Inclisiran beat bempedoic acid on LDL cholesterol in a head-to-head

A head-to-head trial of two newer cholesterol drugs has come down clearly on one side: in VICTORION-Challenge, twice-yearly injected inclisiran lowered LDL cholesterol by 56.3% at day 150, against 15.4% for daily oral bempedoic acid, a between-group gap of 41.0 percentage points [s1]. Two things temper that headline — the trial was open-label and funded by inclisiran's maker, and it measured LDL, a surrogate, rather than heart attacks or strokes.

What the trial compared

Both drugs are add-ons for patients who cannot get their LDL low enough on statins. Inclisiran is a small interfering RNA against PCSK9, given by injection twice a year; its LDL-lowering was established in the phase 3 ORION programme [s2]. Bempedoic acid is a daily oral ATP-citrate lyase inhibitor whose cardiovascular-outcome evidence comes from CLEAR Outcomes, in statin-intolerant patients [s3]. Until now the two had not been tested against each other.

VICTORION-Challenge was a phase 4, open-label trial that randomised patients with atherosclerotic cardiovascular disease and an LDL of at least 70 mg/dL, despite a statin with or without ezetimibe, to one drug or the other [s1]. It enrolled 402 patients: mean age 63.1 years (SD 10.7), 64.2% men, and a baseline LDL of 94.4 mg/dL (SD 28.3) [s1]. The primary endpoint was the percentage change in LDL at day 150 [s1].

The result

Inclisiran won on every LDL measure. The least-squares mean reduction at day 150 was 56.3% with inclisiran versus 15.4% with bempedoic acid, a difference of 41.0 percentage points (95% CI −45.7 to −36.2; p<0.0001) [s1]. In absolute terms LDL fell 53.4 mg/dL on inclisiran against 17.5 mg/dL on bempedoic acid, and the advantage held regardless of whether patients were also taking ezetimibe [s1]. Guideline LDL goals were reached by 78.2% of inclisiran patients versus 20.3% on bempedoic acid — an adjusted odds ratio of 16.36 (95% CI 9.72 to 27.54) [s1].

Safety over the short trial looked comparable. Treatment-emergent adverse events occurred in 63.1% of inclisiran patients and 59.8% on bempedoic acid, with serious events in 5.9% versus 7.5% [s1]. The most common events with inclisiran versus bempedoic acid were nasopharyngitis (10.3% vs 7.5%), hypertension (4.9% vs 4.5%) and myalgia (3.4% vs 5.5%) [s1]. One death, in the inclisiran group, was judged unrelated to treatment [s1].

Why the caveats matter

The size of the gap is not surprising: a PCSK9-targeting therapy would be expected to lower LDL more than bempedoic acid, and the comparison is partly one of drug classes rather than a close contest. What the trial's design does is complicate how much weight to put on the margin.

It was open-label, so both patients and investigators knew which drug was being given — acceptable for an objective lab endpoint like LDL, but a real limitation, and the reason lipid trials of this kind report the number rather than a clinical benefit. The comparison also runs partly on adherence: inclisiran is administered by a clinician twice a year, whereas bempedoic acid depends on a patient taking a pill every day, and any real-world gap in daily adherence would widen the measured difference over 150 days without reflecting the drugs' intrinsic potency. And the funder, Novartis, markets inclisiran; several authors are company employees [s1]. That does not invalidate a prespecified LDL measurement, but it is the context in which a decisive-looking result should be read.

Most important, LDL is a surrogate. VICTORION-Challenge did not measure cardiovascular events, and lowering LDL more is not automatically the same as preventing more heart attacks — though across therapies the two have tracked closely. Bempedoic acid already has a completed outcomes trial behind it in the patients who cannot tolerate statins [s3]; inclisiran's own large cardiovascular-outcome trials are what will show whether its steeper LDL curve converts into fewer events. This trial answers which drug lowers LDL more. It does not answer which one prevents more disease.

This article is informational and does not constitute medical advice.

Sources

• [s1] Inclisiran vs bempedoic acid for low-density lipoprotein cholesterol lowering in high-risk patients: the VICTORION-Challenge trial. European Heart Journal, 31 August 2026. https://doi.org/10.1093/eurheartj/ehag738
• [s2] Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol (ORION-10 and ORION-11). New England Journal of Medicine, 18 March 2020. https://doi.org/10.1056/NEJMoa1912387
• [s3] Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients (CLEAR Outcomes). New England Journal of Medicine, 4 March 2023. https://doi.org/10.1056/NEJMoa2215024