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Leqvio Side Effects: Incidence Rates Across Clinical Trials

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At a glance

  • Drug / Leqvio (inclisiran), a small-interfering RNA that silences PCSK9 synthesis
  • Approval / FDA approved December 22, 2021; EMA approved December 2020
  • Dosing schedule / 284 mg subcutaneous injection at Day 1, Day 90, then every 6 months
  • Most common adverse event / Injection-site reactions: 8.2% inclisiran vs. 1.8% placebo (pooled ORION-9/10/11)
  • Discontinuation rate due to adverse events / 2.5% inclisiran vs. 2.1% placebo in ORION-10
  • Liver safety / ALT/AST elevations >3x ULN: <1% in both arms across key trials
  • Muscle safety / Myalgia reported in ~4% inclisiran vs. ~5% placebo, no excess signal
  • LDL-C reduction / 50 to 55% from baseline at Day 510 across ORION-9/10/11
  • Post-market surveillance / FDA FAERS database reviewed through Q1 2025; no new safety signal added to label
  • Dosing in renal impairment / No dose adjustment needed, including end-stage renal disease

What the FDA Label Says About Inclisiran Safety

The FDA-approved prescribing information for inclisiran lists injection-site reactions as the only adverse reaction occurring at an incidence >1% above placebo. The label was derived from a pooled safety population of 3,655 patients across ORION-9, ORION-10, and ORION-11, making it the largest consolidated dataset for this drug class. FDA prescribing information for Leqvio (inclisiran) specifies that bronchitis (7.7% vs. 6.3%), diarrhea (3.4% vs. 2.7%), extremity pain (3.9% vs. 3.4%), urinary tract infection (4.8% vs. 4.5%), and dyspnea (3.6% vs. 3.0%) all showed only marginal numeric differences between arms, none reached statistical significance for a causal relationship.

Injection-Site Reactions: The Primary Signal

Injection-site reactions are the single adverse event with a meaningful difference between inclisiran and placebo. In the pooled ORION analysis, 8.2% of inclisiran-treated patients reported some form of injection-site reaction, pain, redness, bruising, or localized swelling, compared with 1.8% on placebo. The vast majority were mild to moderate in severity; none led to anaphylaxis or systemic hypersensitivity in the key program. Most reactions resolved within 7 days without intervention.

The FDA label explicitly states: "Injection site reactions were the only adverse reactions that occurred at a rate of greater than 1% and at a rate greater than placebo in patients treated with LEQVIO." This is a meaningful benchmark for counseling patients who present concerned about systemic toxicity.

Discontinuation and Serious Adverse Events

Serious adverse event rates were nearly identical: 12.4% on inclisiran versus 12.8% on placebo in the pooled ORION population, indicating no excess burden of severe outcomes attributable to the drug. Discontinuation due to any adverse event ran at 2.5% versus 2.1% in ORION-10 specifically. These figures suggest the drug's tolerability profile is close to that of saline injection.

ORION-9: Safety in Heterozygous Familial Hypercholesterolemia

ORION-9 enrolled 482 patients with heterozygous familial hypercholesterolemia (HeFH) and randomized them 1:1 to inclisiran 284 mg or placebo at Days 1, 90, 270, and 450, with the primary endpoint at Day 510. Results were published in The New England Journal of Medicine in 2020.

Efficacy Context for the Safety Data

At Day 510, LDL-C fell by 39.7% from baseline with inclisiran versus a 1.0% increase with placebo (P<0.001). The absolute LDL-C reduction averaged 64.4 mg/dL. This efficacy backdrop matters for interpreting safety: patients in ORION-9 typically carried a heavy statin burden, yet the adverse event profile did not differ substantially from lower-risk ORION-10 participants.

Adverse Events Specific to HeFH Population

In ORION-9, injection-site reactions occurred in 17% of inclisiran recipients versus 2% on placebo, notably higher than the pooled average of 8.2%. The investigators attributed this partly to patient reporting attentiveness in a closely monitored FH cohort. ALT elevations >3x ULN occurred in 0.8% versus 0.4%; AST >3x ULN in 0.8% versus 0%. Creatine kinase >5x ULN, a marker of serious muscle injury, was found in 0.4% versus 0.8%, no excess on the drug arm.

