Steven E. Nissen, MD, MACC

A post hoc analysis of the phase 2 ALPACA trial, presented by Steven E. Nissen, MD, of Cleveland Clinic, at the 

European Society of Cardiology (ESC) Congress 2026

 in Munich, Germany, showed lepodisiran produced dose-dependent, durable reductions in 

Lp(a)-associated oxidized phospholipids (OxPL)

. Lepodisiran, an investigational small interfering RNA (siRNA) targeting lipoprotein(a) [Lp(a)], lowered OxPL levels by up to 94% at day 240 with the highest studied dose.¹

Lp(a) is a causal, genetically determined risk factor for atherosclerotic cardiovascular disease and aortic stenosis, with much of its harm hypothesized to stem from the OxPL it carries. In the phase 2 ALPACA trial, lepodisiran previously produced up to 95% average Lp(a) reduction over 1 year with 2 doses given 180 days apart, but its effect on OxPL had not been assessed. This post hoc analysis tested whether near-complete pharmacologic suppression of apolipoprotein(a) [apo(a)] lowers OxPL proportionally and whether reductions relate to systemic inflammation.

"In fact, it is the major reservoir of oxidized phospholipids, and that is why it is such a promising target for treatment," Nissen said in an interview with

Lepodisiran Reduces OxPL Tied to Lp(a), With Steven Nissen, MD

Lepodisiran Effects on OxPL-apo(a) and OxPL-apoB by Dose

The randomized, placebo-controlled ALPACA trial enrolled 320 participants aged ≥ 40 years with Lp(a) levels above 175 nmol/L at 66 centers in 10 countries. Participants received lepodisiran 16 mg, 96 mg, or 400 mg subcutaneously at baseline and again at day 180, or placebo. This post hoc sub-study included 213 participants who received 2 active doses or placebo and had OxPL measured at baseline, day 240, and day 360 in stored samples (placebo, n = 59; 16 mg, n = 31; 96 mg, n = 65; 400 mg, n = 58).

Placebo-adjusted geometric mean percent changes in OxPL-apo(a) at day 240 were −21.9% (95% CI, −45.0% to 11.0%), −65.1% (95% CI, −73.8% to −53.6%), and −94.2% (95% CI, −95.7% to −92.2%) for the 16-mg, 96-mg, and 400-mg groups, respectively. OxPL-apoB changes at day 240 were −39.5% (95% CI, −51.2% to −25.0%), −76.9% (95% CI, −80.6% to −72.5%), and −88.5% (95% CI, −90.4% to −86.3%) across the same dose groups.

Lp(a) Correlations and Safety Findings for Lepodisiran


Lepodisiran is an investigational, extended-duration small interfering RNA (siRNA) that suppresses hepatic apolipoprotein(a) synthesis to produce durable reductions in circulating Lp(a).

How does lepodisiran affect oxidized phospholipids on Lp(a)?


In the ALPACA substudy, the 400-mg dose reduced OxPL-apo(a) by 94.2% and OxPL-apoB by 88.5% at day 240, with effects sustained through day 360.

Does lowering Lp(a) with lepodisiran reduce systemic inflammation?


No significant correlation was observed between changes in OxPL and hsCRP, and no anti-inflammatory effect of Lp(a) lowering has been demonstrated to date.

At day 360, placebo-adjusted percent changes in OxPL-apo(a) were −23.7% (95% CI, −47.0% to 9.8%), −41.6% (95% CI, −56.4% to −21.6%), and −80.7% (95% CI, −85.7% to −73.9%) across the 16-mg, 96-mg, and 400-mg groups. OxPL-apoB changes at day 360 were −30.6% (95% CI, −46.4% to −10.2%), −57.1% (95% CI, −65.2% to −47.2%), and −79.9% (95% CI, −83.8% to −75.2%), respectively.

For the 400-mg group, percent change in Lp(a) correlated strongly with percent change in OxPL-apo(a) at day 240 (95% CI, 0.90-0.96; 

 <.001) and moderately with OxPL-apoB (95% CI, 0.43-0.76; 

 <.001). By day 360, correlations strengthened for OxPL-apo(a) (95% CI, 0.86-0.95; 

 <.001) and OxPL-apoB (95% CI, 0.81-0.93; 

No significant correlation emerged between percent changes in OxPL and high-sensitivity C-reactive protein (hsCRP), a biomarker of systemic inflammation.

