Instalab ResearchAcross the pivotal ORION-9, ORION-10, and ORION-11 trials, which together enrolled more than 3,400 patients, the overall rates of side effects were similar in Leqvio and placebo groups. The one exception was injection site reactions. About 8% of patients on Leqvio reported redness, pain, or swelling where the shot was given, compared to about 2% in placebo groups. These reactions were mild or moderate, typically resolved within days, and led to treatment discontinuation in less than 1% of cases.
One of the most reassuring findings from clinical research is that Leqvio does not appear to increase the risk of severe complications compared to placebo. In the pooled safety analysis covering more than 9,500 patient-years of exposure, serious adverse events occurred at nearly identical rates between groups. Hepatic injury, kidney problems, abnormal blood sugar, and elevated muscle enzymes were no more frequent in those receiving Leqvio than those receiving placebo.
Real-world safety data adds more detail. An analysis of over 2,300 reports from the FDA’s Adverse Event Reporting System found that joint pain, muscle pain, and injection site discomfort were the most frequently observed issues. A small number of reports described more serious events such as acute kidney injury or heart attack, but because patients prescribed Leqvio often already have high cardiovascular risk, it is difficult to prove these events were caused by the drug itself. Controlled trials to date have not shown an increased risk of these complications.
The durability of Leqvio is one of its biggest advantages. In the ORION-3 extension trial, patients who continued Leqvio for nearly five years maintained an average LDL cholesterol reduction of 44 - 47% compared to baseline. Importantly, no new safety issues emerged over that extended period. Injection site reactions were still the most common side effect, reported in about 14% of patients over multiple years, but they remained mild and did not increase with ongoing use.
Another potential concern with long-term use of therapies like this is the development of antibodies that might reduce effectiveness or cause immune reactions. In trials, fewer than 5% of patients developed antibodies against Leqvio, and only about 1% had persistent antibodies. These findings were not associated with increased side effects or reduced cholesterol-lowering benefit, suggesting that immune complications are unlikely to be a problem.
Because high cholesterol is often paired with diabetes or obesity, researchers examined safety and effectiveness across these groups. In pooled analyses of the ORION-9, ORION-10, and ORION-11 trials, patients with diabetes or obesity saw LDL reductions nearly identical to those without these conditions, averaging around 50%. Injection site reactions were the most frequent side effect in all groups, but there were no significant differences in rates of serious events.
Older adults, a group often more prone to medication side effects, also tolerated Leqvio well. Reports of muscle aches and joint stiffness were slightly more common in older patients, but rates were similar to those seen in placebo groups.
Clinical trials are essential, but real-world use can reveal side effects not captured in controlled environments. At a major U.S. academic medical center, 26 patients received a total of 61 doses of Leqvio over 19 months. Only two patients, or 7.7%, discontinued due to side effects. One experienced flu-like symptoms, while another developed both skin and cardiovascular complaints. The vast majority tolerated treatment without issue, providing reassurance that Leqvio’s safety profile extends beyond the trial setting.
For patients, the evidence paints a clear picture. Leqvio lowers LDL cholesterol by about 50% with just two injections per year, a level of convenience unmatched by other treatments. The most common side effects are injection site reactions, but these are usually mild and short lived. Severe side effects are rare, and large trials covering thousands of patients over several years have not shown increased risks of liver injury, kidney problems, muscle breakdown, or diabetes.
Taken together, the evidence supports that Leqvio is both effective and safe for long-term cholesterol management. Patients starting the therapy should expect possible injection site reactions and remain under routine monitoring. For most, the benefits of sustained cholesterol lowering and the reduced treatment burden far outweigh the risks.
