Professor Stephen Nicholls is a world-renowned cardiologist, and leads the Victorian Heart Hospital (VHH) at Monash University.

Stephen J. Nicholls, MD, PhD

Tirzepatide Bests Dulaglutide in Cardiovascular Outcomes in HF, With Stephen Nicholls, MD

atherosclerotic cardiovascular disease (ASCVD)

 who received treatment with tirzepatide, irrespective of prior history of 

, were significantly less likely to experience death due to any cause or an HF event, compared to dulaglutide, according to a prespecified analysis of the SURPASS-CVOT trial.

American Heart Association’s Scientific Sessions 2025

 in New Orleans, Louisiana, by Stephen Nicholls, MD, PhD, director of the Monash Victorian Heart Institute in Melbourne, Australia, and professor of cardiology at Monash University.

“SURPASS-CVOT wasn’t specifically a heart failure study, but 20% of people in the trial had a prior history of heart failure,” Nicholls told 

 in an exclusive interview. “So, it becomes really important because we know there’s emerging data suggesting that the GLP-1 receptor agonists and tirzepatide have favorable effects on quality of life, 6-minute walk, and potential clinical events in patients with obesity-associated heart failure.”

SURPASS-CVOT was an event-driven, randomized, double-blind, active comparator, parallel-group study conducted at 640 sites across 30 countries. Patients were randomly assigned in a 1:1 ratio to either subcutaneous tirzepatide in doses up to 15 mg or dulaglutide 1.5 mg, once weekly. Patients were then followed for cardiovascular outcomes and other measures every 4 weeks for the first 24 weeks, and then every 3 months thereafter.

Patients eligible for inclusion were required to be ≥40 years of age, have 

 treated with either lifestyle or glucose-lowering medications, an HbA1c value ≥7% and ≤10.5% at screening, a body mass index (BMI) ≥25 kg/m2, and established ASCVD. Patients with prior pancreatitis, clinically significant gastric emptying abnormality, acute or chronic hepatitis, and other criteria were excluded.

A total of 13,299 patients were randomized during the trial, with a mean age of 64.1 +/- 8.8 years and a mean BMI of 32.6 +/- 5.5 kg/m2. Ultimately, tirzepatide demonstrated non-inferiority to dulaglutide, reducing major adverse cardiovascular events such as cardiovascular death, myocardial infarction, or 

 (HR, 0.92; 95% CI, 0.83-1.01) in adults with T2D and ASCVD.

In this prespecified analysis, Nicholls and colleagues highlighted the cardiovascular effects displayed in the trial, specifically in patients with and without a history of HF at baseline. Cardiovascular events included time to first occurrence of HF composite – consisting of HF events requiring hospitalization and all-cause or cardiovascular death – and individual outcomes of HF, as well as major adverse cardiovascular events.

Ultimately, the composite of all-cause death or HF events occurred in a substantially lower proportion of patients in the tirzepatide group (10.5% vs 12.1%; HR, 0.86; 95% CI, 0.77-0.95). Among a total of 2678 (20.3%) patients with a history of HF, more patients had a history of coronary artery disease (77.6% vs 61.8%) and prior myocardial infarction (57.8% vs 44.5%) than those without HF.

In patients with a history of HF, Nicholls and colleagues found HRs of 0.83 for all-cause death or HF events (95% CI, 0.7-0.99), 0.85 for cardiovascular death or HF events (95% CI, 0.7-1.03), 0.8 for cardiovascular death (95% CI, 0.63-1.02), and 0.97 for hospitalization or urgent visits for HF (95% CI, 0.73-1.27).

“I think the take-home message is that this is a useful therapeutic in the clinic,” Nicholls said. “It has favorable effects on a range of metabolic parameters which are superior to GLP-1 receptor agonists. It looks like it’s at least as good in terms of atherosclerotic events; if you look at heart failure events combined, there’s a more favorable effect. I think the next step is to see what that looks like in prospective trials in patients with heart failure.”

Nicholls S, D’Alessio D. Once-weekly Tirzepatide versus Dulaglutide for Heart Failure Outcomes in Patients with Type 2 Diabetes, ASCVD, and History of Heart Failure (pre-specified analysis of the SURPASS-CVOT Randomized Clinical Trial). Presented at the American Heart Association’s Scientific Sessions 2025. New Orleans, Louisiana. November 8-10.

