The safety of empagliflozin plus metformin for the treatment of type 2 diabetes

ABSTRACT

Introduction: Metformin is the first-line glucose-lowering medication in type 2 diabetes mellitus (T2DM), but it generally requires soon or later the addition of a second-line therapy, among which a sodium-glucose cotransporter type 2 (SGLT-2) inhibitor, to reach and maintain adequate glucose control.

Areas covered: This narrative review provides an analysis of both efficacy and safety of a dual therapy combining metformin and empagliflozin, a SGLT-2 inhibitor that has proven its’ potential to reduce major cardiovascular (CV) events, mortality, and renal outcomes in patients with T2DM and established CV disease. Pharmacokinetic studies showed the absence of drug–drug interactions and demonstrate bioequivalence between fixed-dose combination (FDC) and individual tablets of empagliflozin and metformin. Focus will be put on the use of this dual therapy in special populations.

Expert opinion: The addition of empagliflozin to metformin therapy improves glucose control, with a minimal risk of hypoglycemia, while reducing body weight and arterial blood pressure. EMPA-REG OUTCOME showed that this combined therapy may be used in patients with established CV disease or heart failure. However, caution may be required in fragile elderly patients and in patients with severe impaired renal function. Further post-marketing surveillance is recommended to demonstrate long-term safety. FDC may improve adherence.

KEYWORDS:

• Cardiovascular disease
• combined therapy
• fixed-dose combination
• chronic kidney disease
• SGLT-2 inhibitor
• type 2 diabetes mellitus

Article highlights

• Metformin and empagliflozin exert their glucose-lowering effects through different, potentially complementary mechanisms.

• No drug–drug pharmacokinetic interactions were reported between metformin and empagliflozin and a FDC showed bioequivalence compared with individual tablets.

• The combination of empagliflozin with metformin results in a better glucose control, without severe hypoglycemia, together with a reduction in body weight and in arterial blood pressure.

• In EMPA-REG OUTCOME that demonstrated cardiorenal protection by empagliflozin, almost 80% of patients received metformin as background therapy.

• The safety profile of each compound is well known and combined therapy is not associated with unexpected adverse events.

The commercialization of an empagliflozin–metformin FDC may facilitate the management of T2DM and possibly increase the adherence to the therapy.

Declaration of interest

A.J. Scheen has received lecturer, advisor, and/or investigator fees from AstraZeneca, Boehringer, Eli Lilly, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, Novartis, NovoNordisk, Sanofi, and Servier. The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.