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

Stephen J. Nicholls, MD, PhD

Obicetrapib is Safe and Well-Tolerated in HeFH and ASCVD, With Stephen Nicholls, MD

Obicetrapib has a history of being safe and well-tolerated in patients with 

heterozygous familial hypercholesterolemia (HeFH)

atherosclerotic cardiovascular disease (ASCVD)

, based on a pooled safety analysis of the BROADWAY and BROOKLYN phase 3 trials.

American College of Cardiology (ACC) Scientific Sessions 2026

 in New Orleans, Louisiana, by Stephen Nicholls, MD, director of the Monash Velos Accelerator, program director of MonashHeart, Intensive Care and Victorian Heart Hospital, and director of the Monash Victorian Heart Institute at Monash Health.

“We saw less new onset diabetes, which we’ve seen with other CETP inhibitors, and we’ve also seen some potential favorable effects in slowing the reduction of eGFR,” Nicholls told 

 in an exclusive interview. “I think we need to understand more about potential mechanisms, but most importantly, this reassures me about safety and tolerability, and if we can combine that with better lipid effects and ultimately a reduction in cardiovascular risks, that would be great for patients.”

BROADWAY was a multinational, placebo-controlled, double-blind phase 3 trial including patients with either HeFH or established ASCVD. Additional criteria included being on maximally tolerated lipid-modifying therapy, a fasting serum LDL-C ≥55 to <100 mg/dL or non-DL-C ≥85 mg/dL to <130 mg/dL, and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m2 at screening, among others. Patients were excluded if they had NYHA class III or IV 

, left ventricular ejection fraction <30%, or major adverse cardiovascular events within 3 months of screening, among other criteria.

A total of 2530 patients were included in the trial and were randomly assigned to either obicetrapib 10 mg or placebo daily for 365 days. Over the course of the study, eGFR decreased significantly more among patients receiving obicetrapib compared to placebo. LDL-C also changed by a comparatively larger amount in the obicetrapib arm (-29.9%) versus placebo (+2.7%).

The BROOKLYN trial, meanwhile, specifically investigated patients with HeFH who were on maximally tolerated lipid-modifying therapy. Patients were excluded if they had NYHA class II or IV heart failure, last known left ventricular ejection fraction <30%, or had been hospitalized for heart failure within 5 years of screening, among other criteria.

The BROOKYLN investigators enrolled 354 patients and randomly assigned them in a 2:1 ratio to either obicetrapib 10 mg or placebo daily for 365 days. During this time, patients exhibited a placebo-adjusted LDL-C change of -36.3%. Secondary endpoints included changes in apolipoprotein B and non-HDL-C, which decreased by 24.4% and 34.5%, respectively.

For the present safety analysis, Nicholls and colleagues pooled data from both trials for a total of 2880 patients. The frequency of overall treatment-emergent adverse events was similar between obicetrapib and placebo groups (60.2% vs 62%). Adverse events leading to discontinuation were 4.1% and 5.3%, respectively. Among predicted events, dizziness, headache, hypertension, and myalgia were infrequent, while new onset diabetes mellitus, worsening glycemic control, and eGFR decline occurred less frequently with obicetrapib. Additionally, macular degeneration was rare and occurred in only 1 obicetrapib recipient.

“We know that many patients don’t get to goal, and every time we update our guidelines, they tell us that high-risk patients should go lower and lower,” Nicholls said. “But every time we lower the target, we’re going to leave more and more people behind. So, we need effective therapies that we can add to statins. Obicetrapib has the potential to be that therapy.”

Editors’ Note: Nicholls reports disclosures with AstraZeneca, NewAmsterdam Pharma, Amgen, Omthera, Merck, Boehringer Ingelheim, and others.

Nelson A, Kastelein J, Hsieh A, et al. Safety of Obicetrapib: An Integrated Pooled Phase III Safety Analysis. Abstract presented at the American College of Cardiology Scientific Sessions 2026, New Orleans, LA. March 28-30, 2026.

NewAmsterdam Pharma. Randomized Study to Evaluate the Effect of Obicetrapib on Top of Maximum Tolerated Lipid-Modifying Therapies (BROADWAY). ClinicalTrials.gov Identifier: NCT05142722. Updated September 19, 2025. Accessed April 2, 2026. 

https://clinicaltrials.gov/study/NCT05142722

Nicholls SJ, Nelson AJ, Ditmarsch M, et al. Safety and efficacy of Obicetrapib in patients at high cardiovascular risk. 

