Obicetrapib shows potential in lowering lipoprotein(a)

September 2026

The cholesteryl ester transfer protein (CETP) inhibitor obicetrapib reduced lipoprotein(a in high cardiovascular risk patients, suggesting a future therapeutic option for patients with mildly elevated levels unable to access specific lipoprotein(a)-targeted RNA therapeutics.

Nicholls SJ, Nelson AJ, Ray KK, et al. Obicetrapib and lipoprotein(a) levels in patients at high cardiovascular risk: a pooled analysis of trials. Eur Heart j 2026; doi.org/10.1093/eurheartj/ehag399

STUDY SUMMARY.

Objective

To investigate the effect of the CETP inhibitor obicetrapib on lipoprotein(a) [Lp(a)].

 

 

Study design

Pooled analysis of two clinical trials evaluating the lipid effects of obicetrapib at 12 weeks and of 12 months duration.

 

 

Study population

2356 individuals (median age 64 years, 36.2% female) with heterozygous familial hypercholesterolaemia (BROOKLYN trial) or ASCVD (atherosclerotic cardiovascular disease, BROADWAY trial), and baseline and week 12 lipid assessments. Overall, 1436 patients were allocated to treatment with obicetrapib; 27% of patients had heterozygous familial hypercholesterolaemia and 82.3% had a history of ASCVD. Almost all patients (91%) received a statin, with 68% on high-intensity statin, 29% received ezetimibe and 5% received a PCSK9 inhibitor.

 

 

Main study variables

 

Change in Lp(a) at week 12; changes in low-density lipoprotein cholesterol (LDL-C) and apolipoprotein (apo) B at week 12.   

 

Methods

Lipid changes from baseline to week 12 between the obicetrapib and placebo treatment groups were compared using two sample Hodges-Lehmann estimates of the midpoint of corresponding 95% confidence intervals (CIs) for location shift and Wilcoxon rank sum test P-values to account for stratification by baseline Lp(a) category (<50 nmol/L, 50 to <150 nmol/L, or ≥150 nmol/L) or tertile of each lipid/lipoprotein and study.

 

Percentages, 95% CIs, and P-values for proportions of patients achieving Lp(a) and LDL-C goals at baseline and week 12 were derived from logistic regression models.

 

Results

Overall, median baseline Lp(a) levels were 42.9 nmol/L; 448 (19.0%) patients had levels between 50 and 150 nmol/L, and 665 (28.2%) patients had levels of at least 150 nmol/L. For the overall cohort, obicetrapib reduced Lp(a) at week 12 by 37.3% (placebo-adjusted) with an absolute reduction of 14.9 nmol/L   (p <0.0001) (Table 1). While there was significant heterogeneity in the percent reduction of Lp(a) by obicetrapib depending on baseline Lp(a), the placebo-adjusted absolute Lp(a) reductions were comparable (Table 1).  However, absolute and percentage placebo-adjusted reductions in LDL-C with obicetrapib were consistent in patients with different baseline Lp(a) levels.

 

Table 1. Lipoprotein(a) at baseline and week 12 by baseline Lp(a) category

Baseline Lp(a)

Placebo

Obicetrapib

Placebo-adjusted

p-value

<50 nmol/L

N=501

N=742

 

 

Baseline, nmol/L

13.5 (5.7,24.8)

13.5 (5.3, 24.4)

 

 

Week 12, nmol/L

12.5 (5.6,24.7)

5.0 (2.8, 10.8)

-6.1

(−7.2, −4.9)

<0.0001

Absolute change, nmol/L

0 (−2.0, 2.2)

-5.0

(−13.4, −1.6)

-6.2

(−7.0, −5.3)

<0.0001

% change

0 (−18.1, 22.6)

-52.4

(−70.8, −18.0)

-50.9

(−54.8, −47.1)

<0.0001

 

 

 

 

 

50 to <150 nmol/L

N=170

N=278

 

 

Baseline, nmol/L

94.2

(67.3, 117.4)

89.2

(66.8, 116.9)

 

 

Week 12, nmol/L

92.5

(62.5, 121.5)

44.8

(20.9, 83.7)

-38.7

(−46.0, −31.4)

<0.0001

Absolute change, nmol/L

-4.5 (−12.3, 8.8)

