Leqvio Side Effects: What the Clinical Data Shows
Injection-Site Reactions Are the Primary Side Effect
The most consistent side effect across all Leqvio trials is mild reactions at the injection site. In the pooled phase 3 analysis of ORION-9, ORION-10, and ORION-11 (3,660 patients total), injection-site adverse events occurred in 5.0% of patients receiving inclisiran versus 0.7% on placebo. These reactions included redness, pain, and itching. None were classified as severe or persistent.
Rates Varied Across Individual Trials
In the ORION-10 trial (patients with atherosclerotic cardiovascular disease), injection-site events occurred in 2.6% of inclisiran patients versus 0.9% on placebo. In ORION-11 (patients with ASCVD or risk equivalents), the rate was 4.7% versus 0.5%. A 2025 meta-analysis of 7 randomized controlled trials (4,790 patients) found a risk ratio of 6.50 (95% CI: 3.20 to 13.20) for injection-site events, confirming the pattern is real but confirming severity remains mild.
Serious Adverse Events Match Placebo
Beyond injection-site reactions, the safety profile of Leqvio closely mirrors placebo. The pooled phase 3 analysis found that liver function, kidney function, creatine kinase, and platelet counts did not differ between groups. A safety analysis across 7 clinical trials (3,576 inclisiran patients, up to 6 years of exposure, over 9,900 patient-years) showed that serious adverse events, events leading to discontinuation, hepatic events, muscle events, kidney events, and incident diabetes all accrued at comparable rates.
Long-Term Safety Over Multiple Years
The ORION-8 trial provides the longest follow-up data. With a mean exposure of 3.7 years and maximum of 6.8 years across 3,274 patients (over 12,000 patient-years), no attenuation of LDL-lowering was observed and no new safety signals emerged. Injection-site events (all mild or moderate) occurred in 5.9% of patients. The ORION-3 extension trial showed similar results over 4 years, with injection-site reactions in 14% of patients cumulatively but serious drug-related events in only 1%.
Anti-Drug Antibodies Are Uncommon
A potential concern with any biologic therapy is whether the body develops antibodies against the drug. In the 7-trial safety analysis, treatment-induced anti-drug antibodies were uncommon at 4.6%, and only 1.4% were persistent. These antibodies were not associated with greater incidence of serious adverse events, events leading to discontinuation, or reduced cholesterol-lowering efficacy.
Safety Across Age, Kidney Function, and Diabetes Status
A pooled analysis of ORION-10 and ORION-11 (2,975 patients with ASCVD) stratified safety by age, sex, race, kidney function, body mass index, and glycemic status. The Leqvio safety profile was consistent across all subgroups. Among patients 75 and older (n=458), those with diabetes (n=1,182), those with obesity (n=1,474), and those with moderate-to-severe chronic kidney disease (n=538), no differential safety concerns were identified.
Meta-Analysis Confirms No Increase in Major Events
The 2025 meta-analysis of 7 RCTs found no significant increase in all-cause mortality (RR 0.92, 95% CI: 0.54 to 1.54), major adverse cardiovascular events (RR 0.98, 95% CI: 0.82 to 1.17), new or worsening type 2 diabetes (RR 1.02, 95% CI: 0.85 to 1.21), or nasopharyngitis (RR 1.10, 95% CI: 0.83 to 1.45). Injection-site reactions remained the only outcome with a statistically significant increase.
How Leqvio Compares to Daily Cholesterol Medications
Unlike statins, which can cause muscle pain and liver enzyme elevations in some patients, Leqvio has not shown increased rates of these effects in controlled trials. Unlike PCSK9 monoclonal antibodies (which require injections every 2 to 4 weeks), Leqvio is administered just twice yearly after an initial dose and a 3-month follow-up dose. For patients who need additional LDL lowering beyond statins, this combination of efficacy and tolerability is why Leqvio has drawn attention as a long-term treatment option.