Dalcetrapib
Early-phase MACE signals predicted outcomes-trial results in 6 of 7 cholesterol drugs, dalcetrapib the exception (Am Heart J Plus 2026)
Original title: Novel cholesterol lowering drugs: Can phase 2/3 clinical trial safety assessments predict cardiovascular event outcome trial efficacy?
An analysis reviewed seven cholesterol-lowering drugs across three classes (CETP inhibitors, bempedoic acid, PCSK9 inhibitors) that had completed both non-cardiovascular-outcomes-trial (non-CVOT) phase 2/3 registration studies and a dedicated cardiovascular outcomes trial (CVOT), comparing the direction of the major adverse cardiovascular events (MACE) treatment effect (harm, neutral, or benefit) across the two trial types. Six of seven drugs showed concordant results between their early non-CVOT MACE signal and their eventual CVOT outcome. Dalcetrapib was the exception: an early trend toward benefit, based on very small event numbers, did not hold up in its CVOT, which was neutral. Risk ratios from non-CVOTs and CVOTs correlated moderately (r = 0.69, p = 0.0893). The authors conclude non-CVOT MACE data have some predictive value for CVOT outcomes, a relevant precedent for interpreting the early pooled MACE signal for obicetrapib ahead of the PREVAIL readout.
Original abstract
Setting: Prior to a cardiovascular outcomes trial (CVOT), novel cholesterol-lowering therapies undergo phase 2/3 studies for their lipid and atherosclerotic effects and safety (non-CVOTs). Since the occurrence of major adverse cardiovascular events (MACE) is part of the safety assessment, nominal reductions or increases may be observed prior to definitive testing of the effect in a CVOT.
Study Objective: To investigate if the observed MACE treatment effect in non-CVOT lipid-lowering registration studies holds value in predicting the outcome in a CVOT trial, typically reported later than the initial lipid-lowering studies.
Design/Participants/Interventions: We reviewed recent development programs for cholesterol-lowering drugs that had completed non-CVOT and CVOT studies. MACE data were compared for phase 2/3 non-CVOT versus pivotal CVOT results.
Main Outcome Measures: Our primary outcome was a qualitative comparison for directionally concordant consistency in MACE risk ratio treatment effects (harm, neutrality, or benefit). Correlation analysis was also performed.
Results: Seven drugs were reviewed in 3 cholesterol-lowering classes: CETP inhibitors, bempedoic acid, and PCSK9 inhibitors. Concordance in non-CVOT vs CVOT results was seen in 6 of 7 drugs. One drug (dalcetrapib) had a trend for benefit observed, albeit with very small numbers, in early development, but showed a neutral CVOT. There was a moderate correlation between the risk reductions or increases from the non-CVOTs and CVOTs: r = 0.69, p = 0.0893.
Conclusion: Within the limitations of the drugs studied and the variability in MACE definitions, there is value in the results of non-CVOTs to predict the CVOT outcome.
the classdalcetrapiboutcomes trials
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.