-39.5

(−57.2, −18.1)

-36.3

(−41.2, −31.4)

<0.0001

% change

-4.1

(−16.3, 10.0)

-46.3

(−71.1, −21.5)

-43.3

(−49.5, −37.1)

<0.0001

 

 

 

 

 

≥150 nmol/L

N=249

N=416

 

 

Baseline, nmol/L

249.6

(197.5, 341.0)

249.0

(200.3, 347.2)

 

 

Week 12, nmol/L

251.6

(191.8, 331.8)

225.0

(161.3, 315.6)

-31.4

(−48.2, −14.6)

0.003

Absolute change, nmol/L

-2.5

(−25.6, 20.7)

-31.8

(−77.8, 2.2)

-32.3

(−40.5, −24.1)

<0.0001

% change

-1.3 (−9.5, 8.8)

-13.3

(−27.7, 0.8)

-12.6

(−15.6, −9.6)

<0.0001

Data are presented as median (interquartile range) for each treatment group and two sample Hodges-Lehmann median of differences 95% confidence interval midpoint for placebo-adjusted differences, reflecting stratification for Lp(a) category.

 

Compared with placebo, a higher percentage of obicetrapib-treated patients achieved >50% Lp(a) lowering baseline (38.4% vs 3.0% on placebo, p<0.0001).  In addition, patients treated with obicetrapib were more likely to achieve both Lp(a) lowering >50% and an on-treatment LDL-C <40 mg/dL (12.0% vs 0% on placebo, p <0.0001), <55 mg/dL (21.7% vs 0.5%, p <0.0001) and <70 mg/dL (27.4% vs 1.2%, p <0.0001).

 

Author conclusions

Obicetrapib lowered LDL-C, apoB, and Lp(a). The absolute reduction in Lp(a) with obicetrapib was similar in patients with mildly elevated Lp(a) levels, who are unlikely to qualify for administration of RNA-targeted Lp(a) lowering agents.

 

Comment

Obicetrapib has proven efficacy in lowering LDL-C and raising high-density lipoprotein    (HDL-C) (1,2). The current pooled analysis extends the profile of lipid modulation, showing an overall reduction of 37% in Lp(a), which was generally consistent across the range of Lp(a) concentration.

 

These findings are relevant given that there are so far limited treatment options for managing elevated Lp(a).  PCSK9 inhibitors lower Lp(a) in patients with elevated baseline levels independently of the extent of LDL-C reduction (3,4); however, the effect is modest, prompting the search for novel specific Lp(a)-lowering therapies. Several are in clinical development, including an antisense oligonucleotide (ASO), siRNA therapeutics and a small molecule inhibitor. These have been shown to be highly effective in patients with high to very high Lp(a) levels, achieving reductions of the magnitude of at least 80% and up to 95% (5-12).  However, the integration of these novel agents into clinical practice, subject to their regulatory approval, may pose practical constraints in terms of their mode of administration (injection) and their cost. Moreover, ongoing major outcomes studies with these agents have set very high Lp(a) inclusion criteria (> 70 mg/dL or >∼175 nmol/ for the ASO pelacarsen, and 175 nmol/L and 200 nmol/L, respectively, for the siRNA therapeutics lepodisiran and olpasiran).

 

Although there is no specific target, current guidelines currently state that Lp(a) levels >125 nmol/L associate with increased cardiovascular risk (13,14).  Given the levels specified for inclusion in trials, most patients with modestly elevated Lp(a) will be unable to access these highly specific treatments once available and would therefore remain at high residual risk.  As evidence now supports a continuous association between Lp(a) concentration and associated ASCVD (15), there is a clear need for other treatments that would be accessible to such patients.

 

The current analysis has shown that in addition to lowering LDL-C, obicetrapib is also effective in lowering Lp(a) in patients with only modestly elevated levels. The Lp(a)-lowering effect of obicetrapib was independent of LDL-C effects. Thus, obicetrapib offers potential for reducing Lp(a)-associated residual cardiovascular risk in these patients, with the practical advantages of an oral therapy.

 

References

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Key words: Lipoprotein(a); Lp(a); obicetrapib; residual cardiovascular risk; BROOKLYN, BROADWAY