Introduction: In mice, C-C motif chemokine receptor (CCR)5 deletion protects against insulin resistance, hepatic steatosis, and glucose intolerance. We aimed to characterize the metabolic effects of cenicriviroc (CVC), a potent CCR2/5 inhibitor, in type 2 diabetes mellitus (T2DM) patients with nonalcoholic steatohepatitis (NASH) fibrosis from the Phase 2b CENTAUR study.
Methods: Subjects from CENTAUR with T2DM, biopsy-proven NASH, and fibrosis Stages F1-3 were included. CVC-exposed subjects for 1 year (Arm A) and placebo (PBO) [Arms B and C] were analyzed. Liver, metabolic, and inflammatory biomarkers were analyzed. Homeostatic model assessments (HOMA-IR and -b) were calculated. Change (from baseline to Year 1) was compared between groups using a general parametric linear model analysis of covariance (2-sided ANCOVA) based on the mITT population.
Results: Of the 289 subjects in CENTAUR, 134 (46%) had T2DM and were included in this analysis. Baseline characteristics were similar for CVC (n=76) and PBO (n=58) groups (mean ±SD): age 57.5 ±7.75 years vs. 55.41 ±8.65 years, HbA1c 7.30 ±1.29 vs. 7.20 ±1.21 %, BMI 33.02 ±5.25 vs. 35.16 ±7.67 kg/m2, NAS 5.25 ±1.06 vs. 5.52 ±1.13, and fibrosis scores of F1 (31.6%), F2 (21%), and F3 (47.4%) vs. F1 (24.2%), F2 (22.4%), and F3 (53.4%), respectively. At 1 year, there was a significant decrease in HOMA-IR and interleukin (IL)-6 in the CVC group. The least squares mean changes (SE) in HOMA-IR (p=0.0159) and IL-6 (p=0.0094), respectively, were −2.75 (1.27) and −1.9 (0.35) for CVC and 1.94 (1.45) and −0.5 (0.39) for PBO. After 1-year exposure to CVC or PBO, no significant differences vs. baseline in HOMA-b, HDL cholesterol, LDL cholesterol, ALT, and AST were noted.
Conclusion: CVC may improve HOMA-IR and pro-inflammatory cytokine IL-6, suggesting that CVC could potentially improve insulin resistance in NASH patients. These findings warrant further investigation.
A.D. Coviello: Consultant; Self; GI Dynamics Inc., Novo Nordisk Inc. Research Support; Self; Allergan plc., GENFIT, Orthus Health. Speaker’s Bureau; Self; Novo Nordisk Inc. G. Rodriguez: Employee; Self; Allergan plc. E.B. Martins: Employee; Self; Allergan plc. Stock/Shareholder; Self; Allergan plc. N. Alkhouri: Research Support; Self; Allergan plc. M.F. Abdelmalek: None.