Dyslipidemia is an elevation of plasma cholesterol, triglycerides, or both, or a low HDL cholesterol level that contributes to the development of atherosclerosis. Elevated levels of low‐density lipoprotein cholesterol (LDL‐C) are well established to be associated with the development of atherosclerotic cardiovascular disease (ASCVD) 1.
Limitations of currently available therapies
Statin therapy is the first‐line lipid‐lowering therapy for the management of dyslipidemia. Statins bring about a reduction in low‐density lipoprotein cholesterol (LDL-C) but are associated with a few side effects, including early onset of diabetes. Some patients with high cardiovascular risk either do not achieve adequate low‐density lipoprotein cholesterol (LDL-C) reductions on statins, or are intolerant to statins and therefore receive suboptimal doses or discontinue statin therapy, and thus remain at increased risk of cardiovascular events. For such patients, additional and/or alternative non-statin lipid-lowering treatment is required.
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History and mechanism of action of PCSK9 inhibitors
In 2003, Nabil Seidah and group from Montreal identified PCSK9 to be encoded by a gene on Chromosome. In the same year, the involvement of PCSK9 in regulating cholesterol metabolism became evident, with the identification of two gain-of-function mutations in PCSK9, in two French families with a clinical diagnosis of ADH and no detectable mutations in LDLR or apoB100 genes3.
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PCSK9 belongs to the group proprotein convertases made by the hepatocytes of liver, which regulates the cellular uptake and recycling of LDL receptor and promotes LDL receptor degradation and in turn, increases the removal of LDL receptors from the surface of liver cells leading to hypercholesterolemia4. PCSK9 inhibitors are monoclonal antibodies, which bind to and inactivate PCSK9 enzyme in the liver thus regulating cholesterol metabolism. Currently, there are two available antibodies against PCSK9: Alirocumab and Evolocumab. Both bind selectively to the LDLR binding site of PCSK9 and prevent circulating PCSK9 from binding to the LDLRs on the hepatocytes, preventing PCSK9-mediated LDLR degradation.
Phase 3 trials of Evolocumab and Alirocumab
Evolocumab has been evaluated in MENDEL-2, GAUSS, OSLER-2, TESLA-B, LAPLACE-2, DESCARTES, RUTHERFORD-2, GLAGOV and FOURIER trials.
These RCTs encompassing 34,420 patients were conducted to determine the safety and efficacy of Evolocumab. The patient characteristics were mixed ranging from dyslipidemia to familial hypercholesterolemia, including patients at risk of ASCVD, statin-intolerant patients, patients experiencing statin-related adverse reactions.
The percentage of low‐density lipoprotein cholesterol(LDL-C) reduction with Evolocumabtreatment was 54.6% and the absolute mean reduction was −78.9 mg/dL vs placebo and −36.3% vs ezetimibe. HDL-C was increased by 7.6% vs placebo and 6.4% vs ezetimibe. Evolocumab significantly reduced total cholesterol, non-HDL-C, and VLDL and LPa5,6
GLAGOV trial studied 968 patients with high-risk coronary artery disease, who were randomized after Intra Vascular Ultrasound for 18 months of treatment of statin monotherapy or statin + Evolocumab therapy. Patients receiving statin monotherapy had a mean LDL-C of 93 mg/dL, which was essentially unchanged, while patients receiving statin therapy with the addition of the PCSK9 inhibitor Evolocumab had a mean LDL-C of 36.6 mg/dL. Analysis of the primary endpoint of change in Percentage Atheroma Volume (PAV), patients on statin monotherapy had neither progression nor regression, however, patients receiving the addition of the PCSK9 inhibitor had a statistically significant change in PAV of –0.95% (P< 0.001); they had less plaque at the end of the trial than. The secondary endpoint of total atheroma volume showed no change in the atherosclerotic plaque in the statin monotherapy group but a decrease in the statin plus Evolocumab group7.
Phase 3 trials on Alirocumab such as ODYSSEY MONO, ODYSSEY COMBO, ODYSSEY FH, DYSSEY LONG TERM, and ODYSSEY OUTCOMES, have been conducted.
These RCTs encompassing 23,560 patients were conducted to determine the safety and efficacy of Alirocumab. The patient characteristics were mixed ranging from dyslipidemia to familial hypercholesterolemia, including patients at risk of ASCVD, and statin-intolerant patients.