Nicholls SJ, Bhatt DL, Buse JB, et al. Comparison of tirzepatide and dulaglutide on major adverse cardiovascular events in participants with type 2 diabetes and atherosclerotic cardiovascular disease: SURPASS-CVOT design and baseline characteristics. Am Heart J. 2024;267:1-11. 

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Nicholls highlights tirzepatide’s capacity to lower the risk of heart failure mortality, as well as hospitalizations or urgent visits.

New findings from the KRAKEN trial highlight the potential of muvalaplin, an oral treatment, for lowering lipoprotein (a) [Lp(a)] levels in adults with elevated Lp(a) and high cardiovascular risk.

American Heart Association (AHA) Annual Scientific Sessions 2024

, the trial represents the first evidence of an oral agent for lowering Lp(a), according to trial sponsor Eli Lilly and Company.

“High levels of Lp(a) have been shown to be a significant risk factor for atherosclerotic cardiovascular disease, affecting over one billion adults globally," said principal investigator Stephen J. Nicholls, MBBS, PhD, director of the Victorian Heart Hospital and Institute, and professor of cardiology at Monash University, Australia. "Current cholesterol-lowering therapies are not approved to lower Lp(a) levels, highlighting an unmet need for people living with cardiovascular disease. These data represent a needed scientific advancement with the potential to reduce the risk of cardiovascular events such as heart attacks or strokes with a once-daily pill."

A 12-week, double-blind, placebo-controlled, phase 2, 233-patient trial conducted in 43 sites across 5 countries, KRAKEN was designed to assess the efficacy and safety of muvalaplin at doses of 10 mg/d, 60 mg/d, or 240 mg/d. The trial’s primary endpoint, placebo-adjusted percentage change in Lp(a) levels, was assessed using intact Lp(a) and apolipoprotein(a)-based assays.

For inclusion in the trial, patients were required to have Lp(a) levels of at least 175 nmol/L and a history of atherosclerotic cardiovascular disease, diabetes, or familial hypercholesterolemia.

At 12 weeks, placebo-adjusted reductions in Lp(a) using the intact assay were 47.6% (95% CI, 35.1% to 57.7%), 81.7% (95% CI, 78.1% to 84.6%), and 85.8% (95% CI, 83.1% to 88.0%) with muvalaplin 10 mg, 60 mg, and 240 mg doses, respectively. Using the apo(a)-based assay, the corresponding reductions were 40.4% (95% CI, 28.3% to 50.5%), 70.0% (95% CI, 65.0% to 74.2%), and 68.9% (95% CI, 63.8% to 73.3%). Secondary endpoints showed reductions in apolipoprotein B levels, while high-sensitivity C-reactive protein remained unchanged.

For more on the trial and the potential of muvalaplin, check out our interview with Nicholls from the floor of AHA 2024.

 HCPLive Nicholls KRAKEN AHA 24

Relevant disclsoures for Nicholls include Amgen, Eli Lilly, Novartis, Sanofi-Regeneron, Silence Therapeutics, and others.

Nicholls SJ, Ni W, Rhodes GM, et al. Oral Muvalaplin for Lowering of Lipoprotein(a): A Randomized Clinical Trial. 

 Published online November 18, 2024. doi:10.1001/jama.2024.24017

Eli Lilly and Company. Lilly’s muvalaplin lowered lipoprotein(a) levels in adults with high risk for cardiovascular events by up to 85% at highest tested dose. Eli Lilly and Company. November 18, 2024. Accessed November 18, 2024. https://investor.lilly.com/news-releases/news-release-details/lillys-muvalaplin-lowered-lipoproteina-levels-adults-high-risk.

Muvalaplin, an oral treatment, shows promise in reducing lipoprotein (a) [Lp(a)] levels in high cardiovascular risk patients, as demonstrated in the KRAKEN trial. This phase 2 trial, presented at the AHA Annual Scientific Sessions 2024, is the first to provide evidence of an oral agent effectively lowering Lp(a). Conducted across 43 sites, the trial involved 233 patients and revealed significant placebo-adjusted reductions in Lp(a) levels with muvalaplin doses of 10 mg, 60 mg, and 240 mg. Secondary endpoints indicated reductions in apolipoprotein B levels, with no change in high-sensitivity C-reactive protein.

