Investigational insulin secretagogues for type 2 diabetes

ABSTRACT

Introduction: Insulin secretory defects are a key feature in the pathophysiology of type 2 diabetes (T2D). Classical insulin-secreting agents such as sulfonlyureas stimulate insulin secretion independent of glucose and cause hypoglycemia. Despite the advantages offered by incretin-based therapies, there is still a medical need for developing new insulin secretagogues for treating T2D.

Area covered: This article discusses: the new advances in the field of incretin-based therapies, glucokinase (GK) activators, free fatty acid receptor (FFAR) or G protein-coupled receptor (GPR) agonists (GPR40, GPR119, GPR120), imeglimin and some other insulin secretagogues with diverse mechanisms of action still in preclinical development.

Expert opinion: New insulin secretagogues should offer major advantages over sulfonylureas and gliptins. The challenge is to avoid uncontrolled insulin secretion and minimize the risk of hypoglycemia, to protect cells from progressive loss of mass and function for a better durability of glucose control, and to offer a good safety profile. Numerous approaches are in development. However, it is too early to decide whether one new pharmacological class will emerge as a clinically useful insulin secretagogue in the near feature.

KEYWORDS:

• Beta cell
• glucokinase activator
• GPR agonist
• imeglimin
• incretin
• insulin secretion
• type 2 diabetes

Article highlights.

• Sulfonylureas remain the most prescribed insulin secreting agents for the treatment of T2D worldwide, although they have some important drawbacks, especially a high risk of hypoglycemia.

• The strategy using incretin-based therapies is increasingly used in T2D; this remains an evolving field and further advances are expected in a near future.

• Although initially considered as promising insulin-secreting agents because of the well-known role of GK in β cells, direct GK activators have been associated with a risk of hypoglycemia, leading to the recent development of more liver-selective GK activators.

• FFAR also called GPR agonists are able to simulate insulin secretion, especially GPR40 agonists, but they have also some limitations and liver safety may be a concern.

• Imeglimin, with its unique mechanism of action targeting mitochondria bioenergetics and function, appears the most advanced new insulin-secreting compound with recent promising results in Phase I–II clinical trials and ongoing Phase III trials.

• Several other insulin secretagogues with diverse mechanisms of action are in preclinical development, although it is too early to decide whether one of them will be successful enough for clinical use.

This box summarizes key points contained in the article.

Financial and competing interests disclosure

The author has received lecture/advisor fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceuticals, Merck Sharp & Dohme, Novartis, NovoNordisk, Sanofi, and Takeda. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.