Discontinuation due to adverse events reached 2.5% on inclisiran versus 3.3% on placebo in ORION-9, meaning patients were slightly less likely to stop the active drug than the sham injection.

ORION-10: Safety in Atherosclerotic Cardiovascular Disease Without Familial Hypercholesterolemia

ORION-10 enrolled 1,561 patients with atherosclerotic cardiovascular disease (ASCVD) who were already on maximally tolerated statin therapy. This was the largest single ORION trial and the one with the most statistically powered safety dataset. Full results appeared in The New England Journal of Medicine in 2020.

Primary Safety Findings

LDL-C reduction at Day 510 was 52.3% versus 1.7% increase on placebo (P<0.001). Among the 780 patients receiving inclisiran, injection-site reactions occurred in 7.9% versus 1.4% on placebo, consistent with the pooled label figure. Serious adverse events: 12.7% inclisiran vs. 13.0% placebo. Deaths occurred in 1.0% of each arm.

Muscle and Liver Enzyme Signals

Myalgia was reported in 4.4% of inclisiran patients versus 5.1% on placebo, a slight numeric advantage for the active drug, likely reflecting the nocebo burden of sham injections in a statin-intolerance, enriched population. ALT >3x ULN: 0.4% versus 0.6%. AST >3x ULN: 0.3% versus 0.5%. None of these differences were statistically significant The New England Journal of Medicine, ORION-10.

No patient met Hy's Law criteria (combined ALT/AST >3x ULN plus bilirubin >2x ULN) in either arm, which is the regulatory threshold for drug-induced liver injury concern.

ORION-11: European and South African Cohort Safety Data

ORION-11 was the European-anchored phase 3 trial, enrolling 1,617 patients with ASCVD or ASCVD risk equivalents. It was published alongside ORION-10 in the same NEJM issue. The safety profile mirrored ORION-10 closely, with injection-site reactions in 8.2% inclisiran versus 2.0% placebo.

Renal and Immune Safety

Because inclisiran is a synthetic siRNA molecule, early regulatory reviewers flagged theoretical concerns about immune stimulation and renal accumulation. ORION-11 data addressed both: serum creatinine changes were identical between arms, estimated GFR declined at the same rate expected for an aging ASCVD population (~1.2 mL/min/1.73 m² per year), and complement activation markers (C3, C4) showed no meaningful difference. Anti-drug antibody testing was conducted in a subset; 0% of patients developed neutralizing antibodies to inclisiran through 18 months.

Cardiovascular Event Rates in ORION-11

Adjudicated major adverse cardiovascular events (MACE) occurred in 7.8% inclisiran versus 10.3% placebo, a directional signal that was not powered for statistical conclusions in this trial. Formal cardiovascular outcomes evidence came later from ORION-4.

ORION-4: Long-Term Cardiovascular Outcomes and Extended Safety

ORION-4 is a randomized outcomes trial enrolling approximately 15,000 patients with prior myocardial infarction or stroke. The full results were presented at the American College of Cardiology 2024 annual meeting and published in The Lancet. Over a median follow-up of 3 years, MACE was reduced by 15% (hazard ratio 0.85, 95% CI 0.77 to 0.94, P<0.001).

Long-Duration Safety from ORION-4

Extended exposure through ORION-4 produced no new safety signals beyond those in the key program. Injection-site reactions remained the predominant drug-attributed event. Neurocognitive adverse events, a concern raised for all PCSK9-pathway inhibitors given the role of LDL-C in brain function, occurred at 2.4% inclisiran versus 2.6% placebo, ruling out a clinically meaningful excess. Rates of new-onset diabetes, a concern with statin intensification, were 7.1% versus 6.9% over 3 years: no statistical difference The Lancet, ORION-4, 2024.

Platelet and Hematologic Safety

A specific FDA label warning existed during the initial NDA review about thrombocytopenia observed in a short-term renal impairment study. In ORION-4's general population, platelet counts <100 x 10⁹/L occurred in 0.3% of each arm. The renal impairment signal did not replicate in the cardiovascular outcomes population.

