Obicetrapib Reduces HbA1c, New-Onset Diabetes Risk in ASCVD, HeFH

New research is shedding light on the impact of treatment with obicetrapib on HbA1c and new-onset diabetes risk in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) and prediabetes or normoglycemia on a background of mostly high-intensity statins.1

The pooled analysis of data from the phase 3 BROOKLYN and BROADWAY trials was led by Stephen Nicholls, MBBS, PhD, director of the Monash Victorian Heart Institute and professor of cardiology at Monash University, and presented at the 9th Annual Heart in Diabetes Conference in Philadelphia, Pennsylvania, with findings suggesting use of obicetrapib reduced HbA1c with a trend toward a lower risk of new-onset diabetes, consistent with other cholesteryl ester transfer protein (CETP) inhibitors.1

“Statins lower low-density lipoprotein cholesterol (LDL-C) and reduce risk of ASCVD but meta-analyses and genetic studies demonstrate that statin therapy increases the risk of diabetes through an on-target effect of HMG-CoA,” Nicholls and colleagues wrote.1 “Although genetics of other LDL-C–lowering pathways predict an on-target effect of lowering Niemann-Pick C1-Like 1 (NPC1L1), and proprotein convertase subtilisin/kexin type 9 (PCSK9) on the risk of NoD, this has only been observed in therapeutic trials of statins.”

Obicetrapib, a highly specific and potent inhibitor of CETP that significantly reduces LDL-C, is currently being evaluated in cardiovascular outcome trials. Most recently, New Amsterdam Pharma announced topline results from the phase 3 BROADWAY trial demonstrating once-daily oral obicetrapib, as an adjunct to statins, significantly reduced LDL-C in patients with ASCVD who do not respond sufficiently to standard therapy. In 2024, the company announced topline results from the phase 3 BROOKLYN trial showing use of obicetrapib was associated with statistically significant reductions in LDL-C when added to maximally tolerated lipid modifying therapies in patients with HeFH.2,3

As compared to other classes of LDL-C–lowering therapies, a meta-analysis of early CETP inhibitor trials demonstrated a reduced risk of new-onset diabetes. However, investigators note the effects of obicetrapib on glycemia and risk of new-onset diabetes are not well understood.1

To evaluate the effect of obicetrapib 10 mg on glycemia and risk of NoD in patients with atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH), investigators conducted a pooled analysis of the BROOKLYN and BROADWAY, phase 3, randomized, double-blind, placebo-controlled trials, both of which evaluated the effect of obicetrapib as an adjunct to maximally tolerated lipid-lowering therapy (LLT).1

Investigators assessed the effect of obicetrapib on HbA1C and risk of NoD in patients without diabetes at baseline and by glycemia strata (prediabetes or normoglycemia) using standard criteria, with adjustments for baseline HbA1c, trial, and statin use at baseline. Additionally, a meta-analysis of the risk of NoD with CETP inhibitors was conducted to assess whether any observed associations were consistent with prior class-level observations.1

Among the 1848 total patients included in the pooled analysis, the mean age was 63.4 years, 38.1% were female, 89.7% were on a statin, median LDL-C was 96 mg/dL (interquartile range [IQR], 78 to 126), and HbA1c was 5.7% (IQR, 5.4% to 5.9%) at baseline.1

Investigators noted placebo-corrected median changes in LDL-C, Lp(a), and HDL-C were -35.3%, -35.6%, and +136.7%, respectively (all P <.0001). Further analysis revealed obicetrapib 10 mg reduced HbA1c among patients without diabetes and demonstrated a consistent trend toward lower risk of NoD in patients with both normoglycemia and prediabetes at baseline.1

Meta-analysis results showed the effects of obicetrapib 10 mg on NoD were similar to trends observed with other CETP inhibitors in 4 prior large randomized controlled trials. Specifically, the overall risk ratio of NoD with CETP inhibitors was 0.83 (95% CI, 0.77 to 0.90), I2 was 13.5%, and the P value for heterogeneity was 0.493, which investigators noted is consistent with an overall class effect for CETP inhibition.1

“As risk of new-onset diabetes accrues over time, larger and longer trials are needed to determine the full degree of the potential protective effects of obicetrapib on risk of new-onset diabetes,” investigators concluded.1

References

1. Ray KK, Szarek M, Navar AM, et al. Effect of Obicetrapib on New-Onset Diabetes in Patients With Elevated LDL-C Receiving Maximally Tolerated Statin Therapy: Pooled Analyses of the BROADWAY and BROOKLYN Trials. Abstract presented at the 9th Annual Heart in Diabetes Conference in Philadelphia, PA, from June 6 - 8, 2025.

2. Iapoce C. Obicetrapib Achieves Robust LDL-C Reductions in Phase 3 ASCVD Trials. HCPLive. May 7, 2025. Accessed June 8, 2025. https://www.hcplive.com/view/obicetrapib-achieves-robust-ldl-c-reductions-in-phase-3-ascvd-trials

3. Campbell P. Obicetrapib Hits Target in Phase 3 BROOKLYN Trial for HeFH. HCPLive. July 29, 2024. Accessed June 8, 2025. https://www.hcplive.com/view/obicetrapib-hits-target-in-phase-3-brooklyn-trial-for-hefh