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Natural Medicine Journal

April 3, 2024

Can Low-Dose Colchicine Lower Cardiovascular Risk?

Results from a randomized, double-blind, placebo-controlled trial

Corey B. Schuler

FNP, MS, CNS, CNSC, DC
Patients who used colchicine saw a 35% risk reduction for cardiovascular events after a myocardial infarction.

Reference

Roubille F, Bouabdallaoui N, Kouz S, et al. Low-dose colchicine in patients with type 2 diabetes and recent myocardial infarction in the Colchicine Cardiovascular Outcomes Trial (COLCOT). Diabetes Care. 2024;47(3):467-470. 

Study Objective

To determine if low-dose colchicine affected rates of ischemic cardiovascular events in patients with type 2 diabetes who had a myocardial infarction (MI) within the last 30 days

Key Takeaway

Low-dose colchicine significantly reduces risk of ischemic events in patients with type 2 diabetes following myocardial infarction.

Design

Randomized, double-blind, placebo-controlled trial

Participants

The study included 959 patients with type 2 diabetes who experienced a myocardial infarction in the last 30 days. The mean age of participants was 62.4 years (22.2% women). Study took place in 167 centers across 12 countries. 

Participants were excluded for a variety of reasons including class 3 or 4 heart failure, left ventricular ejection fraction < 35%; stroke within the past 3 months, type 2 index MI, coronary bypass surgery within the past 3 years or planned, history of noncutaneous cancer within the last 3 years, inflammatory bowel disease or chronic diarrhea, neuromuscular disease, or nontransient creatine phosphokinase greater than 3 times the upper limit of normal (ULN), significant nontransient hematological abnormalities, severe renal disease with serum creatinine greater than twice the ULN, severe hepatic disease, drug or alcohol abuse, chronic systemic steroid therapy, or history of sensitivity to colchicine.

Intervention

The active group received 0.5 mg of colchicine once daily, while the control group received a placebo of undisclosed ingredients once daily.

Study Parameters Assessed

Investigators monitored participants for 22.6 months (median duration) for ischemic cardiovascular events and side effects of medication. They performed clinical evaluations every 3 months but did not statistically evaluate and publish an aggregate biochemical assessment.

Primary Outcome

The primary outcome of the study was a cardiovascular event that included cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina requiring coronary revascularization. A total of 8.7% of participants receiving colchicine experienced such an event, whereas 13.1% of participants in the placebo group met the end point. 

Key Findings

Participants with type 2 diabetes receiving 0.5 mg of colchicine daily following a myocardial infarction experienced significantly fewer major ischemic cardiovascular events than those in the placebo group (0.65 HR; 95% CI, 0.44–0.96; P=0.03). This represents a risk reduction of 35%.

Transparency

The study was funded by the Government of Quebec, the Canadian Institutes of Health Research, and undisclosed philanthropic foundations. Disclosures were stated by authors. One author waived rights to a patent for the use of colchicine after myocardial infarction.

Practice Implications & Limitations

Inflammation plays a pivotal role in the initiation, progression, and destabilization of atherosclerosis. Chronic inflammation can lead to endothelial dysfunction, characterized by impaired vascular homeostasis and increased permeability.1 This dysfunction allows for the entry of lipids and immune cells into the arterial wall, initiating the formation of atherosclerotic plaques, recruitment and activation of immune cells, particularly macrophages and T lymphocytes, within the arterial wall, and instability by releasing proteases that degrade the extracellular matrix and weaken the fibrous cap covering the plaque. Plaque rupture or erosion can lead to thrombus formation and acute cardiovascular events, such as myocardial infarction or stroke.

Individuals with type 2 diabetes are at higher risk of presenting with a cardiovascular event after a myocardial infarction compared to nondiabetic patients.2

Colchicine is a prescription medication derived from the Colchicum autumnale plant. While mostly known for its use acutely and prophylactically for gout and arthritis, it also has use for familial Mediterranean fever (FMF). Colchicine works by disrupting microtubule formation, inhibiting neutrophil migration and activation, and reducing the inflammatory response and potentially other anti-inflammatory mechanisms.3 It is commonly dosed in 0.6-mg increments, such as 1.2 mg per day for gout prophylaxis, 1.2 mg followed by 0.6 mg an hour later for acute gout exacerbations, and off-label use for pericarditis at 0.6 mg once or twice daily.4 However, colchicine has lost favor to nonsteroidal anti-inflammatory drugs (NSAIDs) and oral glucocorticoids for acute gout exacerbations and to urate-lowering allopurinol, a xanthine oxidase inhibitor, for prophylaxis.5 

Individuals with type 2 diabetes are at higher risk of presenting with a cardiovascular event after a myocardial infarction compared to nondiabetic patients.

Colchicine has garnered interest for a variety of uses, including cardiovascular medicine, over the last decade.6 Developing and compelling research has found new uses for colchicine, associated with its inhibition of endothelial inflammation via the NLRP3/C-reactive protein (CRP) pathway, as seen presenting as leukocytosis.7 Colchicine (0.5 mg daily) reduced cardiovascular risk in patients with chronic coronary artery disease as demonstrated in the Low-Dose Colchicine 2 (LoDoCo2) trial.8 A systematic review and meta-analysis found that colchicine users had lower risk of major adverse cardiac events (P<0.001) and significantly reduced high-sensitivity CRP (–4.25, P<0.001).9

This study evaluating colchicine in patients with type 2 diabetes following a myocardial infarction is consistent with a previous trial on a more general population following myocardial infarction that also found that 0.5 mg of colchicine reduced ischemic events when implemented within 30 days of the first event as compared to placebo.10 It is worth noting that implementation was swift, and patients began colchicine on average of 14 days following myocardial infarction in addition to their prescribed discharged or continued polypharmacy cocktail, which often consisted of medications such as aspirin, another antiplatelet agent, a statin, and a beta-blocker as well as typical diabetes management medications. 

