LDL-C, low-density lipoprotein cholesterol). (Based on data presented in: Koren et al. (2014). Anti-PCSK9 monotherapy for hypercholesterolemia: The MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. Journal of the American College of Cardiology, 63, ) (1344 patients [9.8%] vs patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], ; P,.001) and the key secondary end point (816 [5.9%] vs [7.4%]; hazard ratio, 0.80; 95% CI, ; P,.001). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection site reactions, which were more common with evolocumab (2.1% vs. 1.6%) 22. Bococizumab, a humanized monoclonal antibody was studied in two parallel, multinational trials (SPIRE 1/2) with different entry criteria for LDL cholesterol levels in two parallel run multinational trials (150 mg SC twice a week vs. placebo). The trials were stopped early after the sponsor

6 50 SECTION II Preventive Cardiology TABLE 6-3 CLINICAL OUTCOME TRIALS OF PCSK9 INHIBITORS 21 Trial Name Study Drug Patient Population FOURIER NCT ODYSSEY OUTCOMES NCT SPIRE-1 NCT SPIRE-2 NCT Evolocumab (140 mg every 2 weeks or 420 mg monthly) Alirocumab Bococizumab Bococizumab n 5 27,564; history of CVD at high risk of recurrent event; LDL-C 70 mg/dl or non- HDL-C 100 mg/dl; background statin therapy n 5 18,000; acute coronary syndrome,52 weeks earlier; LDL-C 70 mg/dl or non- HDL-C 100 mg/dl; background statin therapy n 5 17,000; high risk of CVD event, primary and secondary prevention; background lipidlowering treatment; LDL-C mg/dl or non-hdl-c mg/dl n ; high risk of CVD event; background lipid-lowering treatment; LDL-C 100 mg/dl or non- HDL-C 130 mg/dl Primary Outcome Measure Follow-Up Result Time to cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, or coronary revascularization Time to cardiovascular death, nonfatal myocardial infarction, hospitalization for unstable angina, or stroke Time to composite major cardiovascular event (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and hospitalization for unstable angina) Time to composite major cardiovascular event (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and hospitalization for unstable angina) 2.2 years 259 %; Sig ( primary end points (P,.05) 64 months Ongoing 10 months (prematurely stopped antidrug antibody formation) 10 months (prematurely stopped antidrug antibody formation) 256 %; NS (P 5.94) 256 %; S (P 5.02) elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the programme. At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of 56.0% in the bococizumab group and 12.9% in the placebo group, for a between-group difference of 59.0 % (P,.001). In the lower risk, shorter duration trial (in which the patients had a baseline LDL cholesterol level of 70 mg per decilitre [1.8 mmol per litre] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], ; P 5.94). In the higher risk, longer duration trial (in which the patients had a baseline LDL cholesterol level of 100 mg per decilitre [2.6 mmol per litre] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, ; P 5.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, ; P 5.08). Injection site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P,.001) 23. An exploratory analysis (pooled analysis of the randomized OSLER-1 and OSLER-2 trials) evaluated the effects of evolocumab on cardiovascular outcomes (Fig. 6-6). The addition of evolocumab versus standard care alone reduced the incidence of a prespecified composite of adjudicated cardiovascular outcomes over a median follow-up of 11 months. LONG-TERM SAFETY PROFILE OF PCSK9 INHIBITORS Long-term safety data are available from the OSLER trials (Table 6-4) with evolocumab (n , median follow-up 11.1 months) and ODYSSEY LONG TERM (Fig. 6-7) with alirocumab (n , 78-week treatment duration). In both reports, adverse events were reported with similar frequency with the PCSK9 inhibitor compared with the comparator (standard

