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      Modern Lipid Management: A Literature Review

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          Abstract

          Pro-protein convertase subtilisin/Kexin type 9 (PCSK9) inhibitors are relatively new, non-statin, lipid-lowering drugs that reduce low-density lipoprotein cholesterol (LDL-C) by 60%. PCSK9 inhibitors reduce the blood concentrations of cholesterol by the degradation of LDL receptors, which subsequently extracts cholesterol from cells. This leads to cardiovascular risk reduction in various at-risk populations, including atherosclerotic coronary artery disease. Despite their promise for advanced lipid-lowering ability, cost-effectiveness is a barrier to their routine use. While searching PubMed, we extracted land-mark trials on two of the anti-PCSK9 monoclonal antibodies, alirocumab and evolocumab. When combined with statins or ezetimibe, they show an exponential fall in LDL-C levels, helping achieve target values in high-risk populations and decreasing cardiovascular adverse events. Ongoing research is exploring the long-term efficacy of these antibodies in established coronary artery disease and familial hypercholesterolemia with more prospects for this novel lipid-lowering therapy.

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          ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia

          John Kastelein, Henry N Ginsberg, Gisle Langslet … (2015)
          Aims To assess long-term (78 weeks) alirocumab treatment in patients with heterozygous familial hypercholesterolaemia (HeFH) and inadequate LDL-C control on maximally tolerated lipid-lowering therapy (LLT). Methods and results In two randomized, double-blind studies (ODYSSEY FH I, n = 486; FH II, n = 249), patients were randomized 2 : 1 to alirocumab 75 mg or placebo every 2 weeks (Q2W). Alirocumab dose was increased at Week 12 to 150 mg Q2W if Week 8 LDL-C was ≥1.8 mmol/L (70 mg/dL). Primary endpoint (both studies) was percentage change in calculated LDL-C from baseline to Week 24. Mean LDL-C levels decreased from 3.7 mmol/L (144.7 mg/dL) at baseline to 1.8 mmol/L (71.3 mg/dL; −57.9% vs. placebo) at Week 24 in patients randomized to alirocumab in FH I and from 3.5 mmol/L (134.6 mg/dL) to 1.8 mmol/L (67.7 mg/dL; −51.4% vs. placebo) in FH II (P < 0.0001). These reductions were maintained through Week 78. LDL-C <1.8 mmol/L (regardless of cardiovascular risk) was achieved at Week 24 by 59.8 and 68.2% of alirocumab-treated patients in FH I and FH II, respectively. Adverse events resulted in discontinuation in 3.4% of alirocumab-treated patients in FH I (vs. 6.1% placebo) and 3.6% (vs. 1.2%) in FH II. Rate of injection site reactions in alirocumab-treated patients was 12.4% in FH I and 11.4% in FH II (vs. 11.0 and 7.4% with placebo). Conclusion In patients with HeFH and inadequate LDL-C control at baseline despite maximally tolerated statin ± other LLT, alirocumab treatment resulted in significant LDL-C lowering and greater achievement of LDL-C target levels and was well tolerated. Clinical trial registration Cinicaltrials.gov (identifiers: NCT01623115; NCT01709500).
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            Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab.

            Gerald F M Watts, Michael Rocco, David Sullivan … (2014)
            This study sought to evaluate the efficacy and safety of subcutaneous evolocumab compared with oral ezetimibe in hypercholesterolemic patients who are unable to tolerate effective statin doses. Statin intolerance, which is predominantly due to muscle-related side effects, is reported in up to 10% to 20% of patients. Evolocumab, a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), demonstrated marked reductions in plasma low-density lipoprotein cholesterol (LDL-C) in a phase 2 study in statin-intolerant patients. The GAUSS-2 (Goal Achievement after Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects) trial was a 12-week, double-blind study of randomized patients (2:2:1:1) to evolocumab 140 mg every two weeks (Q2W) or evolocumab 420 mg once monthly (QM) both with daily oral placebo or subcutaneous placebo Q2W or QM both with daily oral ezetimibe 10 mg. Co-primary endpoints were percent change from baseline in LDL-C at the mean of weeks 10 and 12, and at week 12. Three hundred seven patients (age 62 ± 10 years; LDL-C 193 ± 59 mg/dl) were randomized. Evolocumab reduced LDL-C from baseline by 53% to 56%, corresponding to treatment differences versus ezetimibe of 37% to 39% (p <0.001). Muscle adverse events occurred in 12% of evolocumab-treated patients and 23% of ezetimibe-treated patients. Treatment-emergent adverse events and laboratory abnormalities were comparable across treatment groups. Robust efficacy combined with favorable tolerability makes evolocumab a promising therapy for addressing the largely unmet clinical need in high-risk patients with elevated cholesterol who are statin intolerant. (Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-2; NCT01763905). Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
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              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.

