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

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.

Preclinical research strategies for newly approved drugs as reflected in early publication patterns

“…Therefore, number and type of preclinical studies performed prior to regulatory approval of new drugs are likely to differ considerably. Comparison between the few cases where comprehensive reviews were published summarizing non-clinical data (Eberlin et al 2012;Michel et al 2015;Modjtahedi et al 2014) supports the notion that preclinical strategies may differ considerably, but overall little empirical data is available in this regard.…”

A systematic review of urinary bladder hypertrophy in experimental diabetes: Part 2. Comparison of animal models and functional consequences

“…Oral antidiabetic drugs are the cornerstone of T2DM treatment, but none of them has been tested for effects on bladder hypertrophy. In this regard, SGLT2 inhibitors may be of specific interest because they promote glycosuria . More treatment studies, particularly involving drugs in clinical use for the treatment of T2DM, are urgently needed.…”

Opportunities and Challenges for Drug Development: Public–Private Partnerships, Adaptive Designs and Big Data

“…In a recent survey of academic investigators engaging in project-based, non-clinical collaboration with the pharmaceutical industry, complex contract negotiations were seen as a major hurdle for collaboration, interestingly equally being attributed to legal departments of companies and academic institutions (Amiri and Michel, 2015). Other case studies of project-based collaborations in drug development have recently been reported (Modjtahedi et al, 2014; Michel et al, 2015). Academic investigators engaged in non-clinical drug-related research expressed strong interest in such collaborations (Amiri and Michel, 2015).…”

“…Aspects of non-clinical investigator-initiated research have been discussed in the previous section and reviewed elsewhere (Modjtahedi et al, 2014; Michel et al, 2015; Michel and Korstanje, 2016) Focusing on clinical IIS, Stefan Schröder and Miriam Bach (Bayer, Berlin, Germany) reported that the investigator is responsible for initiating, managing and financing the study, following applicable laws and regulations. These include the rules of Good Clinical Practice and Good Manufacturing Practice as well as article 2 (e) of the European Directive 2001/20/EC.…”