Stephen Nicholls, MBBS, PhD, provides additional insight into KRAKEN trial data and the potential of muvalaplin.

Phase 2 Data Support Muvalaplin for Lowering Lp(a), with Stephen Nicholls, MBBS, PhD

Zerlasiran Achieves Durable Lp(a) Reductions at 60 Weeks, with Stephen J. Nicholls, MD, PhD

Data from the ALPACAR-360 trial, presented at the 

American Heart Association (AHA) Scientific Sessions 2024

, confirm that zerlasiran (formerly SLN360) achieves sustained reductions in lipoprotein(a) [Lp(a)] through 60 weeks. Zerlasiran, a gene-silencing therapy, offers a potential treatment for elevated Lp(a), a genetic risk factor affecting 20% of the global population and a significant driver of 

Launched in 2023, the Phase 2 trial randomized 178 patients with baseline Lp(a) levels >125 nmol/L and high cardiovascular risk to 3 dosing regimens of zerlasiran or placebo therapy. Upon analysis, at 36 weeks, zerlasiran showed a least-squares mean time-averaged Lp(a) reduction of –81.3% to –85.6%.

“I think there’s two elements to the efficacy. There’s the degree of Lp(a) lowering that we can but then there’s the durability,” Stephen J. Nicholls, MD, PhD, Victorian Heart Institute, Monash University, told HCPLive. “If we follow patients out 3-, 6-, and 12-months after an injection, what we’re seeing with these agents is that your Lp(a) doesn’t come back to beeline. Our ability to show more and more durability, more Lp(a) lowering 6-, 12-months after injections, has implications for potentially less frequent dosing.”

These dose reductions were observed in the zerlasiran 450 mg every 24 weeks (–85.6%; 95% CI, –90.9% to −80.3%), 300 mg every 16 weeks (–82.8%; 95% CI, –88.2% to –77.4%), and 300 mg every 24 weeks (–81.3%; 95% CI, –86.7 to 76.0) cohorts, respectively. These reductions remained consistent through 60 weeks, and zerlasiran was well-tolerated. A total of 20 serious adverse events in 17 patients, but none were deemed to be related to the study drug—injection site reactions were the most common treatment-related adverse event.

Nicholls indicated data from the ALPACAR-360 trial demonstrate the competitive profile of zerlasiran as a potential long-term, infrequent-dose therapy. Zerlasiran will progress into Phase 3 trials as a potentially promising new treatment for patients with high Lp(a).

“I think that finding suggests that if you do big enough trials, you do see adverse events.,” Nicholls told HCPLive. “...All seemed to be pretty mild in severity, and they resolve pretty quickly. These are important, not only in terms of the conversation we have with our patients about starting therapy, but then about kind of keeping patients on treatment long term.”

Disclosures: Nicholls reports relevant disclosures including Amgen, Eli Lilly, Novartis, Sanofi-Regeneron, Silence Therapeutics, and others.

Nissen SE, Wang Q, Nicholls SJ, et al. Zerlasiran—A Small-Interfering RNA Targeting Lipoprotein(a): A Phase 2 Randomized Clinical Trial. JAMA. Published online November 18, 2024. doi:10.1001/jama.2024.21957

Packer M. Tirzepatide for Patients with Heart Failure with Preserved Ejection Fraction and Obesity: the SUMMIT Trial. Paper presented at: American Heart Association Scientific Sessions 2024; November 15 - 18; Chicago, Il. Accessed November 16, 2024.

Zerlasiran, a gene-silencing therapy, has shown promising results in the ALPACAR-360 trial, achieving sustained reductions in lipoprotein(a) [Lp(a)] levels over 60 weeks. This Phase 2 trial involved 178 patients with high cardiovascular risk and elevated Lp(a) levels, demonstrating significant Lp(a) reductions across various dosing regimens. Zerlasiran was well-tolerated, with no serious adverse events linked to the drug. The trial's findings suggest zerlasiran's potential as a long-term, infrequent-dose therapy for managing elevated Lp(a), a genetic risk factor for cardiovascular disease, warranting progression to Phase 3 trials.

Stephen J. Nicholls, MD, PhD discusses the robust efficacy and tolerability of zerlasiran for Lp(a) lowering, paving the way for Phase 3 development.

Stephen J. Nicholls, MD, PhD

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