An update on the safety of SGLT2 inhibitors

ABSTRACT

Introduction: Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) are recommended after metformin for a large spectrum of patients with type 2 diabetes, because of a favorable benefit/risk profile despite a variety of adverse events.

Areas covered: This narrative review discusses the safety profile of SGLT2is: initial concerns (cardiovascular safety, acute renal failure, hypoglycemia, urinary and genital infections, volume depletion, bladder cancer), further concerns (euglycemic ketoacidosis, bone fractures) and more recent concerns (lower limb amputation, Fournier’s gangrene).

Expert opinion: Overall, the safety profile of SGLT2is is good. The only increased adverse event that was consistently reported in clinical trials and observational studies is genital mycotic infections, with only a borderline increase in urinary tract infections. Among clinical trials, only the CANVAS program reported an unexpected increase in bone fractures and peripheral amputations. A variety of rare adverse events have been described as case reports, including ketoacidosis, amputations and Fournier gangrene, which led to specific warnings by regulatory agencies. Identifying predisposing patient’s characteristics and/or precipitating clinical conditions would help prevent the most severe complications. These adverse events should not mask the overall cardiovascular and renal benefit of SGLT2is, especially in patients with type 2 diabetes at high cardiovascular risk.

KEYWORDS:

• Adverse event
• cardiovascular disease
• complications
• gliflozin
• safety
• sglt2 inhibitor
• type 2 diabetes mellitus

Article highlights

• SGLT2is are the oral glucose-lowering agents that showed better efficacy to reduce major cardiovascular and renal outcomes in T2DM patients at high risk.

• Mild genital mycotic infections are the most common adverse events whereas the risk of urinary tract infections is only marginally increased.

• Adverse events related to volume depletion (orthostatic hypotension, acute kidney injury) are rare but may occur in fragile patients exposed to some precipitating factors.

• Euglycemic diabetic ketoacidosis is increased with SGLT2is, yet it remains a rare adverse event in T2DM patients that generally occurs in case of insulin deprivation and exposure to deleterious conditions such as post-surgery.

• The increased risk of bone fractures and lower limb amputations reported with canagliflozin in CANVAS (which remains largely unexplained) is not confirmed in most other trials or observational studies (but well in some pharmacovigilance reports) with canagliflozin, dapagliflozin, and empagliflozin so that a class effect remains debatable.

• The pharmacovigilance reports to regulatory agencies are more alarming than findings collected in RCTs and observational studies. Although they may be affected by reporting biases, they point out signals that require future postmarketing surveillance to better delineate the long-term safety profile of SGLT2is.

This box summarizes key points contained in the article.

Declaration of interest

AJ Scheen has received lecturer/advisor fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, NovoNordisk, Sanofi and Servier. AJ Scheen has also worked as clinical investigator in the three cardiovascular outcome trials: EMPA-REG-OUTCOME, CANVAS-R and DECLARE-TIMI 58. 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.

Reviewer disclosures

A reviewer on this manuscript has disclosed that they have served on an advisory board for AstraZeneca, and have received speaker’s fees from AstraZeneca, Bayer and Boehringer Ingelheim. All other peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.