Twice-yearly cholesterol injection: inclisiran

What is inclisiran, and how does it lower LDL cholesterol?

Inclisiran is a small interfering RNA, or siRNA, that reduces the liver’s production of the PCSK9 protein. Lower PCSK9 levels allow more LDL receptors to be recycled and remain available on liver cells, increasing the removal of LDL cholesterol from the bloodstream¹. Inclisiran targets the same biological pathway as evolocumab and alirocumab, but it is not a monoclonal antibody and works through a different mechanism^1,2,3. It acts on PCSK9 messenger RNA; it does not edit DNA or permanently change a patient’s genes^1,2.

What is the twice-yearly injection schedule, and what happens if an appointment is delayed?

Inclisiran has an initial phase followed by twice-yearly maintenance under current prescribing information^1,2. It is administered by a healthcare professional, who must follow the application conditions and sites specified in the prescribing information¹. Delayed appointments require assessment by the prescriber; patients should not recalculate the schedule or attempt to inject the medicine themselves.

Who may be a candidate for inclisiran?

Inclisiran is not automatically appropriate for everyone with high cholesterol. In Brazil, it is approved for adults with primary hypercholesterolemia — heterozygous familial or non-familial — or mixed dyslipidemia, always as an adjunct to diet¹. It may be combined with a statin, alone or with other lipid-lowering therapies, when the maximum tolerated statin dose does not bring LDL to the individual target. It may also be used alone or with other treatments when there is confirmed statin intolerance or a contraindication¹. Contemporary guidelines maintain statins as the foundation of drug therapy and recommend considering additional therapies when the individual LDL target is not reached⁴. The 2022 US consensus considers inclisiran an option in selected circumstances, including adherence difficulties or an inability to use PCSK9 monoclonal antibodies². The decision depends on cardiovascular risk, current LDL, the individual target, previous treatments, tolerability and access.

How much can inclisiran lower LDL, and does it replace a statin?

Inclisiran lowered LDL cholesterol by approximately 50% in its main clinical trials, but this percentage is an average rather than an individual guarantee. In the pooled analysis of ORION-9, ORION-10 and ORION-11, involving 3,660 participants, the placebo-corrected LDL reduction at day 510 was 50.7%, while the adjusted average reduction between days 90 and 540 was 50.5%⁵. Brazilian prescribing information describes a sustained reduction of approximately 50%, while guidelines emphasize that treatment intensity should be based on cardiovascular risk and the individual LDL target^4,1. Most trial participants remained on their maximum tolerated statin dose, with or without ezetimibe, so inclisiran was studied mainly as an addition to background therapy rather than as a routine statin replacement^1,5. Individual responses vary with baseline LDL, concurrent medicines and clinical characteristics. LDL management and indicated treatment should continue throughout the year according to individual risk, without seasonal emphasis.

Has inclisiran been proven to prevent heart attacks or strokes?

Inclisiran has a well-established LDL-lowering effect, but the documentary search conducted on June 27, 2024, did not identify a definitive published result from a large trial specifically designed to demonstrate reductions in heart attack, stroke or cardiovascular death^4,2,6,7,8. A pooled phase 3 analysis found a possible favorable cardiovascular signal, but these events were exploratory, were not the primary outcome and were not evaluated with the rigor of a dedicated cardiovascular outcomes trial; the analysis alone does not prove prevention of heart attack or stroke⁶. On that date, the official registry listed ORION-4 as ongoing and showed no results posted in the registry⁷. VICTORION-2 PREVENT was likewise listed as ongoing, with no results posted in the registry⁸. Because trial status may change, the official registries must be checked again on the article’s publication or update date.

What side effects and precautions should patients know about?

Injection-site reactions are the most characteristic adverse effect of inclisiran. Brazilian prescribing information reports them in 8.2% of inclisiran-treated patients and 1.8% of placebo recipients, including pain, redness, local reactions and rash. They were generally mild or moderate, temporary and without lasting effects, and only 0.2% of treated patients discontinued therapy for this reason¹. Overall adverse-event rates were similar to placebo, and a meta-analysis of four trials involving 2,203 inclisiran recipients and 1,949 placebo recipients found no statistically significant increase in total adverse events or all-cause mortality^1,9. This finding does not exclude rare events or establish absolute safety equivalence. Post-marketing reports have included urticaria, angioedema and anaphylaxis, although their frequency cannot yet be calculated; breathing difficulty, facial or throat swelling, or a severe allergic reaction requires urgent medical attention¹. No dose adjustment is specified for older adults or for mild, moderate or severe kidney impairment, although experience in severe kidney disease is limited. For people receiving hemodialysis, injection timing requires individual coordination between the prescriber and nephrology team, in accordance with current prescribing information¹. Data are insufficient in severe liver impairment. Clinically relevant CYP450 interactions are not expected, including with atorvastatin or rosuvastatin, but clinical interaction data remain limited¹. The Brazilian label is for adults, and pregnancy or breastfeeding requires individual medical assessment because available data are sparse¹.

