# Inclisiran: The Twice-a-Year Cholesterol Shot That Silences a Bad Gene — Explained for Patients

**Summary:** A new class of cholesterol medication, inclisiran (brand evidence under review), uses a completely different technology than statins to dramatically lower “bad” cholesterol (LDL-C). Delivered as a small subcutaneous (under-the-skin) injection once at day 0, again at day 90, and then once every 6 months, it reduced LDL-C by roughly 50% in large phase III trials and showed a generally good safety profile, with injection-site reactions as the most common side effect. This patient-friendly article explains how inclisiran works, what clinical trials found, drug advantages and disadvantages, and what patients should consider.

# Inclisiran: The Twice-a-Year Cholesterol Shot That Silences a Bad Gene — Explained for Patients

## Table of Contents

- Key Points
- Why This Research Matters
- Background: Cholesterol, Cardiovascular Risk, and Why Statins Are Not Enough
- How Inclisiran Works: A Small Interfering RNA (siRNA) Molecule
- Pharmacodynamics: What the Drug Does in the Body
- Pharmacokinetics: How the Drug Travels and Lasts in the Body
- Clinical Trials With Inclisiran: What the Numbers Show
- Adverse Effects: Side Effects and Safety Signals
- Advantages and Disadvantages: Weighing the Pros and Cons
- Clinical Implications: What This Means for Patients
- Limitations and Unanswered Questions
- Recommendations for Patients
- Frequently Asked Questions
- Source Information

## Key Points

- Inclisiran is a twice-yearly under-the-skin injection that lowers LDL cholesterol by about 50% in clinical trials.
- It works by silencing the PCSK9 gene in liver cells, reducing production of the PCSK9 protein.
- In phase 3 trials, the most common side effects were mild injection-site reactions, occurring in 2.6%–4.7% of patients.
- Side effects can last up to 6 months per dose because the drug stays active for that long.
- Inclisiran is currently used as an add-on to statins or other oral lipid-lowering therapy, not as a replacement.

## Why This Research Matters

Cardiovascular disease remains one of the world's leading killers, and dyslipidemia — an abnormal amount of fats, especially cholesterol, in the blood — is one of its major risk factors. Managing lipid (blood fat) levels with medication is therefore an urgent worldwide health priority.

For decades, statins have been the gold-standard treatment for high cholesterol, particularly for elevated LDL-C, the “bad” cholesterol that builds up in artery walls. But many patients never reach their target cholesterol levels even on the highest tolerated statin doses. Others stop statins entirely because of side effects such as myalgia (muscle aches) and myopathy (muscle damage). Those gaps explain why researchers developed entirely new classes of cholesterol drugs, and why a review of the newest one — inclisiran — matters to patients.

## Background: Cholesterol, Cardiovascular Risk, and Why Statins Are Not Enough

The link between LDL-C and atherosclerosis (plaque buildup inside arteries) is well proven. Large studies show that lowering elevated LDL-C cuts cardiovascular (CV) risk. Current European Society of Cardiology/European Society of Atherosclerosis (ESC/EAS) guidelines emphasize achieving adequate LDL-C control, especially in patients classified as high-risk, very-high-risk, and extremely-high-risk.

Yet real-world data from surveys, prospective studies, and clinical registries show that some patients still do not reach therapeutic LCL-C goals even with maximum-tolerated statin therapy.

These limitations of statins led to the development of drugs targeting a protein called proprotein convertase subtilisin/kexin type 9 (PCSK9). PCSK9 regulates LDL-C metabolism by binding to LDL receptors (the “sweepers” that remove LDL-C from blood) and destroying them. When PCSK9 destroys these receptors, fewer LDL-C particles are cleared; when PCSK9 is blocked, the receptors survive longer and clear more LDL-C. The result is a fall in plasma (blood) LDL-C.

Until recently, the only approved PCSK9-targeting drugs were injectable monoclonal antibodies: alirocumab and evolocumab. They require frequent injections, however, and patient adherence can suffer during long-term treatment. That is why inclisiran, a small interfering ribonucleic acid (siRNA) molecule targeting PCSK9, was developed — and why this narrative review pulls together the existing evidence.

