Antisense Inhibition of Glucagon Receptor by IONIS-GCGR_Rx Improves Type 2 Diabetes Without Increase in Hepatic Glycogen Content in Patients With Type 2 Diabetes on Stable Metformin Therapy.

Abstract

To evaluate the safety and efficacy of IONIS-GCGR_Rx, a 2'-<i>O</i>-methoxyethyl antisense oligonucleotide targeting the glucagon receptor (GCGR), and the underlying mechanism of liver transaminase increases in patients with type 2 diabetes on stable metformin therapy. In three phase 2, randomized, double-blind studies, patients with type 2 diabetes on metformin received weekly subcutaneous injections of IONIS-GCGR_Rx (50-200 mg) or placebo for 13 or 26 weeks. Significant reductions in HbA_1c were observed after IONIS-GCGR_Rx treatment versus placebo at week 14 (-2.0% 200 mg, -1.4% 100 mg, -0.3% placebo; <i>P</i> < 0.001) or week 27 (-1.6% 75 mg, -0.9% 50 mg, -0.2% placebo; <i>P</i> < 0.001). Dose-dependent increases in transaminases were observed with IONIS-GCGR_Rx, which were attenuated at lower doses and remained mostly within the normal reference range at the 50-mg dose. There were no other significant safety observations and no symptomatic hypoglycemia or clinically relevant changes in blood pressure, LDL cholesterol, or other vital signs. At week 14, IONIS-GCGR_Rx 100 mg did not significantly affect mean hepatic glycogen content compared with placebo (15.1 vs. -20.2 mmol/L, respectively; <i>P</i> = 0.093) but significantly increased hepatic lipid content (4.2 vs. -2.7%, respectively; <i>P</i> = 0.005) in the presence of transaminase increases. IONIS-GCGR_Rx is a potent inhibitor of hepatic glucagon receptor expression with a potential to improve glycemic control at low weekly doses in combination with metformin. Significant reductions in HbA_1c occurred across the full-dose range tested, with minimal transaminase elevations at lower doses. Furthermore, novel results suggest that despite inhibition of glycogenolysis after GCGR antagonism, IONIS-GCGR_Rx did not increase hepatic glycogen content.