We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Antisense Inhibition of Glucagon Receptor by IONIS-GCGR<sub>Rx</sub> Improves Type 2 Diabetes Without Increase in Hepatic Glycogen Content in Patients With Type 2 Diabetes on Stable Metformin Therapy.
- Authors
Morgan, Erin S.; Li-Jung Tai; Pham, Nguyen C.; Overman, Julia K.; Watts, Lynnetta M.; Smith, Anne; Jung, Shiangtung W.; Gajdošík, Martin; Krššák, Martin; Krebs, Michael; Geary, Richard S.; Baker, Brenda F.; Bhanot, Sanjay; Tai, Li-Jung
- Abstract
<bold>Objective: </bold>To evaluate the safety and efficacy of IONIS-GCGRRx, 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.<bold>Research Design and Methods: </bold>In three phase 2, randomized, double-blind studies, patients with type 2 diabetes on metformin received weekly subcutaneous injections of IONIS-GCGRRx (50-200 mg) or placebo for 13 or 26 weeks.<bold>Results: </bold>Significant reductions in HbA1c were observed after IONIS-GCGRRx 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-GCGRRx, 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-GCGRRx 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.<bold>Conclusions: </bold>IONIS-GCGRRx 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 HbA1c 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-GCGRRx did not increase hepatic glycogen content.
- Subjects
GLUCAGON-like peptide-1 agonists; TYPE 2 diabetes; GLUCAGON receptors; GLYCOGEN; METFORMIN; GLYCEMIC control; BLOOD sugar; CELL receptors; COMPARATIVE studies; RESEARCH methodology; MEDICAL cooperation; RESEARCH; EVALUATION research; BLIND experiment
- Publication
Diabetes Care, 2019, Vol 42, Issue 4, p585
- ISSN
0149-5992
- Publication type
journal article
- DOI
10.2337/dc18-1343