Glycemic management possible with small-molecule glucagon receptor antagonist
Among a cohort of adults with type 2 diabetes, HbA1c and fasting plasma glucose were effectively reduced via treatment with the small-molecule glucagon receptor antagonist RVT-1502, according to findings published in Diabetes Care.
“Glucagon receptor antagonism to treat hyperglycemia in type 2 diabetes by reducing hepatic glucose production has been pursued for several decades, but no drugs with this mechanism of action are currently available for clinical use,” Jeremy H. Pettus, MD, assistant professor of clinical medicine at the University of California, San Diego, and colleagues wrote. “RVT-1502 shows similar reductions in HbA1c at lower doses than other glucagon receptor antagonists tested to date, which could potentially reduce the risk of off-target adverse effects during chronic therapy.”
Pettus and colleagues randomly assigned daily regimens of 5 mg RVT-1502, 10 mg RVT-1502, 15 mg RVT-1502 or placebo to 166 adults with type 2 diabetes (mean age, 56.4 years; 45.2% women; mean HbA1c, 8.2%; mean FPG, 9.5 mmol/L) as part of a phase 2 randomized controlled trial. Participants were already taking metformin at study onset. The researchers followed participants for 12 weeks and measured HbA1c and FPG levels at 2, 4, 8 and 12 weeks.
Participants assigned RVT-1502 experienced greater reductions than those assigned placebo: 0.7% greater with the 5 mg dose, 0.8% greater with the 10 mg dose and 1.1% greater with the 15 mg dose (P < .0001 for all).
The odds of reducing HbA1c below 7% were 3.7 times greater for those taking 5 mg RVT-1502 (OR = 3.7; 95% CI, 1.2-11.4), 4.4 times greater for those taking 10 mg RVT-1502 (OR = 4.4; 95% CI, 1.3-14.6) and 4.3 times greater for those taking 10 mg RVT-1502 (OR = 4.3; 95% CI, 1.4-12.8) vs. placebo. In addition, the odds of reducing HbA1c below 6.5% were greater for those taking 10 mg RVT-1502 (OR = 6.5; 95% CI, 1.1-37) and those taking 15 mg RVT-1502 (OR = 7.9; 95% CI, 1.5-41.2) vs. placebo.
Participants assigned RVT-1502 experienced greater reductions in FPG than those assigned placebo: 2.1 mmol/L more for the 5 mg dose, 2.2 mmol/L more for the 10 mg dose and 2.8 mmol/L more for the 15 mg dose (P < .0001 for all).
There was little difference between groups in adverse events, and “the majority of adverse events were considered mild or moderate in severity,” the researchers wrote.
“Possible endpoints to be considered for future clinical trials would include measurement of liver fat, 24-hour BP monitoring and continuous glucose monitoring,” the researchers wrote. “The results of the current study support continued clinical development of RVT-1502 in subjects with type 2 diabetes.” – by Phil Neuffer
Disclosures: Ligand Pharmaceuticals supported and conducted this study. Pettus reports he has received consultant fees from Diasome, Eli Lilly, Mannkind, Novo Nordisk and Sanofi. Please see the study for all other authors’ relevant financial disclosures.