Long‐term efficacy and safety of combined insulin and glucagon‐like peptide‐1 therapy: Evidence from the LEADER trial

Abstract

Aim Glucagon‐like peptide‐1 receptor agonist (GLP‐1RA) and insulin combination therapy is an effective treatment option for type 2 diabetes, but long‐term data are lacking. The aim was to assess the long‐term efficacy of the GLP‐1RA liraglutide in subgroups by insulin use in the LEADER trial. Materials and Methods LEADER assessed cardiovascular (CV) safety and efficacy of liraglutide (1.8 mg) versus placebo (plus standard of care therapy) in 9340 patients with type 2 diabetes and high risk of CV disease, for up to 5 years. We analyzed CV events, metabolic parameters and hypoglycaemia post hoc in three subgroups by baseline insulin use (basal‐only insulin, other insulin or no insulin). Insulin was a non‐random treatment allocation as part of standard of care therapy. Results At baseline, 5171 (55%) patients were not receiving insulin, 3159 (34%) were receiving basal‐only insulin and 1010 (11%) other insulins. Insulin users had a longer diabetes duration and slightly worse glycaemic control (HbA1c) than the no‐insulin subgroup. Liraglutide reduced HbA1c and weight versus placebo in all three subgroups (P < .001), and severe hypoglycaemia rate in the basal‐only insulin subgroup. The need for insulin was less with liraglutide. CV risk reduction with liraglutide was similar to the main trial results in the basal‐only and no‐insulin subgroups. Conclusions In patients on insulin, liraglutide improved glycaemic control, weight and need for insulin versus placebo, for at least 36 months with no increased risk of severe hypoglycaemia, while maintaining CV safety/efficacy, supporting the combination of liraglutide and insulin for management of type 2 diabetes.

Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea in diabetes

“…SU utilization has declined owing to the introduction of Glp1 agonists and DPP4 inhibitors in the diabetes pharmacopeia. However, the latter drugs are not immune to secondary failures either (28)(29)(30)(31)(32) and suffer from poor patient adherence (33)(34)(35). In addition, as top-line findings from the comparative effectiveness glycemia reduction approaches in type 2 diabetes study (GRADE) study demonstrate, the 5-year therapeutic failure rates of SU (72%) are comparable to those of other secretagogues or insulin (67 to 77%).…”

Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea

“…Why should we then care whether we can revamp it? For three main reasons: first, with time it has become apparent that Glp1 agonists and DPP4 inhibitors are not immune to secondary failures [29][30][31][32][33] , and the former suffer from poor patient adherence [34][35][36] . Second, as topline findings from the comparative effectiveness GRADE study demonstrate, the five-year therapeutic failure rates of SU (72%) are comparable with those of other secretagogues or insulin (67 to 77%).…”

Delphi-Based Consensus on Treatment Intensification in Type 2 Diabetes Subjects Failing Basal Insulin Supported Oral Treatment: Focus on Basal Insulin + GLP-1 Receptor Agonist Combination Therapies

“…Clinical trials have shown that this strategy, compared to basal-bolus regimens, allows equal or better glycaemic control with lower risk of hypoglycaemia, has a beneficial effect on body weight and results in a reduction in total daily insulin dose [9][10][11][12][13]. Furthermore, in this population of patients, GLP-1RA can reduce the risk of adverse cardiovascular outcomes [14].…”