OR31-2 Effects of Colchicine on Insulin Resistance, Pancreatic Beta-Cell Function, and Aspects of the Metabolic Syndrome (MetS) in Adults with Obesity, MetS, and Inflammation: A Pilot Randomized Controlled Trial

Abstract

Abstract Introduction: Low-grade chronic inflammation, due in part to activation of the NLRP3 inflammasome, increases with increasing adiposity and plays a significant role in the development of type 2 diabetes and cardiovascular disease. However, to date, the efficacy of anti-inflammatory medications to improve aspects of the metabolic syndrome (MetS) is not well established. As colchicine has been shown to prevent assembly of the NLRP3 inflammasome and ameliorate other inflammatory conditions, we aimed to evaluate the efficacy and safety of colchicine for improving metabolic and inflammatory outcomes in adults with obesity and MetS. Materials and Methods: We conducted a randomized, double-blind, placebo-controlled pilot trial in which 40 non-diabetic adults with obesity, MetS, and elevated high-sensitivity C-reactive protein (hsCRP≥ 2.0 mg/L) were randomized to colchicine 0.6 mg or placebo twice daily for three months. Fasting labs, insulin-modified frequently sampled intravenous glucose tolerance test (FSIVGTT), and body composition by DXA were performed at baseline and 3-month follow up. The primary outcome was change in FSIVGTT insulin sensitivity (SI) as measured by Bergman’s minimal model. Secondary outcomes included changes in other metabolic parameters and inflammatory markers. ANCOVA was used to examine differences between treatment arms, with age, sex, baseline body fat%, and Δbody fat% as covariates. Data were analyzed according to intention-to-treat and reported as mean±SD. Results: Colchicine significantly reduced inflammatory indices, including hsCRP (-2.8±2.9 vs. 0.4±2.8 mg/L, p=.002), ESR (-5.5±6.4 vs. 0.6±6.3 mm/hr, p=.007), white blood cell count (-1.09±1.23 vs. 0.29±1.16 K/µL, p=.002), and absolute neutrophil count (-1.06±1.05 vs. 0.12±0.93 K/µL, p<.001). However, change in SI was not significantly different between colchicine and placebo arms (2.9x10-6 ± 3.1x10-5 vs 3.4x10-6 ± 2.9x10-5 min-1·mU-1·ml, p=.82). Changes in other metabolic parameters also did not reach significance, although changes in HOMA-IR (p=.097) and glucose effectiveness (SG; p=.067) trended towards improvement in the colchicine group. Adverse events were similar in both groups, and no patients withdrew due to side effects. Post-hoc analyses calculated that a sample size of 166 subjects would be necessary to achieve 80% power to detect a difference in measures of metabolic health (e.g. HOMA-IR, fasting insulin, fasting glucose, SG, and disposition index) between colchicine and placebo groups, for a two-tailed α <0.05. Conclusions: Colchicine significantly improved obesity-associated inflammatory variables and demonstrated a good safety profile among obese non-diabetic adults with MetS. Larger, adequately powered studies are needed to determine whether colchicine has beneficial effects on insulin resistance and other measures of metabolic health in at-risk individuals.