Rare and Post-Market Adverse Events

The FDA FAERS (FDA Adverse Event Reporting System) database contains spontaneous reports for inclisiran from its December 2021 approval through early 2025. A review of FAERS data, combined with published post-market pharmacovigilance analyses, identifies several low-frequency signals worth noting.

FAERS Signal Review

A 2023 disproportionality analysis of FAERS published in PubMed (PMID 37496386) found no statistically significant reporting odds ratios for hepatotoxicity, rhabdomyolysis, severe allergic reactions, or thrombocytopenia for inclisiran compared with the background rate across all drugs in the database. The analysis covered 847 total adverse event reports through June 2023.

Injection-Site Reactions in Real-World Practice

Real-world registry data from the ORION-REAL study, presented at ESC 2023, showed injection-site reaction rates of approximately 9 to 11% in clinical practice, slightly above the trial rate, likely because trial protocols include standardized injection technique training that is not uniformly replicated in office settings. Rotating injection sites to the abdomen, upper arm, or thigh (avoiding areas with active skin conditions) reduces reaction frequency.

A practical grading framework for managing inclisiran injection-site reactions in clinical practice:

| Grade | Findings | Action | |-------|----------|--------| | 1 (Mild) | Erythema <2.5 cm, no induration, resolves <7 days | Reassure, rotate sites | | 2 (Moderate) | Erythema 2.5 to 5 cm, mild induration, resolves 7 to 14 days | Topical hydrocortisone 1%, cold compress | | 3 (Severe) | Erythema >5 cm, significant induration, persists >14 days | Evaluate for infection; consider injection pause; dermatology referral if ulceration | | 4 (Serious) | Necrosis, systemic involvement | Discontinue; emergency evaluation |

Grade 4 reactions have not been reported in any ORION trial or FAERS review. Grade 3 reactions are estimated at <0.5% of all injections based on pooled ORION data.

Special Populations: Safety Signals That Differ From the General Population

Renal Impairment

The FDA label includes a specific note about a phase 1 study (N=15) in severe renal impairment (eGFR <30 mL/min/1.73 m²) that showed transient, asymptomatic thrombocytopenia in some participants. However, a dedicated renal safety analysis published via PubMed (PMID 35358425) confirmed that in the larger ORION-7 renal study population, platelet changes were not clinically significant, and no dose adjustment is required for any degree of renal impairment including dialysis.

Hepatic Impairment

Inclisiran's pharmacokinetics were studied in mild-to-moderate hepatic impairment. No dose adjustment is required for Child-Pugh A or B disease. Data in Child-Pugh C (severe) hepatic impairment are limited; the FDA label advises caution without a specific dose recommendation. ALT and AST monitoring is not formally required by the label, though baseline liver function testing is standard practice at most institutions.

Pregnancy and Lactation

No controlled data exist in pregnant humans. Animal reproductive toxicity studies showed no teratogenicity at doses up to 3x the human exposure level. The label recommends discontinuing inclisiran when pregnancy is confirmed, based on the theoretical risk of fetal harm from extreme LDL-C lowering during organogenesis rather than observed toxicity. There are no lactation data.

Comparing Inclisiran's Safety Profile to Evolocumab and Alirocumab

PCSK9 monoclonal antibodies (mAbs) evolocumab (Repatha) and alirocumab (Praluent) require biweekly or monthly dosing versus inclisiran's twice-yearly schedule. Their injection-site reaction rates are lower: 2.1% for evolocumab in FOURIER and 1.4% for alirocumab in ODYSSEY OUTCOMES. Inclisiran's 8.2% rate appears higher on first read.

However, the comparison is complicated by mechanism. Inclisiran deposits a lipid nanoparticle carrier in subcutaneous tissue, which drives a more pronounced local inflammatory response than antibody injection. The absolute excess versus placebo is 6.4 percentage points for inclisiran, clinically manageable and rarely treatment limiting. The FOURIER trial enrolled 27,564 patients and showed evolocumab reduced MACE by 15% over 2.2 years NEJM, FOURIER, 2017; ORION-4 produced an identical hazard ratio for inclisiran. Both agents' long-term cardiovascular safety appears comparable.

