Pelacarsen, Ziltivekimab Miss CV End Points: What to Know

Two late-stage cardiovascular outcomes trials (CVOTs) have missed their primary end points, according to topline results from their sponsors. Both tested new ways to address residual risk: one by lowering lipoprotein(a) [Lp(a)] and one by blocking interleukin-6 (IL-6). Neither pelacarsen (Novartis) nor ziltivekimab (Novo Nordisk) is approved, so nothing changes on pharmacy shelves. But the pelacarsen headlines are reaching patients who were recently told to get their Lp(a) checked, and pharmacists may be among the first clinicians they ask about it.^1,2,4

Pelacarsen Lowered Lp(a), but Not Events

On September 4, 2026, Novartis announced that the phase 3 Lp(a)HORIZON trial (NCT04023552) did not meet its primary end point compared with placebo. That end point was a composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, and urgent coronary revascularization requiring hospitalization. The trial enrolled 8323 patients with elevated Lp(a) and established cardiovascular disease (CVD) who were already receiving guideline-directed care, including lipid-lowering and antihypertensive therapy. Pelacarsen is an investigational antisense oligonucleotide licensed from Ionis Pharmaceuticals. It lowered Lp(a), but Novartis has not reported the size of that reduction or a hazard ratio. Full data will be presented at an upcoming medical congress.¹

Michael J. Wilkinson, MD, FACC, FNLA, of UC San Diego Health, spoke on Pharmacy Times' The Tell-Tale Heart podcast at the National Lipid Association (NLA) 2026 Fall Clinical Lipid Update. He stressed how little is known so far. "We have the topline result, and what we know is that the trial failed to meet its primary end point," he said. "I think we are still in the stage of figuring out whether going after Lp(a) with a targeted therapy adds to the risk reduction we can achieve with the other interventions we use to lower somebody's cardiovascular risk."^2,3

Other Lp(a)-lowering agents are still in phase 3 outcomes trials, including the small interfering RNAs olpasiran and lepodisiran and the oral agent muvalaplin.^2,3

Ziltivekimab Hits Its Target, But Not MACE

On July 31, 2026, Novo Nordisk reported that the phase 3 ZEUS trial (NCT05021835) did not reduce major adverse cardiovascular events (MACE) compared with placebo (HR, 0.99; 95% CI, 0.88-1.11). ZEUS tested once-monthly subcutaneous ziltivekimab 15 mg, and MACE was defined as cardiovascular death, nonfatal MI, or nonfatal stroke. The trial enrolled more than 6300 patients with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and high-sensitivity C-reactive protein (hsCRP) of 2 mg/L or higher. Ziltivekimab is a monoclonal antibody that targets the IL-6 ligand, and it produced the expected reductions in free IL-6 and hsCRP. Overall adverse event rates were similar to placebo, but serious infections were more common with ziltivekimab. All-cause mortality did not differ.⁴

The result comes as inflammation has been drawing more attention as a residual-risk target. A survey of cardiology clinicians, summarized in Pharmacy Times, found that only 6% consistently tested hsCRP. Fewer respondents were aware of ziltivekimab trials than of trials for colchicine or canakinumab.⁵ Wilkinson did not discuss ZEUS specifically, but highlighted that an hsCRP above 2 mg/L on repeat testing flags higher risk. "As for what to do with that from a pharmacologic perspective, I don't have a straightforward approach currently, but I think it tells us more about an individual's risk," he said.³

What Changes at the Counter—and What Doesn't

Neither result changes a prescription a pharmacist will fill this week, and no Lp(a)-targeted therapy is approved.^1,4

The real impact is likely to be in conversations with patients. Patients who have learned they have elevated Lp(a) may see the pelacarsen news and conclude that the number does not matter or that their current regimen is failing them. The NLA has stated that Lp(a) remains an independent risk factor for ASCVD and that clinicians and patients should continue to measure it.² Wilkinson said a high Lp(a) is actionable now because it prompts "an even more intensive treatment approach to things like low-density lipoprotein cholesterol, blood pressure, glucose control, and other cardiometabolic risk factors." He also pointed to post hoc outcomes data supporting add-on proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor monoclonal antibodies for patients with ASCVD and high Lp(a) who are on a statin but not at their LDL cholesterol goal.^2,3

Wilkinson said pharmacists can help clinicians in "nuanced conversations about risks and benefits," as well as with monitoring, dose adjustments, and follow-up lipid panels.³

REFERENCES

1. Novartis announces Lp(a)HORIZON Phase III topline results for pelacarsen in patients with elevated Lp(a) and established cardiovascular disease (CVD). News release. Novartis. September 4, 2026. Accessed October 13, 2026. https://www.novartis.com/news/media-releases/novartis-announces-lpahorizon-phase-iii-topline-results-pelacarsen-patients-elevated-lpa-and-established-cardiovascular-disease-cvd

2. Top line results from the phase 3 Lp(a)HORIZON trial. National Lipid Association. Published September 14, 2026. Accessed October 13, 2026. https://www.lipid.org/resource/top-line-results-from-the-phase-3-lpahorizon-trial/

3. Beavers C, Wilkinson MJ. Lp(a), PREVENT, and LDL-C Goals: Insights from NLA fall update. Pharmacy Times. Published October 9, 2026. Accessed October 13, 2026. https://www.pharmacytimes.com/view/lp-a-prevent-and-ldl-c-goals-insights-from-nla-fall-update

4. Novo Nordisk provides update on the ZEUS phase 3 trial in people with ASCVD, CKD and inflammation. News release. Novo Nordisk. July 31, 2026. Accessed October 13, 2026. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916587

5. Chahine M, Kanaan AO, Nicolas S. Managing ASCVD: where patients and clinicians still need help. Pharmacy Times. May 12, 2026. Accessed October 13, 2026. https://www.pharmacytimes.com/view/managing-ascvd-where-patients-and-clinicians-still-need-help