NewAmsterdam Pharma. Evaluate the Effect of Obicetrapib in Patients With HeFH on Top of Maximum Tolerated Lipid-Modifying Therapies (BROOKLYN). ClinicalTrials.gov Identifier: NCT05425745. Updated June 11, 2025. Accessed April 2, 2026. 

https://clinicaltrials.gov/study/NCT05425745

Nicholls, S.J., Nelson, A.J., Ditmarsch, M. et al. Obicetrapib in patients with heterozygous familial hypercholesterolemia: the BROOKLYN randomized clinical trial. 

https://doi.org/10.1038/s41591-025-04179-4

Videos

Nicholls discusses his recent pooled analysis of safety data from the BROADWAY and BROOKLYN phase 3 trials, proving the tolerable safety of obicetrapib.

BROADWAY: Obicetrapib Preserves Kidney Function, Prevents CKD, With Stephen Nicholls, MD 

 receiving CETP inhibition with obicetrapib saw preserved kidney function in addition to increased HDL-C, according to the recent BROADWAY trial.

“What we’re trying to demonstrate is that obicetrapib was effective, and that when added to other lipid-lowering therapy, it will produce effective lowering of LDL cholesterol, which ultimately translates to a reduction in cardiovascular events,” Nicholls told 

 in an exclusive interview. “The main take-home message for clinicians about this analysis is that it adds to the reassuring safety and tolerability profile of obesity.”

Patients with cardiovascular disease face a risk of 

 progression due to HDL-C dysfunction, which has shown an association with CKD in prior research. CETP inhibition reduces cardiovascular risk by raising HDL-C, which experts believed could benefit HDL production and protect kidney health. To judge the veracity of this, investigators conducted the BROADWAY trial.

BROADWAY was a multinational, double-blind, placebo-controlled trial including patients with either heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease (ASCVD). Patients were excluded if they had New York Heart Association class III or IV heart failure, left ventricular ejection fraction <30%, major adverse cardiac events within 3 months of screening, uncontrolled severe hypertension, or a formal diagnosis of homozygous familial hypercholesterolemia, among other criteria. A total of 2530 patients were included and randomly assigned to either obicetrapib 10 mg daily or placebo for 365 days.

Among the included patients, all were on maximally tolerated lipid-lowering therapy during the trial. Baseline demographics, blood pressure, and concomitant renoprotective medications (including ACE inhibitors, ARBs, and SGLT2 inhibitors) were all well-balanced, and investigators noted their stability throughout the study duration. Renal function was assessed throughout the full study period.

At baseline, participants had eGFR 84.2 +/- 18 mL/min/1.73 m

 and a median albumin-to-creatinine ratio of 11 mg/g. Over the course of the study, obicetrapib attenuated kidney function decline compared to placebo; annualized eGFR decline was 0.27 mL/min/1.73 m

 with obicetrapib versus 1.19 mL/min/1.73 m

 with placebo (difference 0.92 mL/min/1.73 m

 = .023). Additionally, progression to advanced CKD, which was defined as eGFR <30 mL/min/1.73 m

, occurred in 0.8% of patients versus 1.5% of placebo patients.

Nicholls and colleagues noted moderate eGFR decline (≥25%) in 6.8% of patients in the obicetrapib arm compared to 8.3% in the placebo arm. Albuminuria progression was also lower with obicetrapib (+9 mg/g versus +13.8 mg/g with placebo). Ultimately, no patients required dialysis or kidney transplantation during follow-up.

“We observed no deleterious effects on kidney function with obicetrapib, which is a very reassuring finding, and gives us more hope as we move forward in larger studies in the development program,” Nicholls said. “These findings are important for the practicing clinician in terms of the reassuring safety and tolerability of this agent.”

Vogt L, Davidson M, Kling D, et al. CETP Inhibition With Obicetrapib Preserved Kidney Function in Patients at High Cardiovascular Risk: Results from the BROADWAY Trial. Abstract presented at the American College of Cardiology Scientific Sessions 2026, New Orleans, LA. March 28-30, 2026.

Nicholls discusses the investigational oral CETP inhibitor’s effects on kidney health for patients at high risk of cardiovascular disease due to elevated HDL-C.

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

 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. 

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.

Stephen J. Nicholls, MD, PhD

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