"Nobody, including our own study, has been able to demonstrate an anti-inflammatory effect of lowering of lipoprotein(a)," Nissen said. "hsCRP is only one measure of inflammation, and we may not have measured the right measures."

These findings provide additional biological rationale for the ongoing phase 3 ACCLAIM-Lp(a) cardiovascular outcomes trial (NCT06292013), which is evaluating lepodisiran in around 17,300 participants with elevated Lp(a), though the investigators caution the data do not establish clinical benefit.

 Similar OxPL reductions have been reported with the antisense oligonucleotide pelacarsen and the siRNA olpasiran, placing lepodisiran among a growing class of Lp(a)-lowering nucleic acid therapies under investigation.¹

Nissen SE, Navar AM, Krege JH, et al. Effect on Lipoprotein(a) Oxidized Phospholipids of Lepodisiran, an Extended-Duration siRNA Targeting Lipoprotein(a). 

A Study to Investigate the Effect of Lepodisiran on the Reduction of Major Adverse Cardiovascular Events in Adults With Elevated Lipoprotein(a) - ACCLAIM-Lp(a). ClinicalTrials.gov. Accessed September 4, 2026. 

https://clinicaltrials.gov/study/NCT06292013

Videos

A post hoc ALPACA analysis presented at ESC Congress 2026 shows lepodisiran cut Lp(a)-bound oxidized phospholipids by up to 94% at the 400-mg dose.

Gene and molecular therapies are moving from proof-of-concept to durable, clinically meaningful effect in lipid disorders once considered untreatable at the genetic level, spanning severe familial hypercholesterolemia, ANGPTL3-driven dyslipidemia, and elevated lipoprotein(a). A late-breaking session at the 

 in Munich, Germany, featured key presentations charting this progress.

Steven Nissen, MD, of Cleveland Clinic, moderated the session and shared his takeaways with 

, highlighting presentations spanning gene therapy for homozygous familial hypercholesterolemia (FH), CRISPR-based editing of ANGPTL3, and a small interfering RNA (siRNA) targeting lipoprotein(a).

Gene Therapy Breakthroughs From ESC 2026

AAV8 Gene Therapy for Homozygous Familial Hypercholesterolemia

Ting Li, of the First Affiliated Hospital of Xi'an Jiaotong University, presented results of an AAV8-mediated gene therapy for homozygous familial hypercholesterolemia.¹

"The adenovirus vector for replacing the LDL cholesterol receptor gene was a pretty dramatic effect. It was small, it was only 10 patients. They had homozygous familial hyperlipidemia with LDL cholesterols close to 400. They had 80-90% reductions in LDL cholesterol when they had this gene therapy," Nissen explained. He noted the treatment required corticosteroids and other therapies to manage liver enzyme elevations, calling the approach a promising step for a devastating disease.

CTX310 Durability in CRISPR-based ANGPTL3 Editing

Luke Joseph Laffin, MD, of Cleveland Clinic, presented 1-year durability data for CTX310, a CRISPR-Cas9 gene-editing therapy targeting ANGPTL3.² According to Nissen, Laffin presented results from 1 year after initial treatment with the ANGPTL3 approach, showing about a 50% reduction in triglycerides and a 50% reduction in LDL cholesterol persisting out to a year.

"This is important because the liver undergoes recycling. The cells regenerate maybe 15% per year, and so if the cells that are not edited are replicating more commonly than the cells that are, in fact, treated, then the effect would go away, but it didn't. So it suggests that there's a very high level of editing of the hepatocytes with this CRISPR-based therapy...," Nissen said, noting the 1-year data are set to appear in a short paper in the 

CTX310 previously demonstrated dose-dependent reductions in triglycerides and LDL cholesterol in an initial phase 1 trial published in the 

, without dose-limiting toxic effects related to the therapy.³

Kylo-11 and Durable Lipoprotein(a) Reduction

Ashish Sarraju, MD, of Cleveland Clinic, presented final data from a first-in-human study of Kylo-11, an investigational siRNA targeting lipoprotein(a).⁴ Nissen said the Kylo-11 data were surprising: the therapy lowered lipoprotein(a) by as much as 97%, and at doses of 225 mg or greater, the effect persisted after a single injection out to 48 weeks, essentially a year, with no evidence of rebound.