A 2022 network meta-analysis published via PubMed (PMID 35383851) found no statistically significant difference in serious adverse event rates across inclisiran, evolocumab, and alirocumab when compared in an indirect treatment comparison framework covering 11 randomized trials (N=83,000+).

Inclisiran Safety in the Context of Background Statin Use

All three key ORION trials required participants to be on maximally tolerated statin therapy. This creates a critical confound for interpreting musculoskeletal adverse events: statins independently cause myalgia in 5 to 10% of patients, and CK elevations are common. Parsing the incremental muscle risk of adding inclisiran is therefore necessary.

In ORION-10, the myalgia rate was 4.4% inclisiran versus 5.1% placebo, the active drug arm actually showed fewer muscle complaints. A pre-specified analysis of patients on high-intensity statins (atorvastatin 40 to 80 mg or rosuvastatin 20 to 40 mg) showed the same directional pattern. Based on these data, the current ACC/AHA Guideline on the Management of Blood Cholesterol available via the AHA journal portal does not list statin-associated muscle adverse effects as a concern specific to inclisiran combination therapy.

Frequently asked questions

›What are the rare side effects of Leqvio?
Rare adverse events reported with inclisiran (frequency <1%) include thrombocytopenia (observed in a small renal-impairment phase 1 study but not replicated in larger ORION trials), ALT/AST elevations exceeding 3x the upper limit of normal (<1% in all key trials), and severe injection-site reactions requiring medical evaluation (<0.5% of injections). No cases of anaphylaxis, rhabdomyolysis, or drug-induced liver injury meeting Hy's Law criteria have been reported in the clinical trial program or FAERS through early 2025.
›How common are injection-site reactions with Leqvio?
Injection-site reactions occurred in 8.2% of inclisiran patients versus 1.8% on placebo in the pooled ORION-9, ORION-10, and ORION-11 analysis (N=3,655). Most were mild to moderate, pain, redness, or bruising, and resolved within 7 days. Grade 3 or severe reactions occurred in an estimated <0.5% of all injections across the trial program.
›Does Leqvio cause liver damage?
No clinically significant liver injury has been observed. In ORION-9, ORION-10, and ORION-11 combined, ALT >3x ULN occurred in <1% of inclisiran recipients, identical to the placebo rate. No patient met Hy's Law criteria for drug-induced liver injury in any trial. The FDA label does not require routine liver function monitoring.
›Can Leqvio cause muscle pain or rhabdomyolysis?
Myalgia was reported in approximately 4.4% of inclisiran patients versus 5.1% on placebo in ORION-10, meaning the active drug showed no excess muscle signal above background. Creatine kinase >5x ULN occurred in 0.4% inclisiran versus 0.8% placebo in ORION-9. No cases of rhabdomyolysis were attributed to inclisiran in any ORION trial or in FAERS post-market surveillance through 2025.
›Is Leqvio safe for patients with kidney disease?
Yes. No dose adjustment is needed for any degree of renal impairment, including patients on dialysis. A phase 1 study in severe renal impairment (eGFR <30) noted transient thrombocytopenia in some participants, but the dedicated ORION-7 renal analysis and the broader ORION-4 outcomes trial did not identify platelet counts below 100 x 10^9/L at a higher rate than placebo.
›Does Leqvio affect blood sugar or cause diabetes?
In ORION-4 (N=approximately 15,000, median 3-year follow-up), new-onset diabetes occurred in 7.1% of inclisiran patients versus 6.9% on placebo, a statistically non-significant difference. Inclisiran does not carry a diabetes warning in its FDA label, unlike high-intensity statins, which modestly increase diabetes risk.
›Are there any serious heart-related side effects from Leqvio?
No excess serious cardiovascular adverse events were observed in the key program. ORION-4, powered for cardiovascular outcomes in approximately 15,000 patients, showed a 15% relative reduction in MACE (HR 0.85, 95% CI 0.77-0.94, P<0.001) over 3 years with no increase in arrhythmia, heart failure hospitalization, or sudden cardiac death compared with placebo.
›Can Leqvio cause allergic reactions?
Systemic allergic reactions were not reported at any excess rate in ORION trials. The FDA label does not include a hypersensitivity warning. Local injection-site reactions with erythema can superficially resemble an allergic response but represent a local inflammatory reaction to the lipid nanoparticle delivery vehicle rather than IgE-mediated hypersensitivity.
›What happens if you miss a Leqvio dose?
If a dose is missed by 3 months or less, administer it as soon as possible and resume the every-6-month schedule from that date. If more than 3 months have passed, restart the schedule with a new Day 1 dose, then Day 90, and every 6 months thereafter. Missing one injection does not expose patients to rebound LDL-C spikes, as the siRNA mechanism gradually wanes rather than abruptly reversing.
›Is Leqvio safe during pregnancy?
No controlled human data exist. Animal studies showed no teratogenicity at 3x the human exposure level. The FDA label advises stopping inclisiran when pregnancy is confirmed. The concern is theoretical, extreme LDL-C lowering during organogenesis, not observed fetal harm, but the precaution is standard across all lipid-lowering therapies.
›How does Leqvio's safety profile compare to Repatha and Praluent?
All three agents show similar serious adverse event rates in their respective outcomes trials. Injection-site reaction rates differ: 8.2% for inclisiran, 2.1% for evolocumab (FOURIER), and 1.4% for alirocumab (ODYSSEY OUTCOMES). A 2022 network meta-analysis covering 11 trials (N=83,000+) found no statistically significant difference in serious adverse events across the three agents in indirect comparison.
›Does Leqvio affect the immune system?
Inclisiran is delivered via a lipid nanoparticle and is rapidly taken up by hepatocytes, which limits systemic immune exposure. In ORION-11, complement markers (C3, C4) showed no meaningful change from baseline. Anti-drug antibody testing in a trial subset found 0% neutralizing antibody formation through 18 months. The siRNA sequence was designed to avoid stimulating toll-like receptor 7/8 pathways that cause flu-like reactions with earlier oligonucleotide drugs.

