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Liraglutide may increase hyperglucagonemia in patients with early type 2 diabetes
Adults with early type 2 diabetes assigned liraglutide were more likely to experience hyperglucagonemia compared with those assigned a placebo, despite improvements in insulin secretion and C-peptide response, according to research in The Journal of Clinical Endocrinology & Metabolism.
Caroline K. Kramer , MD, PhD, of the Leadership Sinai Center for Diabetes at Mt. Sinai Hospital in Toronto, Canada, and colleagues analyzed data from 51 adults with an average type 2 diabetes duration of 2.6 years participating in the LIBRA trial, a randomized double blind, parallel-arm, placebo-controlled study. Researchers randomly assigned participants to either daily subcutaneous liraglutide injection (n = 26; mean age, 59 years; 62% men; 73% white) or placebo injection (n = 25; mean age, 57 years; 64% men; 68% white), titrated weekly over 3 weeks from 0.6 mg to 1.2 mg and 1.8 mg, then maintained at 1.8 mg for 48 weeks.
Researchers administered a 2-hour, 75 g oral glucose tolerance test at baseline, 12, 24, 36 and 48 weeks. If participants had an HbA1c of 8% or greater after an OGTT, researchers initiated metformin therapy at 500 mg twice daily for 2 weeks, then 1,000 mg for the remainder of the study period. Six participants required metformin during the study (one in the liraglutide arm; five in the placebo arm).
Researchers found that liraglutide induced an enhancement of the post-challenge insulin and C-peptide response following the 12-week OGTT and throughout the duration of the study when compared with the placebo group, as well as a reduction in post-challenge glycemic excursion.
“Intriguingly, however, liraglutide also induced an unanticipated increase in post-challenge glucagonemia that first emerged at 12 weeks and persisted over the course of 48 weeks of treatment,” the researchers wrote.
Incremental area under the glucagon curve was significantly higher in the liraglutide group compared with placebo at 12 weeks (mean 170.2 vs. 65.4 pg/mL), 36 weeks (mean 162.2 vs. 55.7 pg/mL) and at 48 weeks (mean 155.5 vs. 45.7 pg/mL). The results were unchanged after adjusting for duration of diabetes and excluding the six participants requiring metformin therapy.
Researchers noted three features in the response pattern of the liraglutide arm following each OGTT: a lower or similar fasting glucagon compared with placebo, an enhanced post-challenge glucagonemic excursion and a delayed time to peak serum glucagon concentration, occurring at 60 minutes post-challenge, compared with a 30-minute peak in the placebo group.
“It thus appears that the acute suppressive effect of liraglutide on post-challenge glucagonemia may be lost with longer duration of therapy, highlighting the need for further study to elucidate the alpha cell and islet response to chronic GLP-1 agonist treatment,” the researchers wrote. – by Regina Schaffer
Disclosure: Kramer reports no relevant financial disclosures. Two of the study authors report receiving research funding and consulting honoraria from Novo Nordisk.