- ACRONYMS AND DEFINITIONS
- CAD - Coronary artery disease
- CVD - Cardiovascular disease
- HeFH - Heterozygous familial hypercholesterolemia
- HoFH - Homozygous familial hypercholesterolemia
- PCSK9 - Proprotein convertase subtilisin kexin type 9
- RCT - Randomized controlled trial
- DRUGS IN CLASS
- PCSK9 inhibitors
- Alirocumab (Praluent®)
- Evolocumab (Repatha®)
- MECHANISM OF ACTION
- Proprotein convertase subtilisin kexin type 9 (PCSK9)
- PCSK9 is an enzyme produced primarily in hepatocytes that is involved in cholesterol homeostasis. LDL receptors on the surface of liver cells facilitate the removal of LDL cholesterol from the blood. PCSK9 binds to LDL receptors and causes them to degrade. LDL receptor loss reduces LDL uptake by hepatocytes, and plasma LDL levels rise.
- PCSK9 inhibitors
- PCSK9 inhibitors are human monoclonal antibodies directed against PCSK9. When PCSK9 inhibitors bind PCSK9, they inactivate it and prevent it from stimulating LDL receptor degradation. LDL receptors on the surface of hepatocytes are preserved, and more LDL is removed from the blood.
- FDA-APPROVED INDICATION
- Alirocumab (Praluent®)
- Primary hyperlipidemia (including heterozygous familial hypercholesterolemia) - Alirocumab is indicated as an adjunct to diet, alone or in combination with other lipid-lowering therapies (e.g., statins, ezetimibe), for the treatment of adults with primary hyperlipidemia to reduce low-density lipoprotein cholesterol (LDL-C)
- Prevention of Cardiovascular Events - Alirocumab is indicated to reduce the risk of myocardial infarction, stroke, and unstable angina requiring hospitalization in adults with established cardiovascular disease.
- Homozygous familial hypercholesterolemia (HoFH) - as an adjunct to other LDL-C-lowering therapies in adult patients
- Evolocumab (Repatha®)
- Prevention of cardiovascular events in adults - in adults with established cardiovascular disease to reduce the risk of myocardial infarction, stroke, and coronary revascularization
- Primary hyperlipidemia (including HeFH) in adults - as an adjunct to diet, alone or in combination with other LDL-C-lowering therapies, in adults with primary hyperlipidemia, including HeFH, to reduce LDL-C
- Heterozygous familial hypercholesterolemia (HeFH) in children ≥ 10 years old - as an adjunct to diet and other LDL-C-lowering therapies in pediatric patients aged 10 years and older with HeFH, to reduce LDL-C
- Homozygous familial hypercholesterolemia (HoFH) in children ≥ 10 years old and adults - as an adjunct to other LDL-C-lowering therapies in adults and pediatric patients aged 10 years and older with homozygous familial hypercholesterolemia (HoFH), to reduce LDL-C
- CHOLESTEROL EFFECTS
Effects of PCSK9 Inhibitors on Lipid Parameters | ||||
---|---|---|---|---|
Drug | LDL | Total | Non-HDL | Apo B |
Alirocumab 150 mg every 2 weeks for 24 weeks (N=1553) |
-58% | -36% | -49% | -50% |
Evolocumab 140 mg every 2 weeks for 12 weeks (N=555) |
-63% | -36% | -53% | -49% |
Evolocumab 420 mg once monthly for 12 weeks (N=562) |
-59% | -34% | -50% | -46% |
- SECONDARY PREVENTION OF CVD
- Overview
- The effects of PCSK9 inhibitors on CVD outcomes have been studied in two large randomized controlled trials
- The ODYSSEY trial compared alirocumab to placebo in patients with recent acute coronary syndrome and the FOURIER trial compared evolocumab to placebo in patients with documented CVD. Both studies are detailed below.
