Update review of the safety of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with type 2 diabetes mellitus

ABSTRACT

Introduction: The safety profile of sodium-glucose cotransporter 2 (SGLT2) inhibitors has continued to evolve with the availability of data from clinical trial programs, post-marketing pharmacovigilance and dedicated cardiovascular outcome trials.

Areas covered: This article reviews the safety issues associated with the SGLT2 inhibitors canagliflozin, dapagliflozin, and empagliflozin, particularly the newer/emergent safety data related to US Food and Drug Administration statements regarding these three agents.

Expert opinion: The safety profile of SGLT2 inhibitors is well defined, and the adverse event profile is largely consistent with their mechanism of action. These well-recognized events include genital mycotic infections and volume-associated adverse events. Serious safety issues detected more recently with SGLT2 inhibitor therapy, such as bone fractures, pyelonephritis, urosepsis, and ketoacidosis, have been uncommon. A robust improvement in cardiovascular outcomes in patients with type 2 diabetes mellitus (T2DM) was recently demonstrated with empagliflozin. Given the glucose-lowering efficacy, low risk of hypoglycemia, and other benefits associated with SGLT2 inhibitor therapy, this class of oral glucose-lowering medication is a valuable addition to treatment options for T2DM, and may play an increasingly prominent therapeutic role as emerging data are revealed.

KEYWORDS:

• Canagliflozin
• dapagliflozin
• empagliflozin
• sodium-glucose cotransporter 2 inhibitors
• safety
• tolerability
• type 2 diabetes mellitus

Article highlights

• The risk of hypoglycemia associated with SGLT2 inhibitors is low, unless they are co-administered with insulin or an insulin secretagogue.

• Mycotic genital infections, uncomplicated bacterial urinary tract infections, and intravascular volume depletion are well-established adverse reactions associated with SGLT2 inhibitor therapy, and are likely to be related to the mechanism of action of the drug class. Genital and urinary infections are readily treatable, and patients at risk of volume depletion are likely to be identifiable.

• Data regarding bone safety, including the incidence of fracture and decreased bone density, have been inconclusive with SGLT2 inhibitor therapy. The occurrence of bone-related adverse events has been rare and of uncertain clinical significance.

• Incidence of pyelonephritis or urosepsis is rare in patients treated with SGLT2 inhibitors.

• Ketoacidosis is an uncommon adverse reaction in patients with T2DM undergoing therapy with SGLT2 inhibitors, and euglycemic ketoacidosis is rare. Sub-populations of patients at elevated risk for these adverse reactions are likely to be identifiable and patient self-monitoring for ketonuria or, preferably, ketonemia is warranted in these groups.

• Substantial cardiovascular outcome reduction has been demonstrated with empagliflozin therapy, and cardiovascular outcome trials for other SGLT2 inhibitors are under way.

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Declaration of interest

Writing support was provided by Debra Brocksmith, MB ChB, PhD, of Envision Scientific Solutions, which was contracted and funded by Boehringer Ingelheim Pharmaceuticals, Inc. Boehringer Ingelheim Pharmaceuticals was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. 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 was not funded.