The ‘less side effect, more benefit’ hypothesis: explaining the colchicine paradox

Despite a 2024 ESC Class IIa recommendation for chronic coronary syndrome and a 2025 ACC/AHA Class 2b recommendation following acute coronary syndrome, low-dose colchicine suffers from a profound implementation gap in routine clinical practice. This gap affects negatively on clinical practice particularly in low to mid income countries where a widespread use of a low cost drug yield a substantial benefit. We argue that the prevailing paradigm for evaluating this therapy is incomplete. Currently, gastrointestinal (GI) intolerance is treated merely as a side effect; we propose it is a post-randomization intercurrent event that attenuates the observed efficacy and explains trial heterogeneity. This Commentary introduces the “Less Side Effect, More Benefit” hypothesis. By contrasting the positive COLCOT trial (which had a blunted GI signal) with the neutral CLEAR SYNERGY trial (which suffered from prominent GI toxicity and higher treatment discontinuation), we illustrate how non-adherence acts as an effect modifier. To overcome this tolerability mediator and unlock colchicine’s potential clinical benefit, we propose a dual research agenda: first, developing better-tolerated formulations (e.g. enteric-coated or extended release formula) to bypass gastric toxicity, and second, utilizing more specific biomarkers (like IL-1β) rather than broad hs-CRP to identify ideal responders.