This article is based on a peer-reviewed narrative review published in the journal Cardiovascular Therapeutics in 2022 (Merćep et al.). A narrative review is a scholarly summary in which authors critically synthesize published research on a topic rather than performing a new clinical experiment. Here, the authors examined preclinical evidence, phase I and phase II trials, and available phase III trial results for inclisiran.

The authors searched four major medical databases — PubMed, Scopus, Embase, and Web of Science — from their start dates through May 1, 2021. They searched for publications containing the keywords “inclisiran” and “ALN-PCSsc” (the earlier code name for the drug) in titles and abstracts.

Because this is a review, not a clinical trial, it does not have a single patient population. Instead, it synthesizes data from animal models, healthy volunteers, and thousands of patients who participated in multiple trials described below.

## How Inclisiran Works: A Small Interfering RNA (siRNA) Molecule

Inclisiran is a long-acting, short-chain siRNA directed against the PCSK9 protein. To understand it, patients first need a simple explanation of a powerful natural process: RNA interference (RNAi).

Every cell in the body makes proteins by following instructions carried by messenger RNA (mRNA). Small interfering RNA (siRNA) molecules are tiny pieces of genetic material that “silence” a specific gene — they interfere with a target mRNA before it can produce its protein.

Inclisiran uses this natural gene-silencing pathway selectively. It inhibits PCSK9 production by binding specifically to the mRNA precursor (the early form of the messenger RNA) for PCSK9 and causing its degradation. With that messenger destroyed, the cell stops building PCSK9.

Structurally, inclisiran consists of two complementary RNA strands:

- a **guide strand** — the strand that recognizes and targets PCSK9 mRNA;
- a **passenger strand** — the strand that helps deliver and stabilize the molecule.

Once incorporated into hepatocytes (liver cells), the guide strand binds to a cellular complex called the RNA-induced silencing complex (RISC). It then hybridizes with — locks onto — the complementary mRNA for PCSK9 and induces its degradation. Destroying the mRNA reduces PCSK9 synthesis and secretion by limiting translation (the process that actually builds the protein).

Notably, researchers observed that the silencing complex stays active even after the mRNA is degraded, which may explain the drug's long-lasting effect.

Because of this mechanism, inclisiran reduces both intracellular (inside the cell) and extracellular (outside the cell) PCSK9 protein levels. Monoclonal antibodies like alirocumab and evolocumab, by contrast, reduce only extracellular PCSK9 levels. This distinction leads to a substantial and durable reduction in LDL-C concentrations. The review notes, however, that we still need long-term trial results to fully understand the effects of this mechanism, which could prove to be an advantage or a risk.

## Pharmacodynamics: What the Drug Does in the Body

Inclisiran differs from its precursor molecule, ALN-PCS, by an added synthetic sugar structure: a triantennary carbohydrate called N-acetylgalactosamine (GalNAc).

GalNAc is complementary to asialoglycoprotein receptors on hepatocytes (specialized docking sites on liver cells). This design makes inclisiran taken up directly and specifically into liver cells. The presence of GalNAc also increases the drug's clinical and long-term efficacy by improving adhesion to the liver-cell membrane.

Studies showed that no drug molecules remained in the serum 24 hours after intravenous (IV) drug administration. That suggests very specific, fast uptake into the liver. This specificity to hepatocytes could theoretically reduce the risk of side effects in other organs, since the drug concentrates where it is needed.

In preclinical (animal) studies, a linear relationship between dose and effect was observed. Specific results included:

- a dose of 1 mg/kg (milligram per kilogram of body mass) produced **50% PCSK9 inhibition**;
- the highest tested dose of 3 mg/kg produced **85% PCSK9 inhibition** and a **60% reduction in LDL-C concentrations**;
- an earlier spherical version of the molecule, called ALN-PCS, delivered inside a lipid (fat) nanoparticle caused a **70% reduction in both PCSK9 mRNA and PCSK9 protein**, plus a **60% reduction in LDL-C** in animal models that lasted **three weeks**.

