Insulin-glucagon-like peptide-1 receptor agonist relay and glucagon-like peptide-1 receptor agonist first regimens in individuals with type 2 diabetes: A randomized, open-label trial study.

AIMS/INTRODUCTION: Glucagon-like peptide-1 receptor agonists (GLP-1 RA) might be less effective in patients with severe hyperglycemia, because hyperglycemia downregulated the GLP-1 receptor in an animal study. To examine this hypothesis clinically, we compared the glucose-lowering effects of GLP-1 receptor agonist liraglutide with and without prior glycemic control. MATERIALS AND METHODS: In an open-label, parallel trial, participants with poorly controlled type 2 diabetes were recruited and randomized to receive once-daily insulin therapy, degludec (Insulin-GLP-1 RA relay group, mean 16.8 ± 11.4 IU/day), for 12 weeks and then liraglutide for 12 weeks or subcutaneous injections of GLP-1 RA, liraglutide (GLP-1 RA first group, 0.9 mg), for 24 weeks. The primary efficacy end-points consisted of changes in the levels of fasting plasma glucose and glycated hemoglobin (HbA1c). RESULTS: The median fasting plasma glucose and HbA1c before the study were 210.0 mg/dL and 9.8%, respectively. The levels of fasting plasma glucose and HbA1c significantly decreased in the Insulin-GLP-1 RA relay group (P < 0.001) and GLP-1 RA first group (P < 0.001) by week 24, although no intergroup differences were observed. The reduction of HbA1c in the Insulin-GLP-1 RA relay group tended to be larger than that in the GLP-1 RA first group in the lowest CPR (C-peptide immunoreactivity) quartile (P = 0.072). The adverse events consisted of gastrointestinal problems, followed by hypoglycemia. CONCLUSIONS: The GLP-1 receptor agonist is overall effective without prior glycemic control with insulin in participants with poorly controlled type 2 diabetes. However, in participants with insulinopenic type 2 diabetes, prior glycemic control with insulin might overcome glucose toxicity-induced GLP-1 resistance.