Counter-regulatory hormone responses to hypoglycaemia in people with type 1 diabetes after 4 weeks of treatment with liraglutide adjunct to insulin: a randomized, placebo-controlled, double-blind, crossover trial

Diabetes Obes Metab. 2015 Aug;17(8):742-50. doi: 10.1111/dom.12473. Epub 2015 May 20.

Abstract

Aims: To investigate the effect of glucagon-like peptide 1 receptor agonist liraglutide on the counter-regulatory hormone response to hypoglycaemia in type 1 diabetes.

Methods: We conducted a randomized, double-blind, placebo-controlled, single-centre trial, in which a total of 45 adults with type 1 diabetes [mean ± standard deviation age 34.5 ± 11.2 years, BMI 23.9 ± 2.4 kg/m(2) , glycated haemoglobin (HbA1c) 7.6 ± 0.8%, diabetes duration 16.6 ± 9.4 years] underwent a hypoglycaemic clamp after 4 weeks' crossover treatment with once-daily liraglutide/placebo added to insulin in one of three liraglutide dose groups: 0.6 mg (n = 15); 1.2 mg (n = 14); and 1.8 mg (n = 16). The main outcome measure was glucagon concentration at nadir plasma glucose (2.5 mmol/l). Clinical outcomes were also evaluated. Five participants were withdrawn from the trial; three because of adverse events. All participants were included in the analysis.

Results: Glucagon concentration at nadir plasma glucose was modest, trending towards lower concentrations at increasing liraglutide dose versus placebo: 34.7 versus 38.1 pg/ml, p = 0.555 (0.6 mg); 28.8 versus 37.2 pg/ml, p = 0.126 (1.2 mg); and 28.4 versus 37.5 pg/ml, p = 0.092 (1.8 mg). There was no difference, however, between liraglutide and placebo in incremental change in glucagon during hypoglycaemia. Other counter-regulatory hormone levels increased during hypoglycaemia with no systematic differences between groups. Glucose infusion rates were significantly lower with liraglutide versus placebo during the clamp. After 4 weeks' treatment, HbA1c remained unchanged in the liraglutide and placebo groups. Greater reductions in insulin dose and body weight were seen with liraglutide versus placebo.

Conclusions: Liraglutide did not compromise hypoglycaemic responses in type 1 diabetes after 4 weeks' treatment.

Trial registration: ClinicalTrials.gov NCT01536665.

Keywords: GLP-1; catecholamines; counter-regulation; glucagon; glucose infusion rate; hypoglycaemia; hypoglycaemic clamp; incretin therapy; liraglutide; type 1 diabetes.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Body Weight
  • Cross-Over Studies
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Double-Blind Method
  • Drug Therapy, Combination / methods
  • Female
  • Glucagon / metabolism
  • Glucagon-Like Peptide 1 / therapeutic use
  • Glucose / administration & dosage
  • Glucose Clamp Technique
  • Glycated Hemoglobin A / drug effects
  • Glycated Hemoglobin A / metabolism
  • Humans
  • Hypoglycemia / drug therapy
  • Hypoglycemia / metabolism
  • Hypoglycemic Agents / therapeutic use*
  • Insulin / therapeutic use*
  • Liraglutide / therapeutic use*
  • Male
  • Middle Aged

Substances

  • Glycated Hemoglobin A
  • Hypoglycemic Agents
  • Insulin
  • hemoglobin A1c protein, human
  • Liraglutide
  • Glucagon-Like Peptide 1
  • Glucagon
  • Glucose

Associated data

  • ClinicalTrials.gov/NCT01536665