"It's the most durable, high-intensity reduction in lipoprotein(a) we've seen yet," Nissen said. "It's very early, it's phase 1, lots more work has to be done, but this field just keeps progressing as we get more and more understanding about how to build these small interfering RNAs so that they have the kind of effects that we're looking for."

Li T. AAV8-mediated gene therapy for homozygous familial hypercholesterolemia. Presented at: ESC Congress 2026, Late-Breaking Clinical Trials: Rewriting Cardiovascular Disease on Gene and Molecular Therapies; Munich, Germany.

Laffin LJ. Durability of Effects of CTX310, a CRISPR-Cas9 Gene Editing Targeting ANGPTL3. Presented at: ESC Congress 2026, Late-Breaking Clinical Trials: Rewriting Cardiovascular Disease on Gene and Molecular Therapies; Munich, Germany.

Phase 1 trial of CRISPR-Cas9 gene editing targeting ANGPTL3. N Engl J Med. 2025;393(21):2119-2130. doi:10.1056/NEJMoa2511778

Sarraju A. Extremely Long Duration Lp(a) Reduction Following a Single Dose of Kylo-11: Final Data from a First-in-Human Study. Presented at: ESC Congress 2026, Late-Breaking Clinical Trials: Rewriting Cardiovascular Disease on Gene and Molecular Therapies; Munich, Germany.

Steven Nissen, MD, shares key takeaways on AAV8, CTX310, and Kylo-11 gene and molecular therapies presented at ESC Congress 2026.

Spotlight on Gene and Molecular Therapies at ESC 2026, With Steven Nissen, MD

Tirzepatide Outperforms Dulaglutide in Cardiorenal Outcomes, With Steven Nissen, MD

Tirzepatide treatment resulted in a substantial reduction in a broad 6-component composite of cardiovascular and kidney endpoints compared to dulaglutide, according to a post hoc analysis of the SURPASS-CVOT trial.

American College of Cardiology (ACC) Scientific Sessions 2026

 in New Orleans, Louisiana, by Steven Nissen, MD, chief academic officer of the Heart and Vascular Institute at the Cleveland Clinic and professor of medicine at the Lerner College of Medicine.

“What this tells us is that targeting 2 incretins, which is what tirzepatide does, is actually a better strategy in terms of reducing major morbidity and mortality than just targeting GLP-1 alone,” Nissen told 

 in an exclusive interview. “We’re moving beyond the simple GLP-1 agonists – we’re moving to these more complex therapies that involve targeting more than 1 of the gut hormones.”

SURPASS-CVOT was an active-comparator-controlled, double-blind, noninferiority trial comparing tirzepatide and dulaglutide for cardiovascular outcomes in patients with 

atherosclerotic cardiovascular disease (ASCVD)

. Patients were eligible if they were ≥40 years old with T2D, a glycated hemoglobin level between 7% and 10.5%, a body mass index (BMI) of ≥25, and established ASCVD. Patients were excluded if they had any cardiovascular event within 60 days before screening, had used a GLP-1 RA within 3 months before screening, or had chronic advanced 

Eligible patients were randomized in a 1:1 ratio to either weekly subcutaneous tirzepatide 15 mg or dulaglutide 1.5 mg. Patients were monitored at trial visits every 4 weeks for the first 24 weeks and every 3 months thereafter. A total of 6586 patients entered the tirzepatide arm and 6579 entered the dulaglutide arm. The primary endpoint was a composite of cardiovascular mortality, myocardial infarction, or stroke.

Among the 13,165 patients enrolled in the original trial, the mean age was 64 years (standard deviation [SD], 8.8), and mean hemoglobin A1c was 8.4% (SD, 0.93). A primary endpoint event occurred in 801 patients (12.2%) in the tirzepatide arm and 862 (13.1%) in the dulaglutide arm. Adverse event incidence was similar between the 2 groups, although tirzepatide recipients saw more gastrointestinal adverse events.

In the present analysis, Nissen and colleagues crafted an additional primary endpoint composed of 6 potential events, including all-cause mortality, myocardial infarction, stroke, coronary revascularization, hospitalization for heart failure, and a composite of several adverse kidney outcomes.

This 6-point composite endpoint occurred in 1559 patients (23.7%) receiving tirzepatide and 1803 patients (27.4%) receiving dulaglutide (HR, 0.84; 95% CI, 0.79-0.9; 

 <.001) after a median treatment duration of 46.9 months (interquartile range [IQR], 34.6-50.6). Sensitivity analyses showed similar hazard ratios for a 5-component endpoint excluding kidney outcomes (HR, 0.86; 95% CI, 0.8-0.93).

