Cutting Lp(a) by 78% Did Not Reduce Heart Risk in 8,322 Patients

The inherited risk factor no drug could touch

Lipoprotein(a), a cholesterol particle whose levels are largely set by genetics, affects an estimated 64 million people in the United States and 1.4 billion worldwide, and no approved therapy lowers it. Levels are 80 to 90 percent genetically determined, largely unaffected by diet or standard lipid drugs, which is why guidelines recommend measuring it once in a lifetime. On Saturday at the American Heart Association Scientific Sessions, the first outcomes trial of a drug built specifically to lower Lp(a) reported its full results, with publication in the New England Journal of Medicine the same day. The drug cut Lp(a) dramatically. It did not reduce cardiovascular events.

What the trial found

The Lp(a)HORIZON trial, led by Cleveland Clinic with senior author Steven Nissen, randomized 8,322 patients between December 2019 and July 2022 at 797 sites in 42 countries. All had established cardiovascular disease (a prior heart attack, ischemic stroke, or symptomatic peripheral artery disease) and Lp(a) at or above 70 mg/dL, a level Nissen said puts them in the top 15 to 20 percent worldwide. Participants received pelacarsen, an antisense oligonucleotide that blocks production of apolipoprotein(a) at its source, as an 80 mg monthly subcutaneous injection. Novartis, which licensed the drug from Ionis Pharmaceuticals, funded the trial.

The primary endpoint, time to first major adverse cardiovascular event, occurred in 12.3 percent of patients on pelacarsen versus 12.1 percent on placebo, a hazard ratio of 1.02 (95 percent confidence interval 0.90 to 1.15). Median follow-up ran 4.7 years, and the result was neutral for every component: cardiovascular death, nonfatal heart attack, nonfatal stroke, and urgent coronary revascularization. Even the pre-specified subgroup with the highest baseline Lp(a), at or above 90 mg/dL, showed no separation: 12.3 percent versus 12.3 percent, a hazard ratio of 1.00 (95 percent confidence interval 0.87 to 1.15).

The biomarker itself behaved exactly as designed. Lp(a) fell 78.4 percent at 12 months on the drug versus 3.2 percent on placebo, with median levels dropping from 236 nmol/L to 64.4 nmol/L. LDL cholesterol also fell 13.3 percent. A 78 percent reduction in the target, and event rates did not move.

Why the biology did not pay off

Nissen did not soften the result. "The results were completely neutral across multiple analyses. There was basically no effect on outcomes, not even a trend, even in subpopulations," he said, calling the finding unexpected and surprising to the medical community. Patients were already intensively treated: median LDL cholesterol of about 65 mg/dL, roughly 78 percent on a high-intensity statin, mean systolic blood pressure of 125 mm Hg. Those baselines were, Nissen said, among the lowest of any cardiovascular outcomes trial, which may have left little residual risk for an added mechanism to act on.

Nissen also cautioned against reading too much into one result. "A single trial does not provide definitive evidence of a lack of benefit of lowering lipoprotein(a) as a strategy to reduce cardiovascular risk," he said. Karol Watson of UCLA, the trial's discussant, put the puzzle more bluntly: "even with compelling biology, compelling genetics, everything went right, but cardiovascular events didn't change."

A tolerability bill to pay

The drug was not free of side effects. Drug-related adverse events occurred in 56.8 percent of pelacarsen patients versus 18.0 percent on placebo, and adverse events leading to discontinuation ran 20.6 percent versus 7.5 percent. Constitutional and influenza-like reactions affected 31.9 percent versus 5.8 percent, and investigator-reported hypersensitivity 17.1 percent versus 5.4 percent. Serious adverse events were less frequent on the drug (37.3 versus 41.1 percent), but the tolerability gap is part of why Nissen said the siRNA agents in development cut Lp(a) deeper and are probably better tolerated.

At least four more shots at the question

At least four Phase 3 outcomes trials remain, and none simply repeats Lp(a)HORIZON. Amgen's OCEAN(a)-Outcomes tests olpasiran, a siRNA, in 7,297 patients enrolled at Lp(a) of at least 200 nmol/L, with a coronary-only primary endpoint that excludes stroke and an estimated completion in March 2028. Eli Lilly's ACCLAIM-Lp(a) is the largest at 17,300 patients, enrolled at 175 nmol/L or higher, and includes people at risk of a first event; its estimated completion is March 2029. Lilly's MOVE-Lp(a) takes another route: muvalaplin, the only oral small molecule, blocks assembly of the Lp(a) particle rather than its production, in 10,450 patients, starting September 2025. Amgen's OCEAN(a)-PreEvent moves to primary prevention: about 11,000 patients with no prior event, estimated completion October 2031.

Coverage of the readout noted analysts had watched for even a minor separation from placebo that would favor the siRNA programs; the full data gave none. That raises the stakes for the trials still running, since each changes something Lp(a)HORIZON held fixed: the drug class, the patient population, the endpoint composition, or how far baseline treatment already goes.

Nissen's takeaway will likely outlast the weekend. "The Lp(a)HORIZON trial is not the end of the story," he said. For the millions carrying an inherited risk factor that no approved drug touches, the question of whether lowering Lp(a) helps remains open, now with a first large data point against it.