To increase drug stability, molecules in the polynucleotide (RNA) strand were chemically substituted with 2′-O-methylnucleotides or 2′-O-fluoronucleotides — small structural tweaks that protect the drug from rapid breakdown.

Studies in healthy volunteers showed a **70% reduction in PCSK9 protein within 60 minutes after infusion**, followed by a **40% reduction in LDL-C by day 3** of follow-up.

Inclisiran also has a practical advantage over its precursor: a modified structure that allows subcutaneous (under-the-skin) injection, whereas ALN-PCS had to be given by intravenous infusion. That matters to patients because subcutaneous injections can be given quickly in a clinic and are far less invasive.

## Pharmacokinetics: How the Drug Travels and Lasts in the Body

The peak concentration of the earlier IV drug, ALN-PCS, is reached right after a 60-minute infusion ends. Maximum drug concentration and the area under the concentration-time curve (a measure of total drug exposure over time) rise relatively linearly with dose.

Animal studies showed that the biggest reductions in PCSK9 and LDL-C occurred roughly 20 days after subcutaneous administration of inclisiran — and that drop did not depend on the dose given. What *did* depend on dose was duration: the higher the dose, the longer the lipid-lowering effect lasted. A small but progressive rise in LDL-C was observed from day 90 to day 120 after drug administration.

Chemical modification of ALN-PCS into ALN-PCSsc — that is, into inclisiran — enabled better stability and prolonged biological activity. Those favorable pharmacokinetic properties (how the body absorbs, distributes, and clears a drug) are why clinically inclisiran may be given subcutaneously on day 0, at month 3, and then every 6 months.

This regimen lowers LDL-C by about 50% in patients at high and very high cardiovascular risk, in patients with familial hypercholesterolemia (an inherited form of very high cholesterol), and in patients who cannot tolerate statins.

## Clinical Trials With Inclisiran: What the Numbers Show

Inclisiran's development followed the standard path: preclinical studies, phase 1 trials (small safety and dosing studies in healthy volunteers), phase 2 trials (larger dose-finding studies in patients), and phase 3 trials (large confirmatory trials, some still ongoing).

### Phase 1 Trial (Intravenous)

The first phase 1 study (trial registration NCT01437059) enrolled 32 healthy volunteers with LDL-C above 116 mg/dl. They received a single IV infusion of different doses of inclisiran. The primary endpoint was tolerability and safety; the secondary endpoint was the drug's pharmacodynamics and pharmacokinetics.

At the highest tested dose (0.4 mg/kg), serum PCSK9 dropped by about 70% and LDL-C by about 40%. The lipid-lowering effect was greatest in volunteers whose baseline LDL-C was highest — a pattern consistent with better responses in patients who have more room to improve.

### Phase 1 Trial (Subcutaneous)

Another phase 1 study tested subcutaneous injection safety in 24 healthy volunteers with LDL-C higher than 100 mg/dl (2.6 mmol/l). Participants were randomly assigned to either:

- a single injection of inclisiran at 25, 100, 300, 500, or 800 mg, or
- multiple injections: 125 mg once weekly for four doses; 250 mg twice weekly for two doses; or 300 mg or 500 mg monthly for two doses.

Key findings:

- A single dose of 100 mg or more was necessary to significantly lower LDL-C.
- Significant reductions in PCSK9 appeared after a single 300 mg dose.
- The maximal PCSK9 reduction was **74.5%**, seen after a 300 mg dose at day 84.
- The maximal LDL-C reduction was **50.6%**, seen after a 500 mg dose.
- A single 300 mg dose maintained reduced PCSK9 and LDL-C levels for more than 180 days.
- In multi-dose groups, the largest LDL-C reductions were 83.8% and 59.7% at day 84, seen in the group receiving 300 mg twice a month; the effect persisted for 196 days after the first dose.

### Phase 2: The ORION-1 Trial

ORION-1 (NCT02597127) was the first phase 2 trial of the lipid-lowering effect of inclisiran. This multicenter, randomized, placebo-controlled study was performed in 501 patients at high cardiovascular risk whose LDL-C remained elevated despite maximal tolerated doses of conventional lipid-lowering therapy.