Nissen noted the limited structure of the trial, given its status as a post hoc analysis. Tirzepatide’s explicit superiority in this particular patient cohort cannot be assumed based on these data.

“It’s important to remember that this is a secondary analysis of a trial,” Nissen said. “I happen to be the chair of the study SURMOUNT-MMO, which is studying tirzepatide compared to placebo in both primary and secondary prevention patients without diabetes. We’ll find out in a much broader population whether targeting with a dual incretin therapy really is superior to placebo.”

Editors’ Note: Nissen reports disclosures with Amgen, AstraZeneca, Bristol Myers Squibb, Novartis, Medtronic, Eli Lilly, and others.

Nissen SE, Wolski K, D’Alessio D, et al. Cardiorenal Outcomes With Tirzepatide Compared With Dulaglutide in Patients With Diabetes and Cardiovascular Disease: A Post Hoc Analysis of the SURPASS-CVOT Randomized Clinical Trial. 

. March 28, 2026. Accessed April 10, 2026. 

Nicholls SJ, Pavo I, Bhatt DL, et al. Cardiovascular outcomes with Tirzepatide versus dulaglutide in type 2 diabetes. 

Nissen discusses his post-hoc analysis of the SURPASS-CVOT trial, comparing the 2 drugs for a 6-component composite endpoint of cardiorenal outcomes.

The ALPACA trial demonstrated lepodisiran, a long-acting small interfering RNA therapy, significantly and durably reduces lipoprotein(a) [Lp(a)] levels, with effects lasting up to 18 months.

American College of Cardiology (ACC) 2025 Annual Scientific Sessions

, with Eli Lilly and Company announcing the therapy’s progression to the phase 3 ACCLAIM-Lp(a) trial.

“Nearly a quarter of the world’s population has elevated Lp(a), increasing cardiovascular risk, yet no approved therapies exist,” said Steve Nissen, MD, chief academic officer of the Heart Vascular & Thoracic Institute at the Cleveland Clinic. “These findings suggest siRNA approaches like lepodisiran could offer durable benefits with long-term dosing.”

Conducted across 66 sites on 5 continents, ALPACA randomized 320 patients with elevated Lp(a) to receive placebo or one of several lepodisiran regimens. The primary outcome of the trial was time-averaged percent change in Lp(a) from day 60 to 180. Results suggested patients receiving lepodisiran achieved reductions of 40.8%, 75.2%, and 93.9% for the 16 mg, 96 mg, and pooled 400 mg dose groups, respectively.

Additionally, those receiving 400 mg at baseline and day 180 maintained a 74.2% reduction in Lp(a). Secondary outcome analyses revealed the 400 mg group also experienced sustained reductions in apolipoprotein B, with decreases of 14.1% at day 60 and 13.7% at day 180.

Safety data showed treatment-emergent adverse events in 1% of placebo recipients, 3% of the 16 mg group, 12% of the 96 mg group, and 14% of the 400 mg group. No serious adverse events were linked to lepodisiran, though one death occurred in the 16 mg group due to chronic coronary disease complications.

For more on the trial and its implications, check out our interview with principal investigator Nissen.

Lepodisiran, ALPACA, and Lp(a), with Steve Nissen, MD

Relevant disclosures for AbbVie, Inc., Amgen, arrowhead, Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Encarda, Esperion Therapeutics, Medtronic, Mineralys, New Amsterdam Pharmaceuticals, Novartis, and Silence Therapeutics.

Nissen SE, Ni W, Shen X, et al. Lepodisiran — A Long-Duration Small Interfering RNA Targeting Lipoprotein(a). 

. Published online March 30, 2025. doi: 10.1056/nejmoa2415818

Eli Lilly and Company. Lilly’s lepodisiran reduced levels of genetically inherited heart disease risk factor, lipoprotein(a), by nearly 94% from baseline at the highest tested dose in adults with elevated levels | Eli Lilly and Company. Eli Lilly and Company. Published March 30, 2025. Accessed March 30, 2025. 

https://investor.lilly.com/news-releases/news-release-details/lillys-lepodisiran-reduced-levels-genetically-inherited-heart

Steve Nissen, MD, discusses the phase 2 ALPACA trial and how it informs the potential of lepodisiran for lowering Lp(a). 

Steven E. Nissen, MD, MACC

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