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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.
- Source :
-
Diabetes care [Diabetes Care] 2019 Apr; Vol. 42 (4), pp. 585-593. Date of Electronic Publication: 2019 Feb 14. - Publication Year :
- 2019
-
Abstract
- Objective: To evaluate the safety and efficacy of IONIS-GCGR <subscript>Rx</subscript> , a 2'- O -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.<br />Research Design and Methods: In three phase 2, randomized, double-blind studies, patients with type 2 diabetes on metformin received weekly subcutaneous injections of IONIS-GCGR <subscript>Rx</subscript> (50-200 mg) or placebo for 13 or 26 weeks.<br />Results: Significant reductions in HbA <subscript>1c</subscript> were observed after IONIS-GCGR <subscript>Rx</subscript> treatment versus placebo at week 14 (-2.0% 200 mg, -1.4% 100 mg, -0.3% placebo; P < 0.001) or week 27 (-1.6% 75 mg, -0.9% 50 mg, -0.2% placebo; P < 0.001). Dose-dependent increases in transaminases were observed with IONIS-GCGR <subscript>Rx</subscript> , 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 <subscript>Rx</subscript> 100 mg did not significantly affect mean hepatic glycogen content compared with placebo (15.1 vs. -20.2 mmol/L, respectively; P = 0.093) but significantly increased hepatic lipid content (4.2 vs. -2.7%, respectively; P = 0.005) in the presence of transaminase increases.<br />Conclusions: IONIS-GCGR <subscript>Rx</subscript> 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 <subscript>1c</subscript> 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 <subscript>Rx</subscript> did not increase hepatic glycogen content.<br /> (© 2019 by the American Diabetes Association.)
Details
- Language :
- English
- ISSN :
- 1935-5548
- Volume :
- 42
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Diabetes care
- Publication Type :
- Academic Journal
- Accession number :
- 30765435
- Full Text :
- https://doi.org/10.2337/dc18-1343