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For those interested in health and longevity, “inflammation” is a bit of a dirty word. And for good reason – chronic inflammation has long been recognized for its role in contributing to all four horsemen of chronic disease: metabolic dysfunction, neurodegenerative disease, certain types of cancer, and cardiovascular disease. Indeed, inflammation is widely believed to be partly responsible for the fact that patients with coronary disease remain at higher-than-average risk of cardiovascular events even with effective management of cholesterol levels. This in turn would suggest that anti-inflammatory medications might minimize the residual risk when taken in combination with lipid-lowering drugs. Yet although a link between inflammation and heart disease has been acknowledged for decades, no anti-inflammatory medications had ever been approved by the FDA for the treatment of atherosclerotic cardiovascular disease (ASCVD) – until last month.
FDA Approves Colchicine for ASCVD
In late June, AGEPHA Pharma announced that their drug LODOCO® (or Low-Dose Colchicine, 0.5 mg) had been approved as the first anti-inflammatory drug for reducing risk of major adverse cardiovascular events (MACE; heart attack, stroke, coronary revascularization, and cardiovascular death) among patients with pre-existing ASCVD.
Colchicine has broad effects on inflammation, both inhibiting various pro-inflammatory pathways and promoting anti-inflammatory signaling, and the plant from which it is derived (autumn crocus) was used for treatment of joint pain at least as early as 1500 BCE in ancient Egypt. Indeed, the FDA has previously approved colchicine for the treatment of gout (at acute doses of 1.2 mg/day and prophylactically at 0.6 mg/day) and Mediterranean fever (1.2 to 2.4 mg/day) – both conditions which are characterized by inflammation. (Of note, the dose used by AGEPHA Pharma for CV indications – 0.5 mg – is almost certainly a move to preserve intellectual property by patenting a new dose. It’s extremely unlikely that the effects of 0.5 mg are qualitatively different from the effects of 0.6 mg.)
Still, after the failure of earlier anti-inflammatory drugs (e.g., canakinumab, methotrexate) to gain approval for cardiovascular indications, the recent announcement regarding colchicine has been celebrated as a step forward for heart disease treatment. So what exactly do we know about this new therapeutic option, and how much do patients stand to benefit?
Findings from Clinical Trials
Following promising results in 2013 from a very small, open-label (i.e., no randomization or blinding) trial with low-dose colchicine for ASCVD, researchers conducted a larger, randomized, double-blind trial (LoDoCo2) to assess the effectiveness of this drug in reducing risk of MACE among patients in a clinically stable condition but with established coronary disease. In total, 6528 patients ages 35-80 (mean age 66±8.6 years) were enrolled, and all participants started the study with a 30-day open-label run-in phase in which they received 0.5 mg colchicine once daily. After this period, the 5522 patients who tolerated treatment were then randomized to receive either 0.5 mg colchicine daily or placebo through the follow-up period (median 28.6 months). Clinical evaluations were conducted before run-in, at randomization, and at 6-month intervals afterward.
Publishing their results in 2020, the investigators reported an impressive 31% reduction in risk of MACE among those on colchicine relative to placebo (HR: 0.69; 95% CI: 0.57-0.83; P<0.001), with an incidence rate of 2.5 events per 100 person-years in the colchicine group and 3.6 events per 100 person-years in the placebo group (so the absolute risk reduction was 1.1 events per 100 person-years, slightly less than the effect size of statins). Coronary revascularization and spontaneous heart attack in particular accounted for most of the difference in overall MACE between groups, and risk of each of these events individually was significantly lower among those on colchicine than among those on placebo (HR: 0.75; 95% CI: 0.60-0.94 and HR: 0.70; 95% CI: 0.53-0.93, respectively). It is important to note that nearly all of the participants (>99%) were taking other CV-prevention medication (e.g., lipid-lowering drugs), in addition to their assigned study medication, so the lower rate of MACE in the colchicine group reflected a further reduction in risk beyond that afforded by existing treatments.