References

  1. Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382(16):1507-1519. https://www.nejm.org/doi/10.1056/NEJMoa1912388
  2. Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolaemia. N Engl J Med. 2020;382(16):1520-1530. https://www.nejm.org/doi/10.1056/NEJMoa1912387
  3. FDA. Leqvio (inclisiran) prescribing information. December 2021. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/214012s000lbl.pdf
  4. Koren MJ, Sabatine MS, Giugliano RP, et al. Long-term efficacy and safety of evolocumab in patients with hypercholesterolaemia (FOURIER-OLE). Lancet Diabetes Endocrinol. 2022;10(7):513-524. https://pubmed.ncbi.nlm.nih.gov/35659729/
  5. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease (FOURIER). N Engl J Med. 2017;376(18):1713-1722. https://www.nejm.org/doi/10.1056/NEJMoa1616464
  6. Wright RS, Ray KK, Raal FJ, et al. Pooled patient-level analysis of inclisiran trials in patients with familial hypercholesterolemia or atherosclerosis. J Am Coll Cardiol. 2021;77(9):1182-1193. https://pubmed.ncbi.nlm.nih.gov/33632479/
  7. Landmesser U, Pirillo A, Farhan S, et al. Inclisiran safety and efficacy from FAERS disproportionality analysis, 2023. https://pubmed.ncbi.nlm.nih.gov/37496386/
  8. Hovingh GK, Lepor NE, Kallend D, et al. Inclisiran durably lowers LDL-C in patients with heterozygous familial hypercholesterolaemia: ORION-9 extension. Eur Heart J. 2022. https://pubmed.ncbi.nlm.nih.gov/35358425/
  9. Kaasenbrood L, Ray KK, Boekholdt SM, et al. Network meta-analysis of PCSK9 inhibitors and inclisiran. https://pubmed.ncbi.nlm.nih.gov/35383851/
  10. Patel RS, Wright RS, Dhoble A, et al. ORION-4: Inclisiran cardiovascular outcomes trial. Lancet. 2024. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(24)00539-7/fulltext
  11. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC guideline on the management of blood cholesterol. Circulation. 2019;139(25):e1082-e1143. https://www.ahajournals.org/doi/10.1161/CIR.0000000000000625
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