Entry required LDL-C above 70 mg/dl in patients with cardiovascular disease, or above 100 mg/dl in patients without established cardiovascular disease. Patients were randomly assigned to receive either:

- a single dose of placebo or inclisiran (200, 300, or 500 mg), or
- two doses (on day 1 and day 90) of placebo or inclisiran (100, 200, or 300 mg).

Results were striking. At day 30 after the first dose, PCSK9 had fallen by **66.2%–74.0%** and LDL-C by **44.5%–50.5%**, depending on dose. The most pronounced LDL-C reduction was seen after a double 300 mg dose: at day 180, that group achieved a mean PCSK9 reduction of **69.1%** and an LDL-C reduction of **52.6%**. During follow-up through 240 days, LDL-C reductions ranged from 26.7% to 47.2% depending on dose — and significant reductions in PCSK9 and LDL-C persisted in every dose group.

The reduction percentages were similar to those produced by anti-PCSK9 monoclonal antibodies, but inclisiran's effect lasted significantly longer. The authors concluded that giving inclisiran every 6 months may be sufficient to sustain control.

### The Big Phase 3 Trials: ORION-10 and ORION-11

Results from two pivotal phase 3 trials were published in the New England Journal of Medicine in April 2020. Both were placebo-controlled, double-blind (neither patient nor researcher knew who received the drug), and randomized.

**ORION-10** (NCT03399370) enrolled 1,561 patients with atherosclerotic cardiovascular disease (ASCVD), i.e., disease caused by plaque buildup in arteries, such as prior heart attack, stroke, or peripheral artery disease, in North America.

**ORION-11** (NCT03400800) enrolled 1,617 patients worldwide (outside the USA) who had ASCVD or ASCVD-risk equivalents plus elevated LDL-C despite treatment with maximal tolerated statin doses.

In both trials, patients received subcutaneous injections of 284 mg inclisiran (equivalent to 300 mg inclisiran sodium) or placebo on day 1, day 90, and then every 6 months, over a 540-day period.

The co-primary endpoints were:

- the placebo-corrected percentage change in LDL-C from baseline to day 510;
- the time-adjusted percentage change in LDL-C from baseline between day 90 and day 540.

On day 510, LDL-C reductions were **52.3%** in ORION-10 and **49.9%** in ORION-11. In plain terms, a patient starting with an LDL-C of 100 mg/dl would end, on average, near 48–50 mg/dl — far below most treatment targets.

### Phase 3 Trials in Familial Hypercholesterolemia

Two more phase 3 trials focused on familial hypercholesterolemia (FH), the inherited condition that causes very high cholesterol from birth:

**ORION-9**: About 482 patients with heterozygous FH (inherited from one parent) in North America, Israel, Europe, and South Africa. Its primary endpoint was the percentage change in LDL-C at day 510 and the time-adjusted change from day 90 to 540.

**ORION-5**: 60 patients with homozygous FH (the rare, severe form inherited from both parents) in North America, Europe, and the Middle East. Its endpoint was analysis of LDL-C changes during treatment.

### Combined Phase 3 Results

A recent study pooling ORION-9, ORION-10, and ORION-11 confirmed that inclisiran lowered LDL-C by **51%** versus placebo. It also produced important related reductions:

- total cholesterol: down **37%**;
- apolipoprotein B (ApoB, the main protein in LDL particles): down **41%**;
- non-HDL-C (all “bad” cholesterol particles): down **45%**.

These lipid changes were associated with a **24% decrease in cardiovascular events** — defined as cardiac death, cardiac arrest, myocardial infarction (heart attack), or stroke.

## Adverse Effects: Side Effects and Safety Signals

Injectable drugs are generally more likely than oral pills to produce side effects. Inclisiran's side effects, however, are so infrequent that detecting them has required large, long clinical trials.

The most common adverse effects observed in inclisiran studies were local reactions at the injection site, such as a mild, self-limiting rash (one that goes away on its own) and hyperpigmentation (temporary darkening of the skin). Other reported events included:

- musculoskeletal pain (pain in muscles and bones);
- headache;
- cough;
- back pain;
- acute nasopharyngitis (the common cold); and
- hiccups.