The efficacy outcome for Alirocumab was on similar lines of Evolocumab. LDL-Cwas reduced by over 50% vs placebo. A less marked reduction of LDL-C was found when compared with ezetimibe (−29.9%). HDL-C level increased by a mean of 8%, and there was a reduction of total cholesterol, non-HDL C and Apo-B. 5,6
Clinical Trial Outcomes
FOURIER was a double-blind RCT that enrolled 27564 patients aged 40–85 years old with CVD and LDL-C level ≥70 mg/dL or non-high-density lipoprotein cholesterol ≥100 mg/dL. Patients were randomly assigned to receive subcutaneous injections of Evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or placebo. The primary efficacy endpoint was the composite of CV death, MI, stroke, hospitalization for unstable angina (UA), or coronary revascularization. The key secondary efficacy endpoint was the composite of CV death, MI, or stroke. Primary and secondary endpoints were significantly reduced in the Evolocumab group, compared with placebo. During median follow-up of 2.2 years, the primary endpoint occurred in 1,344 patients (9.8%) in the Evolocumab group and 1,563 patients (11.3%) in the placebo group: hazard ratio (HR) of 0.85 (p<0.001). The key secondary endpoint occurred in 816 patients (5.9%) in the Evolocumab group and 1,013 patients (7.4%) in the placebo group: HR of 0.80 (p<0.001). For individual outcomes, Evolocumab treatment reduced the risk of MI, stroke, and coronary revascularization.8
ODYSSEY OUTCOMES trial was an RCT that enrolled 18924 patients aged 40 years or older with the recent acute coronary syndrome and LDL-Clevel ≥70 mg/dL, non-HDL-C ≥100 mg/dL, or apolipoprotein B ≥80 mg/dL. Patients were randomly assigned to receive Alirocumab (either 75 or 150 mg every 2 weeks) or placebo. In the trial, dose of Alirocumab was adjusted or changed to placebo in blinded fashion to achieve LDL-C level of 15–50 mg/dL. The primary efficacy endpoint was the composite of coronary heart disease (CHD), death, non-fatal MI, ischemic stroke, or hospitalization for UA. The main secondary endpoints were Major CHD event and All-cause mortality, non-fatal MI, or non-fatal ischemic stroke. Compare to placebo, Alirocumab significantly reduced the risk of both primary and secondary endpoints. During median follow-up of 2.8 years, the primary endpoint occurred in 903 patients (9.5%) in the Alirocumab group and 1,052 patients (11.1%) in the placebo group: HR of 0.85 (p=0.0003). The composite of all-cause mortality, non-fatal MI, or non-fatal ischemic stroke occurred in 973 patients (10.3%) in the Alirocumab group and 1,126 patients (11.6%) in the placebo group; HR of 0.86 (p=0.0003). Alirocumab significantly decreased all-cause mortality compared with placebo (3.5% vs. 4.1%); HR of 0.85 (p=0.026). 8
Table 1: Summary of PCSK9i cardiovascular outcome studies: 9
Name of trial Study population Intervention* Control* Follow-up time Primary endpoint Secondary endpoint(s)/subgroup analyses FOURIER ASCVD Evolocumab 140 or 420 mg Placebo 2.2 year 15% reduction ASCVD composite 20% reduction MACE composite (CV death, MI, stroke); similar benefits in those with and without DM; greater benefits in those with MIs <2 years, multiple MIs, high-risk features, and PAD ODYSSEY ACS <1 year Alirocumab Placebo 3.1 years 15% reduction ASCVD composite 12% reduction CHD events; 15% reduction total mortality
*On background statin therapy.
Safety and Tolerability
Both Fourier and Odyssey studies reported an excellent safety profile with no signal alert, either for induced diabetes or for cognitive dysfunction, or for hemorrhagic stroke or muscular pain.10 There were no statistically significant differences in the risk of any, treatment-related, or serious AEs between evolocumab, alirocumab, or ezetimibe and placebo. Monthly doses of Evolocumab 420 mg and alirocumab 300 mg resulted in risk ratios of treatment-related AEs of 1.47 and 1.17 (95% compared with placebo. There were, however, very few treatment-related AEs, and none was considered serious.11At the recommended doses, the most common side effects were injection site reactions nasopharyngitis, upper respiratory tract infection, back pain, arthralgia, influenza, nausea and rash.
