Anti-inflammatory agents in atherosclerosis-and a need for reform: Extraordinary claims require extraordinary evidence.

Since 1858, human atherosclerotic plaques have been shown to contain immune cells. But are these cells suitable therapeutic targets? Dozens of clinical trials of anti-inflammatory agents other than colchicine have been performed in patients with clinically evident atherosclerosis. None of these trials led any regulatory body in any jurisdiction to allow a cardiovascular indication for any of these agents. This discouraging work provides a background to evaluate new data on colchicine. In 2024-2025, new clinical trials of colchicine in patients with atherosclerosis showed benefit, no benefit, or harm. In 2025-2026, over a dozen meta-analyses so far have appeared, drawing on ∼34 trials, but do not agree with each other. One of these meta-analyses, Xie et al.'s in the Journal of Internal Medicine, provides a compelling graphical display of the pre-specified primary outcomes of six long-term clinical trials as they were published over time. The pattern of early positive trials, then newer negative (null) trials, suggests regression to the truth. Jeon and Cho et al.'s population-wide study in the Journal of Internal Medicine of patients with Type 2 diabetes and gout found no benefit from colchicine over nonsteroidal anti-inflammatory drugs on major adverse cardiovascular events. This information suggests several areas for reform of research on inflammation in atherosclerosis. Fully informed consent should require that clinical trials of anti-inflammatory agents in atherosclerotic arterial disease must disclose to trial participants the failures of this approach in over 50 clinical trials to date, spanning decades. Additionally, the field might reconsider its commitment to the Big Idea that inflammation must be a definitive therapeutic target in atherosclerosis. The track record so far for inflammation inhibition in atherosclerosis is extensive and disappointing-a fact that merits wider discussion. Therapeutic successes from targeting cholesterol-rich, apolipoprotein-B-containing lipoproteins-the proven causative agents of this disease-provide extraordinary evidence. Current data for colchicine and other anti-inflammatory therapies do not.