PCSK9 Inhibitors (Evolocumab / Alirocumab / Inclisiran) — Informed Consent

INFORMED CONSENT FOR PCSK9 INHIBITOR THERAPY

§1 PURPOSE AND SCOPE OF THIS DOCUMENT

§1.1 This document constitutes an informed consent agreement between the Patient identified herein (the "Patient") and the Prescribing Physician acting on behalf of the Clinic. Its purpose is to ensure that the Patient has received, understood, and accepted comprehensive information regarding the proposed pharmacological use of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.

§1.2 Health optimization context: The Patient understands that the Clinic operates as a proactive health optimization / cardiovascular risk reduction / longevity practice and is not acting as the Patient's emergency provider.

§1.3 This consent is governed by the laws of Denmark and the European Union, including but not limited to Regulation (EU) 2016/679 (General Data Protection Regulation), the Danish Health Act (Sundhedsloven), and applicable pharmaceutical regulation.

§1.5 By signing this document, the Patient confirms that they have been given adequate time and opportunity to read, consider, and ask questions about its contents before providing consent.

§3 DESCRIPTION OF THE PROPOSED TREATMENT

§3.1 The Prescribing Physician has recommended treatment with a medication belonging to the class of PCSK9 inhibitors. PCSK9 inhibitors are a class of lipid‑lowering medications that dramatically reduce low‑density lipoprotein cholesterol (LDL‑C).

§3.3 PCSK9 inhibitors currently available include:

• Evolocumab (brand name: Repatha) — a fully human monoclonal antibody, administered by subcutaneous injection every 2 weeks or monthly
• Alirocumab (brand name: Praluent) — a fully human monoclonal antibody, administered by subcutaneous injection every 2 weeks or monthly
• Inclisiran (brand name: Leqvio) — a small interfering RNA (siRNA) that silences PCSK9 production, administered by subcutaneous injection twice yearly (after initial doses)

§3.4 The treatment will be administered by subcutaneous injection. The Patient will be instructed on proper self‑injection technique or arrangements will be made for healthcare provider administration.

§3.5 The dosing schedule will be determined by the Prescribing Physician based on the specific agent, the Patient's clinical status, baseline LDL‑C, treatment goals, and response to therapy.

§4 REGULATORY STATUS AND APPROVED INDICATIONS

§4.1 The medication prescribed has been authorised by the European Medicines Agency (EMA) for use within the European Union.

§4.2 EMA‑approved indications for PCSK9 inhibitors generally include:

• Primary hypercholesterolaemia (heterozygous familial and non‑familial) or mixed dyslipidaemia as an adjunct to diet:
• In combination with a statin or statin with other lipid‑lowering therapies in patients unable to reach LDL‑C goals with the maximum tolerated dose of a statin, or
• Alone or in combination with other lipid‑lowering therapies in patients who are statin‑intolerant or for whom a statin is contraindicated
• Homozygous familial hypercholesterolaemia (evolocumab) in combination with other lipid‑lowering therapies
• Established atherosclerotic cardiovascular disease (ASCVD) to reduce cardiovascular risk by lowering LDL‑C levels

§4.3 The Patient understands that the Prescribing Physician may prescribe PCSK9 inhibitors for various clinical scenarios, including but not limited to:

• Secondary prevention in patients with established cardiovascular disease
• Primary prevention in high‑risk patients (e.g., familial hypercholesterolaemia, very high LDL‑C, multiple risk factors)
• Patients who cannot tolerate statins or have inadequate response to maximum statin therapy
• Aggressive LDL‑C lowering as part of a proactive cardiovascular risk reduction strategy

§4.4 Proactive cardiovascular risk reduction / longevity context: If the Patient does not have established cardiovascular disease or familial hypercholesterolaemia, the use of PCSK9 inhibitors may be considered off‑label or outside standard prescribing guidelines. The Patient understands that evidence for primary prevention in lower‑risk populations is less robust than for secondary prevention or high‑risk primary prevention.

§5 MECHANISM OF ACTION AND CLINICAL PHARMACOLOGY

§5.1 What is PCSK9? PCSK9 (proprotein convertase subtilisin/kexin type 9) is a protein produced primarily in the liver. Its function is to bind to LDL receptors on the surface of liver cells and promote their degradation. When PCSK9 levels are high, fewer LDL receptors are available, and LDL‑C remains in the bloodstream at elevated levels.