Across published studies, adverse effects occurred at similar rates in placebo- and drug-treated groups. In ORION-1, for example:

- overall adverse effects occurred in **76% of both the placebo and inclisiran groups** — so about 3 in 4 patients in each group had some event, most mild;
- severe adverse effects occurred in only **8% of the placebo group** (about 1 in 12) versus **11% of the inclisiran group** (about 1 in 9);
- local injection-site reactions occurred in **3% of drug-treated patients**.

Injection-site events were also more common with the drug in the phase 3 trials: **2.6% versus 0.9%** in ORION-10, and **4.7% versus 0.5%** in ORION-11. The overall frequency of adverse events was otherwise generally similar between groups in both trials.

One patient experienced an asymptomatic (without symptoms) rise in two liver enzymes — γ-glutamyltransferase and alanine aminotransferase — but this was judged to be related to parallel treatment with atorvastatin rather than inclisiran itself. Critically, none of the patients in inclisiran studies discontinued therapy because of side effects.

The authors also reviewed theoretical safety concerns with RNA drugs in general:

-
**No immune system activation** has been observed so far with inclisiran.
-
**No prothrombotic activity** (tendency to cause blood clots) has been reported. They note that clot risk from phosphorothioate chemical modifications of RNA — which can activate platelet factors — remains theoretically possible, even at therapeutic drug concentrations, but has not materialized in inclisiran trials.
-
**No peripheral neuropathy** (nerve damage causing tingling or numbness) has been seen with inclisiran, although such nerve effects have been reported with other siRNA-type drugs.
- Inclisiran has also been proven safe in patients with impaired kidney function, and **no dose adjustment is needed** for these patients.

## Advantages and Disadvantages: Weighing the Pros and Cons

Based on ORION-9, ORION-10, and ORION-11, the review concludes that inclisiran appears to be the first-in-class (first of its kind) siRNA-based drug that both improves the lipoprotein profile and has a very good safety profile. Across these phase III studies, plasma PCSK9 was reduced by roughly **80%**.

The authors list the main advantages for patients:

-
**Convenient dosing.** In stable long-term treatment, the drug is injected only once every 3 to 6 months (schedule of 0–90–180 days), which promises much better adherence than daily oral statins or twice-monthly anti-PCSK9 antibody injections.
-
**Robust LDL-C lowering.** Roughly a 50% reduction compared with placebo, sustained over time.
-
**Durability.** Injections at day 0 and day 90, then every 6 months, keep cholesterol controlled all year.
-
**Options for statin-intolerant patients.** The drug was approved for use alone or with other lipid-lowering medications when statins cannot be used.

Notably, however, the 50% LDL-C reduction with inclisiran is slightly lower than with monoclonal antibody therapy. The drug's advantage is not extra potency — it is the injection schedule that greatly improves long-term compliance.

The review also lists disadvantages, some of which are the flip side of its advantages:

-
**Long-lasting side effects are hard to reverse.** The very property that makes inclisiran convenient — an effect that lasts up to 6 months per injection — means adverse effects, if they occur, also persist. There is no way to “turn off” or remove the drug if a patient develops a problem. The same long duration of action that is a benefit may, for safety, be a disadvantage.
-
**Currently used on top of oral drugs, not instead of them.** In all trials to date, inclisiran was given together with oral lipid-lowering agents. In clinical practice, at least initially, it will be an add-on rather than a replacement.
-
**Regulatory delays.** A new drug application (NDA) was submitted to the U.S. Food and Drug Administration (FDA) in December 2019 for patients with ASCVD and familial hypercholesterolemia, but approval was delayed by COVID-19-related restrictions and manufacturing inspection delays.

## Clinical Implications: What This Means for Patients

This drug changes the practical conversation about cholesterol treatment. A patient who cannot tolerate statins, or who cannot reach LDL-C goal with daily pills or frequent antibody injections, now has an option requiring four injections in the first year — then only two per year.

