Chasing—and Catching—the Wild Goose

In this issue, Tardif et al1 report on the results of a retrospective analysis of 2 phase III trials of the cholesteryl ester transfer protein inhibitor, dalcetrabip, dal-OUTCOMES, and dal-PLAQUE-2. Using a hypothesis-free whole genome screening process that could be likened to a wild-goose-chase, they identified genetically distinct subpopulations among the probands, which demonstrated markedly different clinical outcomes when treated with dalcetrabip as a secondary prevention strategy. If substantiated prospectively, the effect of this finding will be paradigm changing.Article see p 372 The pivotal clinical trial, the dal-OUTCOMES study, randomized 15 871 subjects and found no reduction in cardiovascular events with an average of 31 months of follow-up on dalcetrabip compared with placebo.2 The second trial, dal-PLAQUE-2, examining the effects of dalcetrabip on intima-media thickness,3 was prematurely terminated because of these negative results. Changes in high-density lipoprotein (HDL) levels did not correlate with clinical outcomes. That might have been the end of the story, but instead a new question was posed: are there any subgroups that might have actually accrued benefit from the new medicine, despite the failure to find statistical significance in the large group? Tardif et al1 conducted a genome-wide association study on a representative subset of the dal-OUTCOMES cohort for which the requisite blood samples and informed consent were available. This revealed a striking dichotomy in clinical outcomes according to genetic variants of the ADCY9 gene: individuals receiving dalcetrabip who were homozygous for the minor allele (the less common variant) of several single-nucleotide polymorphisms (SNPs) associated with this gene experienced ≈40% reduction in cardiovascular end points compared with placebo-treated controls. This fraction represented ≈20% of the cohort. In contrast, the subset of patients receiving dalcetrabip who were homozygous for the major allele (ie, the alternate form of the SNPs) was found to …