§5.2 Monoclonal antibody PCSK9 inhibitors (evolocumab, alirocumab): These medications are fully human monoclonal antibodies that bind to circulating PCSK9, preventing it from binding to LDL receptors. This allows more LDL receptors to remain on liver cell surfaces, increasing the clearance of LDL‑C from the blood.

§5.3 siRNA PCSK9 inhibitor (inclisiran): Inclisiran is a small interfering RNA (siRNA) that enters liver cells and silences the production of PCSK9 at the genetic level by degrading the messenger RNA (mRNA) that encodes PCSK9. This results in sustained reduction of PCSK9 protein and prolonged lowering of LDL‑C.

§5.4 LDL‑C reduction: PCSK9 inhibitors typically reduce LDL‑C by 50–60% when added to statin therapy, or by similar amounts when used alone. This reduction is substantially greater than that achieved with statins or ezetimibe.

§5.5 Effects on other lipid parameters: PCSK9 inhibitors may also modestly reduce:

• Total cholesterol
• Non‑HDL cholesterol
• Apolipoprotein B (ApoB)
• Lipoprotein(a) [Lp(a)] — particularly evolocumab and alirocumab, with reductions of approximately 20–30%
• Triglycerides (modest reduction)

§5.6 PCSK9 inhibitors may slightly increase HDL cholesterol.

§6 EXPECTED BENEFITS OF TREATMENT

§6.1 The Patient understands that the potential benefits of PCSK9 inhibitor therapy include:

§6.1.1 Substantial LDL‑C reduction: PCSK9 inhibitors are among the most potent LDL‑lowering agents available, capable of reducing LDL‑C by 50–60% or more, often achieving LDL‑C levels below 1.0 mmol/L (40 mg/dL).

§6.1.2 Cardiovascular event reduction: In large randomised controlled trials (FOURIER for evolocumab, ODYSSEY OUTCOMES for alirocumab), PCSK9 inhibitors reduced the risk of major adverse cardiovascular events (MACE) — including myocardial infarction, stroke, and coronary revascularisation — in patients with established atherosclerotic cardiovascular disease. Absolute risk reductions depend on baseline risk.

§6.1.3 Lipoprotein(a) reduction: PCSK9 inhibitors reduce Lp(a) levels, which may provide additional cardiovascular benefit, particularly in patients with elevated Lp(a).

§6.1.4 Alternative for statin‑intolerant patients: For patients who cannot tolerate statins due to muscle symptoms or other side effects, PCSK9 inhibitors offer an effective alternative for LDL‑C lowering.

§6.1.5 Atherosclerotic plaque regression: Some imaging studies suggest that aggressive LDL‑C lowering with PCSK9 inhibitors may promote regression (shrinkage) of atherosclerotic plaques.

§6.2 No guarantee of benefit: The Patient acknowledges that benefits are potential and not guaranteed. Individual response varies, and achieving low LDL‑C does not eliminate cardiovascular risk entirely.

§7 MATERIAL RISKS AND ADVERSE EFFECTS

§7.1 The Patient has been informed of the following risks and adverse effects associated with PCSK9 inhibitor therapy. This list is not exhaustive.

§7.2 Common adverse effects (occurring in ≥1% of patients):

• Injection site reactions: Pain, redness, swelling, or itching at the injection site. These are generally mild and transient.
• Upper respiratory tract symptoms: Nasopharyngitis (common cold symptoms), sinusitis, cough
• Influenza‑like symptoms: Muscle aches, fatigue, mild fever (especially early in treatment)
• Back pain or musculoskeletal pain
• Headache

§7.3 Uncommon adverse effects (occurring in 0.1–1% of patients):

• Allergic reactions: Rash, urticaria (hives), pruritus
• Dizziness
• Nausea
• Elevated liver enzymes (transient)

§7.4 Rare but potentially serious adverse effects:

§7.4.1 Severe allergic reactions (hypersensitivity): Rarely, serious allergic reactions including angioedema (swelling of face, lips, throat) and anaphylaxis have been reported. The Patient must seek emergency medical care immediately if difficulty breathing, severe swelling, or signs of anaphylaxis occur.

§7.4.2 Injection site hypersensitivity: Some patients develop persistent or severe reactions at injection sites requiring discontinuation.

