The potential of SGLT2 inhibitors in phase II clinical development for treating type 2 diabetes

ABSTRACT

Introduction: There is now an abundance of anti-diabetic agents. However, only few patients achieve glycemic targets. Moreover, current glucose-lowering agents mainly depend upon insulin secretion or function. Sodium glucose co-transporter type 2 (SGLT2) inhibitors present a novel glucose-lowering therapy, inducing glycosuria in an insulin-independent fashion.

Areas covered: In this review, the authors discuss the key efficacy and safety data from phase II clinical trials in type 2 diabetes mellitus (T2DM) of the main SGLT2 inhibitors approved or currently in development, and provide a rationale for their use in T2DM.

Expert opinion: Despite the very promising characteristics of this new therapeutic class, a number of issues await consideration. One important question is what to expect from head-to-head comparison data. We also need to know if dual inhibition of SGLT1/SGLT2 is more efficacious in reducing HbA_1c and how this therapy affects metabolic and cardiovascular parameters. Additionally, several SGLT2 agents that have not yet come to market have hitherto been evaluated in Asian populations, whereas approved SGLT2 inhibitors have been frequently studied in other populations, including Caucasian subjects. Thus, we need more information on the potential role of ethnicity on their efficacy and safety.

KEYWORDS:

• Diabetes mellitus
• oral hypoglycemic agents
• phase II trials
• SGLT2 inhibitors

Article highlights

• Despite the abundance of anti-diabetic agents, only few patients achieve glycemic targets.

• Sodium glucose co-transporter type 2 (SGLT2) inhibitors present a novel glucose-lowering therapy, inducing glycosuria in an insulin-independent fashion.

• It has been suggested that selective SGLT2 inhibitors contribute to inhibition of renal glucose reabsorption mainly under hyperglycemic conditions, whereas the role of SGLT1 in renal glucose management is increasingly important mainly under lower glycemic conditions.

• A dual SGLT1 and SGLT2 inhibitor appears to be linked with some novel characteristics, namely significant elevations of GLP-1 and peptide YY and improvements in metabolic and cardiovascular parameters.

• Empaglifllozin has already shown additional beneficial actions in high-risk patients: reduction in total and cardiovascular disease mortality, fewer hospitalizations for heart failure.

• Given the great number of available SGLT2 agents and those under development, there is a clear need for head-to-head data.

This box summarizes key points contained in the article.

Declaration of interest

N Papanas has been an advisory board member of TrigoCare International, Astra-Zeneca, Boehringer Ingelheim, MSD, Novo Nordisk and Pfizer; has participated in sponsored studies by Astra-Zeneca, GlaxoSmithKline, Novo Nordisk, Novartis and Sanofi-Aventis; has received honoraria as a speaker for Astra-Zeneca, Boehringer Ingelheim, Eli-Lilly, ELPEN, MSD, Mylan, Novo Nordisk, Pfizer, Sanofi-Aventis and Vianex; and attended conferences sponsored by TrigoCare International, Eli-Lilly, Galenica, Novo Nordisk, Pfizer and Sanofi-Aventis. E Maltezos has participated in sponsored studies by Astra-Zeneca, GlaxoSmithKline, Novo Nordisk, Novartis and Sanofi-Aventis; and attended conferences sponsored by Wyeth, Pfizer, and Bayer. The authors have 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.

Additional information

Funding

This paper received no funding.