- The ODYSSEY trial enrolled 18,924 patients with a recent history of acute coronary syndrome (myocardial infarction or unstable angina)
Main inclusion criteria
- Acute coronary syndrome 1 to 12 months prior to randomization
- LDL ≥ 70 mg/dl, non-HDL level ≥ 100 mg/dl, or Apo B level ≥ 80 mg/dl after ≥ 2 weeks of atorvastatin (40 - 80 mg) or rosuvastatin (20 - 40 mg)
Main exclusion criteria
- Uncontrolled BP (>180/110)
- NYHA class III or IV heart failure
- Fasting triglycerides > 400 mg/dl
- LFTs > 3 X ULN
Baseline characteristics
- Average age 58 years
- Diabetes - 29%
- Average LDL - 92 mg/dl
- Qualifying event: STEMI - 34% | NSTEMI - 48% | Unstable angina - 17%
Randomized treatment groups
- Group 1 (9462 patients) - Alirocumab 75 mg SQ every 2 weeks
- Group 2 (9462 patients) - Placebo injection every 2 weeks
- All patients continued statins during the study
- Among patients assigned to the alirocumab group, protocol-specified dose-adjustment algorithms were used to target an LDL cholesterol level of 25 to 50 mg/dl and to avoid sustained levels below 15 mg/dl
Primary outcome: Composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke,
or unstable angina requiring hospitalization
Results
Duration: Median of 2.8 years | |||
Outcome | Alirocumab | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 9.5% | 11.1% | HR 0.85, 95%CI [0.78 - 0.93], p<0.001 |
Overall mortality | 3.5% | 4.1% | HR 0.85, 95%CI [0.73 - 0.98] |
Nonfatal myocardial infarction | 6.6% | 7.6% | HR 0.86, 95%CI [0.77 - 0.96] |
Ischemic stroke | 1.2% | 1.6% | HR 0.73, 95%CI [0.57 - 0.93] |
Average LDL level at 1 year | 48 mg/dl | 96 mg/dl | N/A |
|
Findings: Among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular
events was lower among those who received alirocumab than among those who received placebo
- The FOURIER trial enrolled 27,564 patients with cardiovascular disease and an LDL ≥ 70 mg/dl
Main inclusion criteria
- Age 40 - 85 years
- History of myocardial infarction, nonhemorrhagic stroke, or symptomatic peripheral artery disease + one major risk factor for CVD (e.g. diabetes, smoker, age ≥ 65 years) or two minor risk factors (e.g. HDL < 40, CRP > 2.0, metabolic syndrome)
- LDL ≥ 70 mg/dl or non-HDL cholesterol ≥ 100 mg/dl while taking a statin at least equivalent to atorvastatin 20 mg
Main exclusion criteria
- Stroke or MI within 4 weeks
- NYHA class III or IV heart failure or EF < 30%
- SBP > 180, DBP > 110
- GFR < 20 ml/min
- AST/ALT > 3 X ULN
Baseline characteristics
- Average age 63 years
- Diabetic - 37%
- Smoker - 28%
- Taking moderate-to-high intensity statin - 99%
- Median LDL - 92 mg/dl
- Median HDL - 44 mg/dl
- Qualifying event: MI - 81% | Stroke - 19% | PAD - 13%
Randomized treatment groups
- Group 1 (13,784 patients) - Evolocumab 140 mg every 2 weeks or 420 mg every month
- Group 2 (13,780 patients) - Placebo
- Two week or once monthly dosing was based on patient preference
- Statins were continued
Primary outcome: Major cardiovascular events, defined as the composite of cardiovascular death, myocardial infarction, stroke,
hospitalization for unstable angina, or coronary revascularization
Results
Duration: Median of 2.2 years | |||
Outcome | Evolocumab | Placebo | Comparisons |
---|---|---|---|
Primary outcome | 9.8% | 11.3% | HR 0.85, 95%CI [0.79 - 0.92], p<0.001 |
Overall mortality | 3.2% | 3.1% | HR 1.04, 95%CI [0.91 - 1.19], p=0.54 |
Myocardial infarction | 3.4% | 4.6% | HR 0.73, 95%CI [0.65 - 0.82], p<0.001 |
Stroke | 1.5% | 1.9% | HR 0.79, 95%CI [0.66 - 0.95], p=0.01 |
Cardiovascular death | 1.8% | 1.7% | HR 1.05, 95%CI [0.88 - 1.25], p=0.62 |
Coronary revascularization | 5.5% | 7.0% | HR 0.78, 95%CI [0.71 - 0.86], p<0.001 |
Injection site reactions | 2.1% | 1.6% | p<0.001 |
|
Findings: In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per
deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering
of LDL cholesterol levels below current targets.
