Cholesterol 7 Alpha–Hydroxylase (CYP7A1) Activity and 7–Alpha–Hydroxy–4–Cholesten–3–One (C4) Are Not Translatable Biomarkers of Glucagon Receptor (GCGR) Activation

Abstract

Glucagon-like peptide 1 receptor/glucagon receptor (GLP–1R/GCGR) dual agonists are being pursued for obesity and type 2 diabetes mellitus (T2DM). A biomarker for GCGR would aid in optimizing receptor balance and in modeling dose selection to avoid potential adverse events from excess GCGR agonism. It has been reported that glucagon treatment decreases CYP7A1 transcription in primary rat and human hepatocytes, whereas GCGR antagonists increase CYP7A1 mRNA in mice and its product, 7–HCO (the precursor of C4), in diabetic patients. We tested glucagon, insulin, dulaglutide, and a GLP–1R/GCGR dual agonist, Cpd. A, in primary human and cynomolgus monkey hepatocytes. All treatments decreased CYP7A1 expression in monkey hepatocytes. C4 was undetectable in the culture media. Lean mice or rats treated with Cpd. A showed no changes in non–fasting C4. Diet–induced obese mice treated with Cpd. A or a GCGR–null analog had decreased non–fasting C4. To test whether GCGR (and/or GLP–1R) agonism affects plasma C4 in higher species, we infused saline or glucagon (at two different rates) on a background of somatostatin infusion in cynomolgus monkeys dosed with dulaglutide the day before. C4 levels did not differ between treatment groups. To determine whether this lack of an effect was specific to pre-clinical species, T2DM patients were dosed once a week for 4 weeks with a placebo or 2 doses of a second GLP-1R/GCGR dual agonist. There were no statistically significant differences in C4 levels between groups. Hence, in contrast to GCGR antagonists, GCGR and/or GLP–1R agonists did not modulate C4 levels in pre–clinical species or in T2DM patients. Disclosure R. Camacho: Employee; Self; Janssen Research & Development. W. Li: None. T. Kirchner: None. R. Zhang: Employee; Self; Janssen Research & Development. F. Bonilla: None. W. Jian: None. B. Gao: None. R. SinhaRoy: Employee; Self; Janssen Research & Development. Employee; Spouse/Partner; Bristol–Myers Squibb Company. Stock/'Shareholder; Self; Merck & Co., Inc.. Stock/Shareholder; Spouse/Partner; Merck & Co., Inc. J. Leonard: Employee; Self; Janssen Research & Development. T. Connolly: None.