Obesity and especially metabolic syndrome are pro-inflammatory conditions, that can give rise to hypertension, dyslipidemia, insulin resistance, diabetes, and cardiovascular disease. Colchicine, an anti-inflammatory agent, is frequently used for gout, pericarditis and familial Mediterranean fever.
In this small randomized clinical trial, authors found that colchicine 0.6 mg twice daily decreased inflammatory markers CRP, ESR, WBC, and ANC in patients with obesity and metabolic syndrome. These results could provide some basis for designing outcome-driven clinical trials, such as evaluating diabetes and CVD risk reduction with colchicine.
Diabetes, Obesity and Metabolism
To evaluate the efficacy and safety of colchicine for improving metabolic and inflammatory outcomes in people with obesity and metabolic syndrome (MetS).
Materials and methods
Adults with obesity and MetS, but who did not have diabetes, were randomized to colchicine 0.6 mg BID or placebo capsules BID for 3 months.
Primary outcome was change in insulin sensitivity (SI) as estimated by insulin‐modified frequently sampled intravenous glucose tolerance tests.
Secondary outcomes included changes in other metabolic variables and inflammatory markers.
Of 40 participants randomized (21 colchicine, 19 placebo), 37 completed the trial.
Compared with placebo, colchicine significantly reduced:
C‐reactive protein (P <0.005)
Erythrocyte sedimentation rate (P <0.01)
White blood cell count (P <0.005)
Absolute neutrophil count (P <0.001)
Change in insulin sensitivity was not significantly different between colchicine and placebo arms (P = 0.82). However, changes in following secondary outcomes suggested metabolic improvements in the colchicine versus placebo group:
Homeostatic model assessment of insulin resistance (P = 0.0499)
Fasting insulin (P = 0.07)
Glucose effectiveness (P = 0.08)
Adverse events were generally mild and similar in both groups.
This pilot study found colchicine significantly improved obesity‐associated inflammatory variables and showed a good safety profile among adults with obesity and MetS who did not have diabetes.
These results suggest a larger, adequately powered study should be conducted to determine whether colchicine improves insulin resistance and other measures of metabolic health in at‐risk individuals.
More from the publication
Over one third of adults in the United States, 84 million people, have prediabetes; 5-10% of individuals with prediabetes develop diabetes annually, and an estimated 70% of individuals with prediabetes will progress to diabetes during their lifetimes. Although many new pharmaceutical options have been developed for the treatment of diabetes, limited proven medical therapies exist for prediabetes to prevent diabetes onset.
Mouse models and human studies suggest that obesity‐induced inflammation is an important mechanism promoting insulin resistance and the progression to diabetes. Circulating inflammatory effectors, such as saturated fatty acids and uric acid, are found in higher concentrations in obesity and stimulate the innate immune system. The resultant chronic inflammatory state leads to progressive insulin resistance and decreased pancreatic beta‐cell reserve. It has been proposed that suppression of this chronic low‐level inflammatory state may slow the onset of diabetes and cardiovascular disease.
Nod‐like Receptor Family Pyrin Domain Containing 3 (NLRP3), a member of the innate immune system, has recently been shown to play an integral role in promoting the inflammatory state in obesity. Upon stimulation by danger‐associated molecular patterns such as saturated fatty acids or cholesterol esters, NLRP3 uses microtubules to synchronize with an adaptor protein and caspase‐1 within the cytosol of macrophages to create a multimeric inflammasome. The activated NLRP3 inflammasome produces activated cytokines interleukins, IL‐1β and IL‐18, thereby initiating and propagating the inflammatory cascade.
COLCHICINE, a microtubule inhibitor, is classically used to suppress or prevent inflammation in disorders such as gout, Familial Mediterranean Fever, and pericarditis.
One mechanism by which colchicine exerts its anti‐inflammatory effects is by inhibiting NLRP3 inflammasome formation and activation. A recent retrospective study suggested that among patients with gout, long‐term colchicine treatment may have glycaemic benefit; however, to date no RCT has investigated colchicine's long‐term effects on glucose metabolism in adults with obesity and metabolic syndrome (MetS).