Right patient profile for PCSK9i
- Homozygous or heterozygous familial hypercholesterolemia or mixed dyslipidemia
- Patients with high risk for CVD: ≥3 risk factors or 10-yr risk >15% (Major CVD risk factors: ≥45 years in males and ≥55 years in female; family history of premature CVD <55 years in a male or <65 years in a female first degree relative; current tobacco use; hypertension; HDL <40 mg/dl in males and <55 mg/dl in females) 12,
- Where there was a contraindication to statin use or statin intolerance, or
when target cholesterol level (of LDL-C <70 mg/dl and non-HDL-C <100 mg/ dl) were not reached with statins with or without other lipid-lowering drugs.
- low‐density lipoprotein cholesterol (LDL C > 200mg/dl
In conclusion, Evolocumab and Alirocumab therapy either as a monotherapy or in combination therapy effectively lowered mean LDL-C levels in treatment groups and overall significantly reduced the risk of MI, stroke, and coronary revascularization. They were associated with reductions in LDL-C of 54% to 74% versus placebo and 26% to 46% versus ezetimibe in patients already on statin therapy. There is evidence to suggest that PCSK9i may also significantly increase HDL-C and decrease non-HDL-C, ApoB, and Lp(a) levels, and these may further contribute to the decrease in cardiovascular morbidity and mortality. PCSK9i are indicated for treatment of FH, and it may be considered cost-effective in Homozygous and Heterozygous FH patients with or without existing ASCVD. More importantly, patients with high-risk CVD such as multivessel disease, multiple myocardial infarctions or multiple interventions and those with polyvascular disease, whose LDL-C levels remain above 50 mg/dL in spite of maximally tolerated statin therapy, would have considerable benefit in having their LDL-C values reduced.
- Lloyd-Jones DM, Morris PB, Ballantyne CM et al. Focused Update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am CollCardiol. 2017; 70:1785–1822.
- Mancini GB, Tashakkor AY, Baker S, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian Working Group Consensus update. Can J Cardiol. 2013; 29:1553–68.
- Abifadel M, Varret M, Rabe ´s JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003; 34:154–156
- Chaudhary R, Garg J, Shah N, Sumner A. PCSK9 inhibitors: A new era of lipid-lowering therapy. World Journal of Cardiology 2017; 9(2):76.
- Habeichi W, Katira R. “Evolocumab and Alirocumab: A Review of the Emerging Role of proprotein convertase subtilisin/Kexin Type 9 (PCSK9) Inhibitors in the Management of Hyperlipidaemia”. EC Cardiology 5.9. 2018: 621-629.
- Gupta S. Development of proprotein convertase subtilisin/Kexin type 9 inhibitors and the clinical potential of monoclonal antibodies in the management of lipid disorders. Vascular Health and Risk Management. 2016; 12:421-433.
- Nissen S, Nicholls S. Results of the GLAGOV trial. Cleveland Clinic Journal of Medicine. 2017; 84(12 suppl 4): e1-e5.
- Lee E, Yoon K. How to Interpret Recent CV Outcome Trials and Future: PCSK9 Inhibitors. Journal of Lipid and Atherosclerosis. 2018;7(1):1
- Wong ND, Shapiro M. Interpreting the Findings From the Recent PCSK9 Monoclonal Antibody Cardiovascular Outcomes Trials. Frontiers in Cardiovascular Medicine. 2019; 6: 14.
- Sabouret P, Angoulvant D, Pathak, A. FOURIER to ODYSSEY: the end of the journey for lipid-lowering therapy trials? Lessons from recent clinical trials with anti-PCSK9 antibodies. EuroIntervention. 2018; 14(2): 144-146.
- Worthy G, GandraS, Bridges, Worth G, Dent R, Forbes C et al. A Systematic Review and Network Meta-Analysis on the Efficacy of Evolocumab and other Lipid-Lowering Therapies for the Management of Lipid Levels in Hyperlipidemia. Value in Health. 2016; 19(3): A53.
Dr. Jamshed J Dalal is a renowned cardiologist and the Director of Cardiac Sciences at Kokilaben Hospital, Mumbai