- Professional recommendations
- See cholesterol treatment guidelines for recommendations from various professional organizations
- SIDE EFFECTS
- Injection site reactions
- Alirocumab (Praluent®)
- Injection site reactions including erythema, itching, swelling, and pain were reported more frequently in patients receiving alirocumab than placebo (7.2% vs 5.1%)
- Injection site reactions rarely led to discontinuation (0.2%) [1]
- Evolocumab (Repatha®)
- Injection site reactions including erythema, pain, and bruising have occurred. In trials, 3.2% of evolocumab-treated patients reported reactions compared to 3% of placebo patients. [3]
- Injection site reactions rarely led to discontinuation (0.1%) [3]
- Hypersensitivity reactions
- Alirocumab (Praluent®)
- Hypersensitivity reactions including pruritus, rash, urticaria, vasculitis, angioedema, and nummular eczema have been reported in patients receiving alirocumab
- In trials, allergic reactions were reported in 8.6% of alirocumab-treated patients and 7.8% of placebo-treated patients
- Evolocumab (Repatha®)
- Allergic reactions including angioedema, rash, eczema, erythema, and urticaria have been reported in patients receiving evolocumab
- In trials, allergic reactions were reported in 5.1% of evolocumab-treated patients and 4.6% of placebo patients [3]
- Elevated liver function tests (alirocumab)
- In trials, elevated liver function tests were reported in 2.5% of alirocumab-treated patients and 1.8% of patients treated with placebo
- Drug antibodies
- Biologic medications like PCSK9 inhibitors have the potential to induce a host immune response that leads to the production of antibodies that bind the drug. In some cases, these anti-drug antibodies reduce the efficacy of the drug and increase the risk of hypersensitivity reactions. In other cases, they have no meaningful effect.
- Alirocumab (Praluent®)
- In a cardiovascular outcome trial, 5.5% of patients treated with alirocumab developed anti-alirocumab antibodies compared to 1.6% of placebo-treated patients. Patients with anti-alirocumab antibodies had a higher incidence of injection site reactions compared to patients without antibodies (7.5% vs 3.5%). The long-term effects of anti-alirocumab antibodies of drug efficacy are unknown. [1]
- Evolocumab (Repatha®)
- In pooled trials, 0.1% of patients who received at least one dose of evolocumab developed anti-evolocumab antibodies
- Anti-evolocumab antibodies were not associated with a loss of efficacy, but long-term effects are unknown [3]
- CONTRAINDICATIONS
- Alirocumab and Evolocumab
- Known hypersensitivity to PCSK9 inhibitors or any of their excipients
- PRECAUTIONS
- Kidney disease
- Alirocumab (Praluent®)
- CrCl ≥ 30 ml/min: no dose adjustment necessary
- CrCl < 30 ml/min: has not been studied
- Evolocumab (Repatha®)
- No dose adjustment necessary in renal impairment
- Liver disease
- Alirocumab (Praluent®)
- Mild-moderate (Child-Pugh A and B): no dose adjustment necessary
- Severe (Child-Pugh C): has not been studied
- Evolocumab (Repatha®)
- Mild-moderate (Child-Pugh A and B): no dose adjustment necessary
- Severe (Child-Pugh C): has not been studied
- SAFETY OF VERY LOW LDL
- Overview
- Patients on PCSK9 inhibitors often achieve very low LDL levels (< 70 md/dl). While low LDL levels are beneficial for CVD, questions have arisen as to whether very low LDL levels have other detrimental effects. Some observational studies have suggested that very low LDL levels adversely affect cognition function.
- Two studies have looked at the affects of evelocumab-induced very low LDL levels and adverse events. The first study looked specifically at cognitive function, and the other looked at ten safety outcomes. Neither study found a significant association between very low LDL levels and adverse events.
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Alirocumab and Evolocumab
- No significant drug interactions are known
- Metabolism and elimination
- PCSK9 inhibitors are proteins, and they are metabolized through proteolytic pathways to smaller peptides and individual amino acids
- PCSK9 inhibitors do not undergo liver metabolism
- DOSING
- LONG-TERM SAFETY
- Alirocumab and evolocumab were both FDA-approved in 2015
- There is no long-term safety data for PCSK9 inhibitors, but they have been studied in several very large trials and appear to be safe
- BIBLIOGRAPHY
- 1 - Praluent PI
- 2 - PMID 25773378 Efficacy and safety of alirocumab in reducing lipids and cardiovascular events, NEJM (2015)
- 3 - Evolocumab PI
- 4 - PMID 28304229 - Antidrug Antibodies in Patients Treated with Alirocumab, NEJM (2017)