§7.5 Neurocognitive effects: Early in the development of PCSK9 inhibitors, theoretical concerns were raised about potential effects of very low LDL‑C on brain function, since cholesterol is a component of neuronal membranes. Large clinical trials (EBBINGHAUS and others) found no significant difference in neurocognitive function between patients on PCSK9 inhibitors and placebo. However, the Patient should report any subjective concerns about memory, concentration, or cognition to the Prescribing Physician.

§7.6 New‑onset diabetes: Some observational data suggest a possible small increase in risk of new‑onset diabetes with aggressive LDL lowering, though this has not been consistently demonstrated with PCSK9 inhibitors specifically.

§7.7 Unknown long‑term effects: PCSK9 inhibitors are a relatively new class of medications (approved since 2015). Long‑term data beyond 5–7 years are limited. The Patient understands that unforeseen adverse effects may emerge with longer use.

§8 CONTRAINDICATIONS AND PRECAUTIONS

§8.1 The Patient confirms that they have disclosed all relevant medical history to the Prescribing Physician.

§8.2 Absolute contraindications:

• Known hypersensitivity or allergy to the prescribed PCSK9 inhibitor or any of its excipients
• History of serious allergic reaction to a previous dose of the same medication

§8.3 Relative contraindications and precautions:

• Moderate to severe hepatic impairment (limited data; use with caution)
• Patients with end‑stage renal disease on dialysis (limited data for some agents)

§9 DRUG INTERACTIONS

§9.1 PCSK9 inhibitors have a low potential for drug‑drug interactions because they are monoclonal antibodies (or siRNA) that are catabolised by normal protein degradation pathways rather than metabolised by cytochrome P450 enzymes.

§9.2 There are no known clinically significant pharmacokinetic interactions with statins, ezetimibe, fibrates, or other common medications.

§9.3 The Patient should nonetheless inform the Prescribing Physician of all current medications, supplements, and herbal products.

§9.4 For inclisiran specifically, patients should be aware that certain medications affecting hepatic uptake mechanisms could theoretically interact, though no clinically significant interactions have been identified to date.

§10 ADMINISTRATION AND STORAGE

§10.1 PCSK9 inhibitors are administered by subcutaneous injection using pre‑filled pens or syringes.

§10.2 Evolocumab (Repatha): Typically 140 mg every 2 weeks or 420 mg once monthly.

§10.3 Alirocumab (Praluent): Typically 75 mg or 150 mg every 2 weeks, or 300 mg monthly.

§10.4 Inclisiran (Leqvio): 284 mg at initiation, again at 3 months, then every 6 months thereafter. Usually administered by a healthcare professional.

§10.5 Storage: Pre‑filled pens/syringes must be stored in a refrigerator (2–8°C). Do not freeze. Protect from light. Allow medication to reach room temperature before injection. Check expiry dates before use.

§10.6 Injection technique: The Patient will be provided with training on self‑injection technique for evolocumab and alirocumab, including proper hand hygiene, site rotation (abdomen, thigh, upper arm), and disposal of sharps. For inclisiran, administration is typically by a healthcare professional.

§10.7 The Patient agrees to store, handle, and administer the medication according to the instructions provided.

§11 MONITORING REQUIREMENTS

§11.1 The Patient agrees to undergo the following monitoring as recommended by the Prescribing Physician:

§11.1.1 Baseline lipid panel: LDL‑C, total cholesterol, HDL‑C, triglycerides, and Lp(a) if available, before starting treatment.

§11.1.2 Follow‑up lipid panel: 4–8 weeks after initiation to assess response, then periodically (e.g., every 3–6 months or annually) depending on clinical status.

§11.1.3 Liver function tests: Baseline and as clinically indicated (particularly if combining with statins).

§11.1.4 Assessment of cardiovascular risk factors: Blood pressure, HbA1c (if diabetic), and other relevant markers.

§11.1.5 Clinical assessment: Periodic review of symptoms, adherence, injection technique, and any adverse effects.

§11.2 The Patient understands that failure to attend monitoring appointments or obtain required tests may result in the Clinic being unable to safely continue the prescription.

§12 ALTERNATIVE TREATMENTS

§12.1 The Patient has been informed that alternative or adjunctive treatments for LDL‑C lowering and cardiovascular risk reduction include:

§12.1.1 Statins (e.g., atorvastatin, rosuvastatin): First‑line therapy for most patients requiring LDL‑C reduction. Well‑established cardiovascular outcome benefits.

