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

Autor: Martin Gajdošík, Julia K. Overman, Erin S. Morgan, Richard S. Geary, Li-Jung Tai, Shiangtung W. Jung, Lynnetta Watts, Brenda F. Baker, Martin Krššák, Michael Krebs, Sanjay Bhanot, Anne Smith, Nguyen C. Pham
Rok vydání: 2019
Předmět:
Zdroj: Diabetes Care. 42:585-593
ISSN: 1935-5548
0149-5992
DOI: 10.2337/dc18-1343
Popis: OBJECTIVE 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. 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-GCGRRx (50–200 mg) or placebo for 13 or 26 weeks. RESULTS 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. CONCLUSIONS 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.
Databáze: OpenAIRE
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