More recently, the LoDoCo2 investigators reported results from a subsequent exploratory study of the initial trial data, in which analysis was restricted to participants who remained alive and on study medication at each yearly analysis interval post-randomization. Results followed a pattern similar to that revealed in the primary report, with MACE hazard ratios of 0.68 (32% relative risk reduction) for years 1 and 2 (Y1 95% CI: 0.50-0.93; Y2: 0.47-0.99) for the colchicine group relative to placebo. Further separation in risk was observed between groups in year 3 (HR: 0.61; 95% CI: 0.41-0.92) and year 4 (HR: 0.53; 95% CI: 0.33-0.87), which might indicate that benefits of colchicine treatment increase over time. However, we can’t say if this trend is significant; due to the low number of patients who remained alive and on their trial medication by year 4, the study was underpowered by latter time points and confidence intervals were large.
A Better Estimate of Efficacy than of Effectiveness
Overall, these data indicate that low-dose colchicine reduces incidence of MACE in patients with established coronary disease, supporting the FDA’s decision to approve this medication for cardiovascular indications. However, a few noteworthy limitations leave room for the possibility the LoDoCo2 trial may somewhat overestimate the drug’s benefits.
As described above, the researchers began the study with a 30-day run-in treatment prior to randomization. This period ultimately resulted in the exclusion of 15.4% of participants who had perceived side effects, had failed to adhere to the treatment, or had otherwise refused to continue the study. This practice thus introduces a bias in the study cohort in favor of those who were most likely to continue treatment. In a more general population, compliance is likely to be lower than in the randomized cohort, so the true reduction in risk on a population level is almost certainly less than the 31% reported by the investigators.
Indeed, the study results themselves hint at the impact of such a bias. While the main analyses reported above were conducted according to an intention-to-treat principle (i.e., including all patients who underwent randomization, regardless of whether they remained in the study or continued treatment through the full follow-up period), the authors also conducted secondary analyses according to a per-protocol principle (i.e., including only participants who completed the protocol as directed), and the latter analyses trend toward a greater risk reduction (36%; HR: 0.64; 95% CI: 0.53-0.78) than the former. In other words, excluding those who discontinue treatment increases the apparent effects of colchicine on lowering CV risk, so although excluding non-compliant patients from the run-in phase will result in a better assessment of efficacy (i.e., the success of the intervention in a controlled situation in which protocols are followed perfectly), doing so likely overinflates the apparent effectiveness (i.e., the “real-world” success of an intervention when factoring in the likelihood of patients failing to follow prescribed treatment protocols).
Other Limitations
We should also point out that patients in this trial had a fairly advanced form of coronary disease. Therefore, results only speak to that population, and we don’t yet have any data on colchicine’s effects at earlier stages of disease, which might inform optimal timing and context of colchicine treatment. For instance, would starting treatment earlier slow the decades-long process of ASCVD progression and result in greater benefits, as we see with lipid-lowering medications? Or perhaps does colchicine merely stabilize existing plaques?
Clues on the answers to these questions might be gleaned from metrics such as lipid levels, inflammatory state, or blood pressure, but such measurements were not included in baseline clinical evaluations or at subsequent time points in this trial. In the absence of this information, we cannot be certain that colchicine and placebo groups were truly at equivalent risk at baseline, nor can we know if the observed protection afforded by colchicine treatment was in fact due to a reduction in systemic inflammation. Note that colchicine is known to have effects beyond impacting inflammatory pathways, as it also disrupts microtubule polymerization, a process involved in intracellular transport, cell division, and various other functions at the cellular level. Additionally, because biomarkers of systemic inflammation (most notably, C-reactive peptide levels) were neither used as eligibility criteria for participants nor measured throughout the trial, we cannot know if such biomarkers might be useful in predicting which patients will or will not find benefit from colchicine treatment.
Another Tool in the Fight Against ASCVD
Even with these caveats in mind, the results of the LoDoCo2 trial provide strong evidence that colchicine is a viable therapeutic for meaningfully reducing risk of cardiovascular events in those with coronary disease. Real-world effectiveness might be overestimated at a reported risk reduction of 31%, but eliminating cohort biases is unlikely to completely abolish the evident benefit.
But the approval of colchicine for treating ASCVD isn’t just about one drug. It is the first success story following years of hypotheses and investigations into inflammation as a potential therapeutic target for cardiovascular disease, and it may herald renewed interest in and excitement for this class of medications. Importantly, no one is suggesting that anti-inflammatory drugs can or should take the place of existing CVD medications – in the LoDoCo2 trial, participants on colchicine were overwhelmingly taking it in combination with other therapies – but this class of medications may nonetheless serve as an additional tool to further reduce risk of cardiovascular events, chipping away at the residual risk observed in coronary disease patients with well-managed lipid levels.
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