              Jennifer Robinson, Bettina S Nedergaard, William J Rogers … (2014)
              In phase 2 studies, evolocumab, a fully human monoclonal antibody to PCSK9, reduced LDL-C levels in patients receiving statin therapy. To evaluate the efficacy and tolerability of evolocumab when used in combination with a moderate- vs high-intensity statin. Phase 3, 12-week, randomized, double-blind, placebo- and ezetimibe-controlled study conducted between January and December of 2013 in patients with primary hypercholesterolemia and mixed dyslipidemia at 198 sites in 17 countries. Patients (n = 2067) were randomized to 1 of 24 treatment groups in 2 steps. Patients were initially randomized to a daily, moderate-intensity (atorvastatin [10 mg], simvastatin [40 mg], or rosuvastatin [5 mg]) or high-intensity (atorvastatin [80 mg], rosuvastatin [40 mg]) statin. After a 4-week lipid-stabilization period, patients (n = 1899) were randomized to compare evolocumab (140 mg every 2 weeks or 420 mg monthly) with placebo (every 2 weeks or monthly) or ezetimibe (10 mg or placebo daily; atorvastatin patients only) when added to statin therapies. Percent change from baseline in low-density lipoprotein cholesterol (LDL-C) level at the mean of weeks 10 and 12 and at week 12. Evolocumab reduced LDL-C levels by 66% (95% CI, 58% to 73%) to 75% (95% CI, 65% to 84%) (every 2 weeks) and by 63% (95% CI, 54% to 71%) to 75% (95% CI, 67% to 83%) (monthly) vs placebo at the mean of weeks 10 and 12 in the moderate- and high-intensity statin-treated groups; the LDL-C reductions at week 12 were comparable. For moderate-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 115 to 124 mg/dL to an on-treatment mean of 39 to 49 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 123 to 126 mg/dL to an on-treatment mean of 43 to 48 mg/dL. For high-intensity statin groups, evolocumab every 2 weeks reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 35 to 38 mg/dL; monthly evolocumab reduced LDL-C from a baseline mean of 89 to 94 mg/dL to an on-treatment mean of 33 to 35 mg/dL. Adverse events were reported in 36%, 40%, and 39% of evolocumab-, ezetimibe-, and placebo-treated patients, respectively. The most common adverse events in evolocumab-treated patients were back pain, arthralgia, headache, muscle spasms, and pain in extremity (all <2%). In this 12-week trial conducted among patients with primary hypercholesterolemia and mixed dyslipidemia, evolocumab added to moderate- or high-intensity statin therapy resulted in additional LDL-C lowering. Further studies are needed to evaluate the longer-term clinical outcomes and safety of this approach for LDL-C lowering. clinicaltrials.gov Identifier: NCT01763866.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cureus
                Journal ID (iso-abbrev): Cureus
                Journal ID (issn): 2168-8184
                Title: Cureus
                Publisher: Cureus (Palo Alto (CA) )
                ISSN (Electronic): 2168-8184
                Publication date (Electronic, pub): 24 July 2020
                Publication date (Electronic, collection): July 2020
                Volume: 12
                Issue: 7
                Electronic Location Identifier: e9375
                Affiliations
                [1 ] Cardiology, Rawalpindi Institute of Cardiology, Rawalpindi, PAK
                [2 ] Hematology and Medical Oncology, Fauji Foundation Hospital, Rawalpindi, PAK
                [3 ] Internal Medicine, KRL Hospital, Islamabad, PAK
                Author notes
                Article
                DOI: 10.7759/cureus.9375
                PMC ID: 7444996
                PubMed ID: 32850243
                SO-VID: 98c3877d-964f-479c-9284-fd6b8de289a2
                Copyright © Copyright © 2020, Malik et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 13 July 2020
                Date accepted : 24 July 2020
                Categories
                Subject: Cardiology
                Subject: Allergy/Immunology
                Subject: Epidemiology/Public Health

                Keywords: pcsk9 inhibitors,hyperlipidemia,atherosclerosis,coronary artery disease,hypercholesterolemia,ldl-c,alirocumab,evolocumab
                Data availability:
                Keywords: pcsk9 inhibitors, hyperlipidemia, atherosclerosis, coronary artery disease, hypercholesterolemia, ldl-c, alirocumab, evolocumab

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