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A comprehensive review of the pharmacodynamics of the SGLT2 inhibitor empagliflozin in animals and humans

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Abstract

Empagliflozin (formerly known as BI 10773) is a potent, competitive, and selective inhibitor of the sodium glucose transporter SGLT2, which mediates glucose reabsorption in the early proximal tubule and most of the glucose reabsorption by the kidney, overall. Accordingly, empagliflozin treatment increased urinary glucose excretion. This has been observed across multiple species including humans and was reported under euglycemic conditions, in obesity and, most importantly, in type 2 diabetic patients and multiple animal models of type 2 diabetes and of type 1 diabetes. This led to a reduction in blood glucose, smaller blood glucose excursions during oral glucose tolerance tests, and, upon chronic treatment, a reduction in HbA1c in animal models and patients. In rodents, such effects were observed in early and late phases of experimental diabetes and were associated with preservation of pancreatic β-cell function. Combination studies in animals demonstrated that beneficial metabolic effects of empagliflozin may also manifest when added to other types of anti-hyperglycemic treatments including linagliptin and pioglitazone. While some anti-hyperglycemic drugs lead to weight gain, empagliflozin treatment was associated with reduced body weight in normoglycemic obese and non-obese animals despite an increased food intake, largely due to a loss of adipose tissue; on the other hand, empagliflozin preserved body weight in models of type 1 diabetes. Empagliflozin improved endothelial dysfunction in diabetic rats and arterial stiffness, reduced blood pressure in diabetic patients, and attenuated early signs of nephropathy in diabetic animal models. Taken together, the SGLT2 inhibitor empagliflozin improves glucose metabolism by enhancing urinary glucose excretion; upon chronic administration, at least in animal models, the reductions in blood glucose levels are associated with beneficial effects on cardiovascular and renal complications of diabetes.

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Abbreviations

AUC:

Area under the curve

OGTT:

Oral glucose tolerance test

FPG:

Fasting plasma glucose

NF-κB:

Nuclear factor κB

SGLT:

Sodium glucose transporter

STZ:

Streptozotocin

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Conflict of interest

MCM and EM are employees of Boehringer Ingelheim. VV serves as a consultant for Boehringer Ingelheim and Janssen Pharmaceutical; work in his lab has been supported by the National Institutes of Health (R01DK56248, R01HL094728, P30DK079337), by the US Department of Veterans Affairs, and by investigator-initiated research grants from Astra-Zeneca, Boehringer Ingelheim, and Bristol-Myers Squibb.

Many of the empagliflozin studies being cited included co-authors from and/or had been supported by Boehringer Ingelheim.

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Authors and Affiliations

  1. Department of Pharmacology, Johannes Gutenberg University, Mainz, Germany

    Martin C. Michel

  2. Department of Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany

    Martin C. Michel

  3. Department of Cardiometabolic Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Strasse 65 Biberach an der Riss, 88397, Ingelheim, Germany

    Eric Mayoux

  4. Division of Nephrology and Hypertension, Departments of Medicine and Pharmacology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA

    Volker Vallon

  5. Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Dr. (9151), San Diego, CA, 92161, USA

    Volker Vallon

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  1. Martin C. Michel
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  2. Eric Mayoux
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  3. Volker Vallon
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Correspondence to Eric Mayoux or Volker Vallon.

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Michel, M.C., Mayoux, E. & Vallon, V. A comprehensive review of the pharmacodynamics of the SGLT2 inhibitor empagliflozin in animals and humans. Naunyn-Schmiedeberg's Arch Pharmacol 388, 801–816 (2015). https://doi.org/10.1007/s00210-015-1134-1

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  • DOI: https://doi.org/10.1007/s00210-015-1134-1

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