7 Chapter 6 Long-Term Cardiovascular Outcomes with PCSK9 Inhibitors 51 Cardiovascular event rate at 1 year (%) Hazard ratio 0.47 (96% confidence interval ) (P=0.003) 2.18% 0.95% 0 Standard care Evolocumba 120 mg Q2W or 420 mg QM + standard care Figure 6-6. Effect of evolocumab on cardiovascular outcomes in a pooled analysis of the OSLER-1 and OSLER-2 trials. (Based on data presented in: Sabatine et al. (2015). Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. New England Journal of Medicine, 372, ) TABLE 6-4 SUMMARY OF ADVERSE EVENT (AE) DATA (%) FOR EVOLOCUMAB IN OSLER STUDY OSLER Evolocumab Any adverse event Adverse event leading to 2.4 NA discontinuation Injection site reactions 4.3 NA Muscle-related AE Standard of Care of care in OSLER vs. evolocumab, and placebo in ODYSSEY LONG TERM versus alirocumab) 24,25. In FOURIER trial, there was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection site reactions, which were more common with evolocumab (2.1% vs. 1.6%). NEWER PCSK9 INHIBITORS (GENE SILENCER) Fitzgerald et al. reported that inclisiran, a longacting RNA interference (RNAi) therapeutic inhibitor of PCSK9, is safe and effective in the lowering of low-density lipoprotein (LDL) cholesterol among healthy volunteers. The advantage of inclisiran is sustained suppression of PCSK9 and LDL cholesterol for at least 6 months, which allows for twiceyearly administration. In the recently published ORION-1 phase II, multicentre, double-blind study, multiple-ascending-dose % 82.5% Alirocumab (n=1550) Placebo (n=788) % patients Any AE 7.2% 5.8% AE leading to discontinuation 10.1% 9.5% General allergic reaction 5.9% 4.2% 5.4% 2.9% 4.2% 4.4% Local injection site reaction Myalgia Neurologic event Figure 6-7. Tolerability profile in the ODYSSEY LONG-TERM trial: adverse events of interest (AE, adverse events). (Based on data presented in: Robinson, J. G., et al. (2015). Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. New England Journal of Medicine, 372, )

8 52 SECTION II Preventive Cardiology trial of inclisiran administered as a subcutaneous injection in patients at high risk for CVD who had elevated LDL cholesterol levels 26. Patients were randomly assigned to receive a single dose of placebo or 200, 300 or 500 mg of inclisiran or two doses (at days 1 and 90) of placebo or 100, 200 or 300 mg of inclisiran. A total of 501 patients underwent randomization. Patients who received inclisiran had dose-dependent reductions in PCSK9 and LDL cholesterol levels. At day 180, the least-squares mean reductions in LDL cholesterol levels were 27.9% 41.9% after a single dose of inclisiran and 35.5% 52.6% after two doses (P,.001 for all comparisons vs. placebo). The two-dose 300-mg inclisiran regimen produced the greatest reduction in LDL cholesterol levels: 48% of the patients who received the regimen had an LDL cholesterol level below 50 mg per decilitre (1.3 mmol per litre) at day 180. At day 240, PCSK9 and LDL cholesterol levels remained significantly lower than at baseline in association with all inclisiran regimens. Serious adverse events occurred in 11% of the patients who received inclisiran and in 8% of the patients who received placebo. Injection site reactions occurred in 5% of the patients who received injections of inclisiran. SUMMARY (KEY POINTS) 1. Familial hypercholesterolaemia is the most common genetic disorder in the world and yet.99% of patients worldwide never receive the diagnosis that would facilitate intensive therapy to reduce their LDL cholesterol. 2. Reducing the activity or expression of PCSK9 increases the number of LDL receptors, which reduces circulating LDL cholesterol. 3. PCSK9 inhibitors reduced LDL cholesterol by.50% in randomized trials in patients with hypercholesterolaemia. 4. Preliminary data from the ODYSSEY study suggest a reduced frequency of adverse cardiovascular outcomes associated with a PCSK9 inhibitor in patients with hypercholesterolaemia. 5. PCSK9 inhibitors have been generally well tolerated in clinical trials. 6. The main side effects associated with these agents are injection site reactions, which is unsurprising for an injectable treatment. 7. The tolerability and safety profiles of these agents so far support long-term administration for lifelong conditions such as hypercholesterolaemia. 8. Current indications of PCSK9 inhibitors: People with familial hypercholesterolaemia, people with statin, people at high cardiovascular risk who are not at their LDL cholesterol goal. 9. Inclisiran, RNAi of PCSK9, is relatively safe and effective in reducing LDL cholesterol. References 1. Centers for Disease Control and Prevention, Heart Disease facts and statistics (2013). (2015). Deaths: Final data for National Vital Statistics Report, 64(2). 2. Nordestgaard, B. G., Chapman, M. J., Humphries, S. E., Ginsberg, H. N., Masana, L., & Descamps, O. S., et al. (2013). Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: Guidance for clinicians to prevent coronary heart disease: Consensus statement of the European Atherosclerosis Society. European Heart Journal, 34, a. 3. Karalis, D. G., Victor, B., Ahedor, L., & Liu, L. (2012). Use of lipid-lowering medications and the likelihood of achieving optimal LDL cholesterol goals in coronary artery disease patients. Cholesterol, 2012, Bangalore, S., Breazna, A., DeMicco, D. A., Wun, C. C., & Messerli, F. H. (2015). Visit-to-visit low-density lipoprotein cholesterol variability and risk of cardiovascular outcomes: Insights from the TNT Trial. Journal of the American College of Cardiology, 65, Bandolier. Patient compliance with statins. bandolier.org.uk/booth/cardiac/patcomp.html Accessed 20th October Mann, D. M., Glazer, N. L., Winter, M., Paasche-Orlow, M. K., Muntner, P., Shimbo, D., et al. (2013). A pilot study identifying statin nonadherence with visitto-visit variability of low-density lipoprotein cholesterol. American Journal of Cardiology, 111, Hopewell, J. C., Reith, C., & Armitage, J. (2014). Pharmacogenomics of statin therapy: Any new insights in efficacy or safety? Current Opinion in Lipidology, 25, Go, G. W., & Mani, A. (2012). Low-density lipoprotein receptor (LDLR) family orchestrates cholesterol homeostasis. Yale Journal of Biology and Medicine, 85, Cohen, J. C., Boerwinkle, E., Mosley, T. H. Jr., & Hobbs, H. H. (2006). Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. New England Journal of Medicine, 354, Benn, M., Nordestgaard, B. G., Grande, P., Schnohr, P., & Tybjaerg-Hansen, A. (2010). PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. Journal of the American College of Cardiology, 55, De Castro-Orós, I., Pocoví, M., & Civeira, F. (2010). The genetic basis of familial hypercholesterolemia: Inheritance, linkage, and mutations. Application of Clinical Genetics, 3, Blom, D. J., Hala, T., Bolognese, M., Lillestol, M. J., Toth, P. D., Burgess, L., et al. (2014). A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. New England Journal of Medicine, 370,