Despite its potential benefits, colchicine is associated with several side effects, including gastrointestinal symptoms such as diarrhea, nausea, and abdominal pain. These side effects may limit its tolerability. Increased rates of nausea and pneumonia were seen in this low-dose trial, which warrants monitoring if colchicine is selected as a treatment. Colchicine impairs neutrophil recruitment and migration, which is 1 theory as to the increased immune compromise.

While not subjected to the same rigor in clinical trials as colchicine, other natural compounds that act on the NLRP3/CRP pathway have intriguing preliminary evidence. Curcumin, resveratrol, quercetin, omega-3 fatty acids, vitamin D, and berberine are candidates for supporting inflammation specific to this pathway.11-16 However, dosing strategies and outcome measures are not available for comparison between these supplement options and low-dose colchicine.

Categorized Under

Corey B. Schuler

FNP, MS, CNS, CNSC, DC

Corey B. Schuler, FNP, CNS, CNSC, DC, serves as director of medical science for Gaia Herbs. He is a family nurse practitioner, certified nutrition specialist, and nutrition support clinician. He received his chiropractic doctorate from Northwestern Health Sciences University, master of science in human nutrition from the University of Bridgeport, and master of science in nursing at Graceland University. He continues his education in the doctor-of-nursing practice program at Fort Hays State University. He has additionally earned an executive master of business administration and an undergraduate degree in chemistry. Schuler authored a chapter in the textbook Integrative Medical Nutrition Therapy (Springer, 2020) and serves as an adjunct professor in nutrition and business programs. Schuler practices holistic primary care in Minnesota.

References

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  2. Goldberg RB, Mellies MJ, Sacks FM, et al. Cardiovascular events and their reduction with pravastatin in diabetic and glucose-intolerant myocardial infarction survivors with average cholesterol levels: subgroup analyses in the cholesterol and recurrent events (CARE) trial. The Care Investigators. Circulation. 1998;98(23):2513-2519.
  3. Dalbeth N, Lauterio TJ, Wolfe HR. Mechanism of action of colchicine in the treatment of gout. Clin Ther. 2014;36(10):1465-1479.
  4. Medscape. Colchicine. Medscape website. https://reference.medscape.com/drug/colcrys-mitigare-colchicine-342812. Accessed April 2, 2024.
  5. Richette P, Doherty M, Pascual E, et al. 2016 updated EULAR evidence-based recommendations for the management of gout. Ann Rheum Dis. 2017;76(1):29-42.
  6. Dasgeb B, Kornreich D, McGuinn K, Okon L, Brownell I, Sackett DL. Colchicine: an ancient drug with novel applications. Br J Dermatol. 2018;178(2):350-356.
  7. Kajikawa M, Higashi Y, Tomiyama H, et al. Effect of short-term colchicine treatment on endothelial function in patients with coronary artery disease. Int J Cardiol. 2019;281:35-39.
  8. Mohammadnia N, Los J, Opstal TSJ, et al. Colchicine and diabetes in patients with chronic coronary artery disease: insights from the LoDoCo2 randomized controlled trial. Front Cardiovasc Med. 2023;10:1244529.
  9. Bytyçi I, Bajraktari G, Penson PE, et al. Efficacy and safety of colchicine in patients with coronary artery disease: a systematic review and meta-analysis of randomized controlled trials. Br J Clin Pharmacol. 2022;88(4):1520-1528.
  10. Tardif JC, Kouz S, Waters DD, et al. Efficacy and safety of low-dose colchicine after myocardial infarction. N Engl J Med. 2019;381(26):2497-2505.
  11. Du X, Amin N, Xu L, Botchway BOA, Zhang B, Fang M. Pharmacological intervention of curcumin via the NLRP3 inflammasome in ischemic stroke. Front Pharmacol. 2023;14:1249644.
  12. Wang Y, Li W, Zhang T, et al. Resveratrol alleviates MSU-induced gouty arthritis in rats through inhibition of HIF-1α- and NLRP3-derived IL-1β secretion in macrophages. Cell Mol Biol (Noisy-le-grand). 2023;69(7):28-34. 5
  13. Alattar A, Alshaman R, Althobaiti YS, et al. Quercetin alleviated inflammasome-mediated pyroptosis and modulated the mTOR/P70S6/P6/eIF4E/4EBP1 pathway in ischemic stroke. Pharmaceuticals (Basel). 2023;16(8):1182.
  14. Wang CP, Lee CC, Wu DY, Chen SY, Lee TM. Differential effects of EPA and DHA on PPARγ-mediated sympathetic innervation in infarcted rat hearts by GPR120-dependent and -independent mechanisms. J Nutr Biochem. 2022;103:108950. 0
  15. Wu M, Lu L, Guo K, Lu J, Chen H. Vitamin D protects against high glucose-induced pancreatic β-cell dysfunction via AMPK-NLRP3 inflammasome pathway. Mol Cell Endocrinol. 2022;547:111596.
  16. Zhong C, Xie Y, Wang H, et al. Berberine inhibits NLRP3 inflammasome activation by regulating mTOR/mtROS axis to alleviate diabetic cardiomyopathy. Eur J Pharmacol. 2024;964:176253.

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