Incretin-based therapies in prediabetes: Current evidence and future perspectives

Abstract

The prevalence of type 2 diabetes (T2D) is evolving globally at an alarming rate. Prediabetes is an intermediate state of glucose metabolism that exists between normal glucose tolerance (NGT) and the clinical entity of T2D. Relentless β-cell decline and failure is responsible for the progression from NGT to prediabetes and eventually T2D. The huge burden resulting from the complications of T2D created the need of therapeutic strategies in an effort to prevent or delay its development. The beneficial effects of incretin-based therapies, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, on β-cell function in patients with T2D, together with their strictly glucose-depended mechanism of action, suggested their possible use in individuals with prediabetes when greater β-cell mass and function are preserved and the possibility of β-cell salvage is higher. The present paper summarizes the main molecular intracellular mechanisms through which GLP-1 exerts its activity on β-cells. It also explores the current evidence of incretin based therapies when administered in a prediabetic state, both in animal models and in humans. Finally it discusses the safety of incretin-based therapies as well as their possible role in order to delay or prevent T2D.

Keywords: Type 2 diabetes, Prediabetes, Impaired fasting glucose, Impaired glucose tolerance, Glucagon-like peptide-1, Dipeptidyl peptidase-4 inhibitors, Glucagon-like peptide-1 receptor agonists

Core tip: The beneficial effects of incretin-based therapies on β-cell function in patients with type 2 diabetes (T2D) suggested their possible use in individuals with prediabetes, when greater β-cell mass and function are preserved. Both dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists have demonstrated improvements on β-cell function both in preclinical studies and short-term clinical studies. Until future date for their safety are available, large, long term, prevention trials will be required in order to determine whether they can stabilize or reverse β-cell loss and promote a sustained reduction in the development of T2D in this population.