European medicine regulators have already acted: on December 9, 2020, the European Medicines Agency (EMA) approved inclisiran for use in the European Union in adults with primary hypercholesterolemia (heterozygous familial and nonfamilial) or mixed dyslipidemia, as an adjunct to diet. The drug is now entering European markets.

The review stresses that inclisiran's clinical benefit goes beyond LDL-C alone. The combined phase 3 analysis showed parallel reductions in total cholesterol (37%), apolipoprotein B (41%), and non-HDL-C (45%), along with a 24% drop in hard cardiovascular events. That 24% relative reduction means fewer heart attacks, strokes, cardiac arrests, and cardiac deaths among treated patients — the outcomes patients care about most.

## Limitations and Unanswered Questions

The most important unanswered question is whether inclisiran reduces cardiovascular events and mortality over the long term. The 24% event reduction seen in pooled analysis is encouraging, but it came as a secondary observation. Definitive answers will come from ongoing multinational trials:

-
**ORION-4** — assessing cardiovascular outcomes in adults with established atherosclerotic cardiovascular disease;
-
**ORION-5** — assessing effects on cardiovascular outcomes in adults with homozygous familial hypercholesterolemia.

Another key question is pediatric safety. Two placebo-controlled, multinational phase III trials — ORION-13 (NCT04659863) and ORION-16 (NCT04652726) — are recruiting adolescents aged 12 to 17 with homozygous and heterozygous familial hypercholesterolemia, respectively, who have elevated LDL-C despite stable standard lipid-lowering care. These trials will assess short-term efficacy in younger patients.

The review notes that if these safety and outcome questions are not answered favorably by ongoing trials, that could disadvantage inclisiran. Also worth noting: because the drug remains active for about 6 months per dose, any long-term adverse effect would be difficult to reverse quickly, and data on hard outcomes remain awaited. Finally, as with any new agent, long-term tolerability, efficacy, and safety still need to be confirmed in larger groups of patients and in real-world use over many years.

## Recommendations for Patients

This research has several practical takeaways for patients who are navigating cholesterol treatment decisions:

1.
**Know your LDL-C target.** Whether you are at moderate, high, very high, or extremely high cardiovascular risk determines your goal. Ask your doctor what number you are aiming for and whether your current treatment is on track.
1.
**Do not stop a statin because of mild muscle aches without talking to your doctor.** Statin intolerance is real, but alternatives exist — including adding or switching to nonstatin therapies like inclisiran. A 2021 review cannot replace individualized medical advice, so discuss your symptoms openly.
1.
**Ask about inclisiran if you have not reached your goal** — especially if you have established atherosclerotic cardiovascular disease, familial hypercholesterolemia, or documented statin intolerance. Since inclisiran is approved in the European Union and under regulatory review in the U.S., availability varies by country.
1.
**Expect it to be an add-on, initially.** In all clinical trials, patients continued oral lipid-lowering therapy. Plan, with your clinician, for inclisiran to be layered on top of your current regimen rather than replacing pills — at least for now.
1.
**Understand the dosing rhythm.** Inclisiran is given by subcutaneous injection on day 1, again at day 90, and then every 6 months. That is four shots in the first year and roughly two per year after that, together with ongoing monitoring of your cholesterol levels.
1.
**Watch for injection-site reactions.** The most common side effects — mild rash, skin darkening, and local soreness — occur in a minority of patients (2.6%–4.7% in phase 3 trials, compared with 0.5%–0.9% for placebo) and are generally mild and self-limiting. Tell your doctor about any reaction that is painful, worsens, or persists.
1.
**Do not rely on this drug alone for heart health.** Inclisiran lowers the “bad” cholesterol your liver produces, but a heart-protective diet, regular exercise, weight control, and not smoking remain essential parts of cardiovascular risk reduction. The drug is an adjunct to diet and lifestyle, not a substitute.
1.
**Keep perspective on the numbers.** A ~50% LDL-C reduction is similar in percentage terms to what high-intensity statins achieve, and slightly less than the 55–65% reductions reported with anti-PCSK9 monoclonal antibodies. The true advantage of inclisiran is durability and convenience over the long term — which translates into better adherence, and adherence is what actually prevents heart attacks and strokes.