What practical questions should be addressed before treatment?

Inclisiran should be considered only after an individual medical assessment of cardiovascular risk, cholesterol results, the LDL target, associated conditions, previous treatments and access. Registration by Brazil’s National Health Surveillance Agency, Anvisa, authorizes marketing after the assessment of quality, safety and efficacy, but it does not automatically mean nationwide incorporation or provision by the Sistema Único de Saúde, or SUS; those decisions require evaluation by Conitec^1,10. The dyslipidemia PCDT available from the Brazilian Ministry of Health predates the current Brazilian availability of inclisiran; by itself, that document does not establish nationwide SUS incorporation of the medicine^11,10. Do not stop a statin, ezetimibe or another medicine on your own. Foreign visitors, expatriates and crew members staying along the São Paulo coast or passing through the Port of Santos should, whenever possible, bring recent test results, a medication list, injection dates and allergy information to support safe continuity of care. References linked to the numerical citations:⁴ Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. European Heart Journal. 2020;41(1):111-188. DOI: https://doi.org/10.1093/eurheartj/ehz455.¹ Novartis Biociências S.A. SYBRAVA® (inclisiran): prescribing information for healthcare professionals. Anvisa Electronic Drug Information Database, 2023. URL: https://consultas.anvisa.gov.br/#/bulario/q/?nomeProduto=SYBRAVA. Accessed June 27, 2024.² Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk. Journal of the American College of Cardiology. 2022;80(14):1366-1418. DOI: https://doi.org/10.1016/j.jacc.2022.07.006.⁵ Wright RS, Ray KK, Raal FJ, et al. Pooled Patient-Level Analysis of Inclisiran Trials in Patients With Familial Hypercholesterolemia or Atherosclerosis. Journal of the American College of Cardiology. 2021;77(9):1182-1193. DOI: https://doi.org/10.1016/j.jacc.2020.12.058.⁶ Ray KK, Raal FJ, Kallend DG, et al. Inclisiran and cardiovascular events: a patient-level analysis of phase III trials. European Heart Journal. 2023;44(2):129-138. DOI: https://doi.org/10.1093/eurheartj/ehac594.⁹ Khan SA, Naz A, Qamar Masood M, Shah R. Meta-Analysis of Inclisiran for the Treatment of Hypercholesterolemia. American Journal of Cardiology. 2020;134:69-73. DOI: https://doi.org/10.1016/j.amjcard.2020.08.018.⁷ University of Oxford; ClinicalTrials.gov. A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease — ORION-4. Record NCT03705234, initiated in 2018. URL: https://clinicaltrials.gov/study/NCT03705234. Accessed June 27, 2024.⁸ Novartis Pharmaceuticals; ClinicalTrials.gov. Study of Inclisiran to Prevent Cardiovascular Events in Participants With Established Cardiovascular Disease — VICTORION-2 PREVENT. Record NCT05030428, initiated in 2021. URL: https://clinicaltrials.gov/study/NCT05030428. Accessed June 27, 2024.¹¹ Brazil. Ministry of Health. Clinical Protocol and Therapeutic Guidelines for Dyslipidemia: prevention of cardiovascular events and pancreatitis. Brasília: Ministry of Health, 2019. URL: https://www.gov.br/conitec/pt-br/midias/protocolos/20221101_pcdt_dislipidemia.pdf. Accessed June 27, 2024.³ Fitzgerald K, White S, Borodovsky A, et al. A Highly Durable RNAi Therapeutic Inhibitor of PCSK9. New England Journal of Medicine. 2017;376(1):41-51. DOI: https://doi.org/10.1056/NEJMoa1609243.¹⁰ Brazilian National Committee for Health Technology Incorporation in the Unified Health System — Conitec. About Conitec. Ministry of Health, 2024. URL: https://www.gov.br/conitec/pt-br/assuntos/a-comissao/conheca-a-conitec. Accessed June 27, 2024. This content is provided solely for informational and educational purposes and does not replace an individual medical assessment, diagnosis, prescription or consultation.