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Increased Glucagon Levels Paradoxically Associated with Liraglutide

Aug 21, 2015

A recent study lists liraglutide as potentially having an early, unanticipated effect on glucagon in type 2 diabetes patients…

In a recent randomized controlled trial, authors evaluated the use of liraglutide in 51 patients with type 2 diabetes for an average of 2.6 years. Patients were given either liraglutide or placebo for 48 weeks with assessment of glucose, insulin, C-peptide and glucagon responses to oral glucose tolerance tests (OGTT) every 12 weeks.


Not surprisingly, liraglutide increased insulin and C-peptide levels after the OGTT when compared to the placebo. Unexpectedly, however, there was an unanticipated increase in glucagonemia that persisted through the 48 weeks.

Areas under the curve glucagon levels were significantly higher and nearly three times as much in the liraglutide group. This number did diminish from 170 pg/mL to 155.5 pg/mL over the 48 weeks, however.

Three important outcomes were noted by the study: a lower or similar fasting glucagon compared to placebo, delayed time to peak glucagon concentration and an enhanced glucagonemic excursion.

Nonetheless, researchers were surprised by this finding in the LIBRA trial. They concluded this hyperglucagonemia may be acute and lost with a longer duration of therapy.

Future studies may consider investigating more into the alpha cell and islet response to GLP-1 agonists and look at GLP-1 agonists with varying half-lives in comparison to liraglutide.

Practice Pearls:

  • A recent study highlighted 51 patients from the LIBRA trial and their OGTT performance when taking either liraglutide or placebo.
  • While the liraglutide group showed increased insulin and C-peptide levels, it surprisingly showed an increased amount of glucagon in the blood.
  • Researchers concluded this hyperglucagonemia may be temporary in nature, but more research should be done to investigate how GLP-1 agonists impact alpha cell and islet response to create such a response.

Kramer, Caroline K, Bernard Zinman, Haysook Choi, et al. “The Impact of Chronic Liraglutide Therapy on Glucagon Secretion in Type 2 Diabetes: Insight from the LIBRA Trial.” The Journal of Clinical Endocrinology & Metabolism (2015). Web. 10 Aug. 2015.