9 Chapter 6 Long-Term Cardiovascular Outcomes with PCSK9 Inhibitors Roth, E. M., Taskinen, M. R., Ginsberg, H. N., Kastelein, J. J., Colhoun, H. M., Robinson, J. G., et al. (2014). Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: Results of a 24 week, double-blind, randomized Phase 3 trial. International Journal of Cardiology, 176, Raal, F. J., Honarpour, N., Blom, D. J., Hovingh, G. K., Xu, F., Scott, R., et al. (2014). Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): A randomised, double-blind, placebo-controlled trial. Lancet, 385(9965), Raal, F. J., Stein, E. A., Dufour, R., Turner, T., Civeira, F., Burgess, L., et al. (2014). PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): A randomised, double-blind, placebo-controlled trial. Lancet, 385 (9965), Robinson, J. G., Nedergaard, B. S., Rogers, W. J., Fialkow, J., Neutel, J. M., Ramstad, D., et al. (2014). Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: The LAPLACE-2 randomized clinical trial. JAMA, 311, Stroes, E., Colquhoun, D., Sullivan, D., Civeira, F., Rosenson, R. S., Watts, G. F., et al. (2014). Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: The GAUSS-2 randomized, placebocontrolled phase 3 clinical trial of evolocumab. Journal of the American College of Cardiology, 63, Koren, M. J., Lundqvist, P., Bolognese, M., Neutel, J. M., Monsalvo, M. L., Yang, J., et al. (2014). Anti-PCSK9 monotherapy for hypercholesterolemia: The MEN- DEL-2 randomized, controlled phase III clinical trial of evolocumab. Journal of the American College of Cardiology, 63, Cannon, C. P., Cariou, B., Blom, D., McKenney, J. M., Lorenzato, C., Pordy, R., et al. (2015). Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolemia on maximal tolerated daily statin: Results from the ODYSSEY COMBO II study. European Heart Journal, 36(19), Kastelein JJ, Ginsberg HN, Langslet G, et al. (2015). ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J, 36, Stoekenbroek, R. M., Kastelein, J. J., & Huijgen, R. (2015). PCSK9 inhibition: The way forward in the treatment of dyslipidemia. BMC Medicine, 13, 258. doi: /s Sabatine, M. S., Giugliano, R. P., Keech, A. C., Honarpour, N., Wiviott, S. D., Murphy, S. A., et al. (2017). Evolocumab and clinical outcomes in patients with cardiovascular disease. New England Journal of Medicine, 376, Ridker, P. M., Revkin, J., Amarenco, P., Brunell, R., Curto, M., Civeira, F., et al (2017). Cardiovascular efficacy and safety of bococizumab in high-risk patients. New England Journal of Medicine, 376, Sabatine, M. S., Giugliano, R. P., Wiviott, S. D., Raal, F. J., Blom, D. J., Robinson, J., et al. (2015). Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. New England Journal of Medicine, 372, Robinson, J. G., Farnier, M., Krempf, M., Bergeron, J., Luc, G., Averna, M., et al. (2015). Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. New England Journal of Medicine, 372, Ray, K. K., Landmesser, U., Leiter, L. A., Kallend, D., Dufour, R., Karakas, M., et al. (2017). Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. New England Journal of Medicine, 376,

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