§12.1.2 Ezetimibe: A cholesterol absorption inhibitor that reduces LDL‑C by approximately 15–20% and can be combined with statins.

§12.1.3 Bempedoic acid (Nilemdo): An oral medication that inhibits cholesterol synthesis upstream of statins; may be used in statin‑intolerant patients.

§12.1.4 Lifestyle modifications: Dietary changes (reduced saturated fat, increased fibre, plant sterols), regular exercise, weight management, and smoking cessation.

§12.1.5 Fibrates or omega‑3 fatty acids: May be used for elevated triglycerides.

§12.2 The Patient understands that PCSK9 inhibitors are typically used when LDL‑C targets cannot be achieved with statins ± ezetimibe, or when statins are not tolerated.

§12.3 The Patient has been given the opportunity to discuss these alternatives with the Prescribing Physician.

§14 PATIENT RESPONSIBILITIES

§14.1 The Patient agrees to:

• Administer the medication as directed by the Prescribing Physician
• Store the medication properly (refrigerated, protected from light, not frozen)
• Attend scheduled monitoring appointments and obtain required blood tests
• Report any new symptoms, side effects, or concerns promptly to the Clinic
• Inform the Clinic of any new medications (including over‑the‑counter and supplements)
• Not share this medication with any other person
• Maintain a relationship with a primary care physician and appropriate specialists for comprehensive healthcare

§14.2 The Patient understands that failure to comply with these responsibilities may compromise the safety and effectiveness of treatment and may result in discontinuation of the prescription.

§15 LIMITATION OF LIABILITY

§15.1 The Clinic and Prescribing Physician have provided this treatment recommendation in good faith based on available clinical information and current medical knowledge.

§15.2 The Patient understands that no treatment is without risk and that cardiovascular events may occur despite optimal lipid‑lowering therapy.

§15.3 To the fullest extent permitted by law, the Clinic's liability is limited to cases of wilful misconduct or gross negligence. The Clinic is not liable for unforeseeable adverse events or for outcomes related to the Patient's failure to provide accurate information or comply with treatment recommendations.

§15.4 This limitation does not affect the Patient's statutory rights under Danish law or EU consumer protection regulations.

§16 WITHDRAWAL OF CONSENT

§16.1 The Patient may withdraw consent and discontinue treatment at any time by notifying the Clinic in writing or through secure messaging.

§16.2 Withdrawal of consent will not affect the lawfulness of processing or treatment carried out before withdrawal.

§16.3 The Patient understands that abrupt discontinuation of PCSK9 inhibitor therapy will result in LDL‑C levels returning to baseline. There is no known "rebound" effect, but the cardiovascular protection afforded by low LDL‑C will diminish.

§17 DATA PROTECTION

§17.1 Personal data collected in connection with this consent and treatment will be processed in accordance with the Clinic's Privacy Policy and Regulation (EU) 2016/679 (GDPR).

§17.2 Data will be used for the purpose of providing medical treatment, clinical documentation, and legal compliance.

§17.3 The Patient has the right to access, rectify, erase (subject to legal retention requirements), and port their personal data as provided by GDPR.

§18 ACKNOWLEDGMENTS AND DECLARATIONS

By consenting, the Patient confirms the following:

• I have read this consent document in its entirety, or it has been read to me, and I understand its contents.
• I understand the nature of PCSK9 inhibitor therapy, including its mechanism of action and method of administration (subcutaneous injection).
• I understand the expected benefits, including substantial LDL‑C reduction and potential cardiovascular risk reduction.
• I have been informed of the material risks and adverse effects, including injection site reactions, allergic reactions, and the limited long‑term data available.
• I understand that alternative treatments (statins, ezetimibe, lifestyle modifications) exist and have been discussed.
• I understand the storage and handling requirements for the medication (refrigeration, protection from light).
• I understand that regular monitoring (lipid panels) is required.
• I understand the contraindications and have disclosed all relevant medical history.
• I have disclosed all relevant medical history and current medications to the Clinic.
• I understand I must seek urgent/emergency care for severe symptoms (chest pain, stroke symptoms, severe allergic reaction) and that the Clinic is not an emergency service.
• I have had the opportunity to ask questions and my questions were answered.
• I voluntarily consent to commence or continue treatment with the prescribed medication under the regimen agreed with my clinician.