A comparative safety review between GLP-1 receptor agonists and SGLT2 inhibitors for diabetes treatment

ABSTRACT

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium glucose cotransporter 2 inhibitors (SGLT2i) are of particular interest in type 2 diabetes treatment strategies, due to their efficacy in reducing HbA1c with a low risk of hypoglycaemia, to their positive effects on body weight and blood pressure and in light of their effects on cardiovascular risk and on nephroprotection emerged from the most recent cardiovascular outcome trials.

Since it is therefore very likely that GLP-1RA and SGLT2i use will become more and more common, it is more and more important to gather and discuss information about their safety profile.

Area Covered: adverse events and the safety concerns most often emerged in trials with GLP-1RA namely, exenatide long acting release (LAR), dulaglutide, liraglutide, semaglutide, lixisenatide or SGLT2i, namely empagliflozin, dapagliflozin, canagliflozin and SGLT2i with an attempt at comparing the safety profiles of molecules of these two classes.

Expert opinion: GLP-1RA and SGLT2i, although each associated with different specific side effects, share a ‘similar’ safety profile and are both drugs relatively easy to handle. The potentially complementary mechanisms of action, the cardio and nephroprotective effects demonstrated by molecules of both classes, make these drugs potentially useful even in add on to each other.

KEYWORDS:

• GLP-1 receptor agonists
• SGLT2 inhibitors
• cardiovascular
• safety
• outcome studies

Article highlights

• Neither GLP-1RA nor SGLT2i have so far been associated with any major safety concern. In diabetic patients treated with either GLP-1RA or SGLT2i the hypoglycemia risk is very low: it was similar to, or less than, that observed with placebo (when the agents were not used in association with insulin and/or sulphonylureas). Euglycemic ketaoacidosis is a rare adverse event possibly associated with SGLT2i treatment. It is largely predictable (and thus preventable), since it only occurs in specific conditions (β-cell failure, LADA, physical stress, surgery).

• GLP-1RA and SGLT2i are safe for the cardiovascular system: indeed molecules of these classes have demonstrated cardiovascular protection in very high risk diabetic subjects.

• Genital infections are the most common adverse event during treatment with SGLT2i. They are more frequent in sexually active, female patients. They are generally mild, do not tend to recur and are responsive to topical anti-fungine treatment. Although a modest increase in the incidence of urinary tract infections has been reported with the use of SGLT2i, a comprehensive analysis of the available data does not seem to confirm the existence of such an increase in risk.

• GLP-1RA use is not associated with an increased risk to develop pancreatitis and a previously issued warning on this regard has been removed from their summary of product characteristics (SPCs).

• SGLT2i treatment has been associated with a modest increase in the risk of fracture and an increased risk for lower limbs amputation has been recently reported in only one trial with a molecule of the class. No conclusive data are however at present available neither on the risk of fracture nor on the risk of amputation possibly associated with SGLT2i use.

• Neither GLP-1RA nor SGLT2i seem to be associated with increased risk of developing cancer or specific alterations in electrolytes levels.

This box summarizes key points contained in the article.

Declaration of interest

A.Consoli has received speaker fees and/or consulting honoraria from Astra Zeneca, Boehringer Ingelhaim, Eli Lilly, Merck Sharp & Dhom, Novartis, Novo Nordisk, Roche Diagnostics, Sanofi-Aventis, Takeda and has received research grant support from Eli Lilly and Novo Nordisk.

G.Formoso has received speaker fees from Eli Lilly, Merck Sharp & Dohme, Menarini Diagnostics and Servier. 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. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper has not been funded.