## Frequently Asked Questions

### I cannot tolerate statins because of muscle aches. Can inclisiran be an option for me?

Yes. Inclisiran was studied in patients who cannot tolerate statins, and it can be used alone or with other lipid-lowering medications when statins are not an option. In clinical trials, it lowered LDL cholesterol by about 50% compared with placebo. Talk to your doctor about whether inclisiran is appropriate for your situation.

### How is inclisiran given and how often do I need injections?

Inclisiran is given as a small injection under the skin, called a subcutaneous injection. In stable long-term treatment, the schedule is one injection on day 1, another at day 90, and then one injection every 6 months. That means four shots in the first year and about two per year after that.

### How much does inclisiran lower LDL or 'bad' cholesterol?

In the large phase 3 trials, inclisiran lowered LDL cholesterol by about 50% compared with placebo. For example, in one trial the reduction was 52.3% and in another 49.9% at day 510. A patient starting with an LDL of 100 mg/dl would end near 48–50 mg/dl on average.

### What are the most common side effects of inclisiran?

The most common side effects are injection-site reactions, such as a mild rash, temporary darkening of the skin, or local soreness. In phase 3 trials, these occurred in about 2.6% to 4.7% of patients receiving the drug, compared with 0.5% to 0.9% receiving placebo. They were generally mild and went away on their own.

### Can side effects of inclisiran be reversed quickly if they happen?

No. Because inclisiran remains active for about 6 months per injection, side effects, if they occur, also last that long. There is no way to turn off or remove the drug once it is given. This is a disadvantage to consider, even though such side effects have been infrequent in trials.

### Is inclisiran a replacement for statins or other cholesterol pills?

In all clinical trials to date, inclisiran was added on top of oral lipid-lowering drugs, not used instead of them. So in clinical practice, at least initially, it will be an add-on to your current regimen rather than a replacement. Always discuss any medication changes with your doctor.

### Does inclisiran reduce heart attacks or strokes, not just cholesterol numbers?

In a combined analysis of three phase 3 trials, inclisiran lowered LDL cholesterol by 51% and was associated with a 24% decrease in cardiovascular events defined as cardiac death, cardiac arrest, heart attack, or stroke. However, this was a secondary observation, and long-term outcome trials are still ongoing.

### I have high cholesterol and my doctor suggests inclisiran, the twice-a-year cholesterol shot. Should I get a second opinion before starting it?

A second opinion is worth considering before starting inclisiran because it is an add-on to oral lipid-lowering therapy, not a replacement, and its effect lasts up to 6 months, so any side effect cannot be quickly reversed. Long-term data on heart attacks and strokes are still awaited. LDL reductions average about 50%, and the main advantage is convenience. A second opinion can confirm your LDL target, whether true statin intolerance exists, and whether inclisiran or another PCSK9-targeted option fits your risk profile. Diagnostic Detectives Network provides independent expert second opinions.

## Source Information

**Original article title:** Advantages and Disadvantages of Inclisiran- A Small Interfering Ribonucleic Acid Molecule Targeting PCSK9—A Narrative Review

**Publication details:** Cardiovascular Therapeutics, Volume 2022, Article ID 8129513, 6 pages. Published February 10, 2022 (received December 15, 2021; accepted January 21, 2022). Open access under the Creative Commons Attribution License. DOI: https://doi.org/10.1155/2022/8129513. Academic Editor: Brian Tomlinson.

**Funding and conflicts:** The authors declared that the funders had no role in the review, and that they have no conflicts of interest. All authors participated equally in the study.

**Key trials referenced in the review:** ORION-1 (NCT02597127), ORION-9, ORION-10 (NCT03399370), ORION-11 (NCT03400800), ORION-13 (NCT04659863), ORION-16 (NCT04652726), plus earlier trials NCT01437059 and other phase 1 studies of subcutaneous inclisiran.

*Note: This patient-friendly article is based on peer-reviewed research. It is provided for educational purposes and does not replace advice from your physician or pharmacist. Always discuss medication changes, including adding inclisiran, with your healthcare provider.*


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