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Instalab ResearchThe cholesterol-lowering power of Leqvio is impressive and well-documented. Phase III clinical trials (ORION-10 and ORION-11) showed that patients already taking statins experienced about a 50% additional reduction in LDL cholesterol compared to placebo. That's on top of whatever benefit they were already getting from their statin.
Even more encouraging, this effect holds up over time. A 4-year extension study (ORION-3) found LDL reductions averaging 44-48% were maintained consistently, with no weakening of the effect. The drug also reduced PCSK9 (the protein it targets) by 62-78%.
A recent phase 4 trial (VICTORION-Difference) comparing an inclisiran-based approach to standard care found that 85% of patients reached their LDL cholesterol goals, compared to just 31% with conventional therapy. LDL dropped by roughly 59.5% in the inclisiran group.
This is where things get more nuanced. We know from decades of research that lowering LDL cholesterol reduces cardiovascular events. Large meta-analyses show that for every 1 mmol/L reduction in LDL, major cardiovascular events drop by about 26%, regardless of whether you achieve that reduction through statins or other drugs.
For Leqvio specifically, there are encouraging early signals. A pooled analysis of ORION-9, ORION-10, and ORION-11 trials (3,655 patients followed for 18 months) found a 26% relative reduction in composite major cardiovascular events (heart attack, stroke, death, and unstable angina). However, the reductions in individual outcomes like heart attack or stroke alone weren't statistically significant. These were also exploratory outcomes, meaning the studies weren't designed to measure them.
One real-world observational study from 2025 found that adding inclisiran to high-intensity statins in patients with coronary artery disease was associated with large reductions in mortality, heart attack, and stroke compared to adding ezetimibe instead. But observational studies can't prove cause and effect, and these results could be influenced by other factors.
The definitive answer requires dedicated outcome trials, and several are underway:
Until these results come in, the drug's approval rests primarily on its ability to lower LDL cholesterol and its safety profile, not on proven event reduction.
The safety data so far looks reassuring. Across multiple trials and follow-up periods extending up to 6-7 years, serious drug-related adverse events were rare (about 1%). The main issue is injection-site reactions, which occurred in roughly 14% of patients but were mostly mild.
A systematic review and meta-analysis of 7 randomized controlled trials (4,790 patients) found that inclisiran did not increase all-cause mortality, major cardiovascular events, diabetes, or infections. The only notable finding was significantly more injection-site reactions (about 7 times higher than placebo), though again, these were typically mild.
A network meta-analysis comparing different PCSK9-targeting drugs actually ranked inclisiran best for having the fewest serious adverse events, though this needs to be interpreted cautiously given the limited outcome data.
Long-term extension studies (ORION-3 and ORION-8, with up to 4-6.8 years of exposure) showed no new safety signals emerging over time.
For most people, no. Current guidelines consistently recommend statins as first-line therapy for lowering LDL cholesterol. Statins have decades of evidence showing they reduce heart attacks, strokes, and death. Leqvio's track record on actual health outcomes is still being established.
That said, Leqvio may make sense in certain situations:
A monotherapy trial in lower-risk patients without cardiovascular disease (VICTORION-Mono) showed inclisiran reduced LDL by about 46% versus 11% with ezetimibe over 150 days. So it does work on its own. But the lack of long-term outcomes data means any switch away from statins should be made carefully with your doctor's guidance.
Leqvio represents a genuinely innovative approach to cholesterol management. Its twice-yearly dosing could solve the adherence problem that plagues daily medications. And the LDL reductions are substantial and sustained.
If you're already on a statin but not at goal, or if you truly can't tolerate statins, Leqvio is worth discussing with your doctor, especially if you're at high cardiovascular risk. But don't abandon statins based solely on convenience. We have strong evidence that statins prevent heart attacks and strokes. For Leqvio, we have strong evidence it lowers cholesterol and reasonable biological grounds to expect it prevents cardiovascular events, but we're waiting for the trials that will prove it.
The 2026-2029 timeframe will be important. If ORION-4 and the VICTORION trials confirm meaningful reductions in heart attacks and strokes, Leqvio's role in cardiovascular prevention will be much clearer.