We hypothesized that administration of colchicine to adults with MetS, but who had not yet developed type 2 diabetes, would improve their obesity‐associated metabolic and inflammatory dysregulation.
Results from this pilot RCT show that colchicine was well tolerated by adults with obesity, MetS and evidence for inflammation. Colchicine significantly reduced multiple markers of obesity‐associated inflammation, including hsCRP and ESR. Colchicine is well known to have anti‐inflammatory properties, although its effect on obesity‐associated inflammation has not previously been investigated. Classically it has been posited that colchicine blocks inflammation by impeding leukocyte locomotion, diapedesis, and, ultimately, recruitment to sites of inflammation.
Colchicine may exert its effects through other mechanisms as well, including blocking the production of chemotactic and adhesion molecules. Recently, it has been shown that colchicine also inhibits the formation of the NLRP3 inflammasome, an important component of the obesity‐associated inflammatory cascade. In the current study, participants in the colchicine arm had moderate but statistically significant reductions in WBC, monocytes, neutrophils and platelets, without significant effects on lymphocyte count. Further work is needed to investigate specifically which inflammatory pathways are suppressed, and which remain unaffected, by colchicine in obesity.
The suppression of inflammation from colchicine treatment was not associated with significant improvement in our primary outcome, SI estimated from the FSIVGTT. However, some of the secondary outcomes related to glucose homeostasis, including HOMA‐IR and fasting insulin, had changes that suggest colchicine treatment may potentially improve hepatic insulin sensitivity. Additionally, the trend towards improvement in DI in the colchicine group suggests that colchicine might potentially be able to delay the onset of diabetes mellitus in at‐risk individuals. However, larger follow‐up studies will be needed to confirm and extend these findings.
A recent large cardiovascular trial found that canakinumab did successfully decrease hsCRP and the primary composite endpoint of non‐fatal myocardial infarction, non‐fatal stroke or cardiovascular death in individuals with prior myocardial infarction. Similarly, the LoDoCo study found that subjects with known coronary artery disease randomized to colchicine 0.5 mg daily had fewer composite cardiovascular events than the placebo arm.
Strengths of this study include the prospective, randomized, double‐blind, placebo‐controlled trial design; participants' excellent adherence to study regimen; and the small number of participants who did not complete the trial. The small sample size limited the opportunity to observe significant effects from colchicine on most metabolic measurements and precluded adjustment of significance tests for comparisons among the secondary study outcomes.
However, as this investigation was designed as a pilot, it enabled us to calculate that a reasonable sample size (<160 participants) would allow an adequately powered examination of relevant study endpoints. Another possible weakness is that we did not utilize the FDA‐approved version of colchicine available at the time on the US market (Colcrys); rather, we used colchicine USP powder in study capsules at the FDA‐approved dose so that we could produce an identical‐appearing placebo.
Because we did not avoid enrolment of individuals with extremely high BMI, it is possible that results might have been different in a sample restricted, for example, to BMI < 40 kg/m2. Additionally, as the phase of the menstrual cycle can affect insulin sensitivity, we attempted to schedule baseline and final visits in the same self‐reported phase for the 11 premenopausal female subjects.
While we were largely successful in this effort, we did not have objective evidence (eg, measured serum progesterone) to confirm that this was the case. Lastly, the subjects studied had only insulin resistance or prediabetes rather than diabetes. It is possible that a study of a more metabolically unhealthy group might find greater difference between placebo and colchicine. Future studies are also needed to characterize more completely the metabolic and anti‐inflammatory effects of colchicine administration in MetS, including measurements of IL‐1 beta and IL‐18 concentrations.
In conclusion, in this pilot study, colchicine successfully suppressed obesity‐induced inflammation but did not significantly improve the study's primary outcome. However, several metabolic measures did suggest improvement in glucose homeostasis in the colchicine arm. Larger trials are needed to investigate whether colchicine has efficacy in improving insulin resistance and/or preventing the onset of diabetes mellitus in at‐risk individuals with obesity‐associated inflammation.