A review of the mechanism of action, metabolic profile and haemodynamic effects of sodium‐glucose co‐transporter‐2 inhibitors

Abstract

Inhibition of glucose transport in the kidney, to produce glucosuria and thus directly lower blood glucose seems a remarkably simple way to treat diabetes (type 1 or type 2). The development of sodium-glucose co-transporter-2 (SGLT2) inhibitors and their subsequent clinical development has on one hand shown this to be true, but at another level has helped reveal a complex web of interacting effects starting in the kidney and modulating multiple metabolic pathways in a variety of other organs. These underlie the now clear benefits of this class of drugs in the management of type 2 diabetes from glucose lowering, weight loss and blood pressure reduction through to the reductions in cardiovascular and renal complications observed in long-term outcomes trials. They also explain some of the adverse effects that have emerged, including the risk of diabetic ketoacidosis. This review describes the effects of SGLT2 inhibition in relation to this complex physiology, and shows how this can favourably alter the pathophysiology of type 2 diabetes.anti-diabetic drug, clinical physiology, type 2 diabetes, SGLT2 inhibitor 1 | INTRODUCTION Sodium glucose transporter 2 inhibitors (SGLT2i) are one of the newest classes of drugs available to lower glucose in people with type 2 diabetes, but their origins go back to the 19th century, when phlorizin, extracted from the bark of apple trees was shown to induce glucosuria. Phlorizin was later used experimentally as a tool to help understand renal glucose transport and the effects of glucose toxicity, as it could be used to lower blood glucose without directly affecting insulin secretion or sensitivity. 1 However its therapeutic potential was limited, due to poor oral bioavailability, and effects on gut glucose absorption that resulted in diarrhoea; phlorizin also has an active metabolite (phloretin) that inhibits the GLUT1 glucose transporter that is important for normal glucose transport in many tissues. 2 Research conducted in the last 20 years has now identified the specific mechanisms by which phlorizin is able to induce glucosuria and lower blood glucose, and led to the development of drugs that are highly selective inhibitors of renal (and/or gut) glucose transport. These drugs work by inhibiting the facilitative sodium glucose co-transporters (SGLTs) that are responsible for renal glucose reabsorption (predominantly SGLT2 with some contribution from SGLT1, which also has a major role in gut glucose absorption). 3 Despite early concerns about some adverse effects that occur as a result of glucosuria, the development of SGLTi (and potentially dual inhibitors of SGLT1 and SGLT2) has led to greater understanding of the fundamental physiological processes involved in glucose transport in the kidney and gastrointestinal (GI) tract. These medications have both predictable and surprising effects that underpin some of their observed therapeutic benefits and adverse effects. This review will focus on the underlying physiology and show how this is modified by pharmacological inhibition of SG...

Effects of sodium‐glucose co‐transporter‐2 inhibitors on serum alanine aminotransferase levels in people with type 2 diabetes: A multi‐institutional cohort study

“…We categorized patients according to SGLT2 inhibitor received (dapagliflozin or empagliflozin) to evaluate class effects of ALT reduction. To determine whether improvements in ALT values were independent of renal function, key to the pharmacological actions of SGLT2 inhibitors, we stratified patients by baseline renal function (eGFR >90 vs. ≤90 mL/min/1.73m 2 ). In addition, we stratified patients by their changes in HbA1c (≤0.7 vs. >0.7%) and body weight (≤1.7 vs. >1.7 kg) after 1 year of treatment to examine if the improvements of ALT values were independent of glucose or weight‐lowering effects.…”

Sodium-glucose co-transporter-2 inhibitors: peculiar “hybrid” diuretics that protect from target organ damage and cardiovascular events

“…However, these drugs lead to natriuresis and osmotic diuresis dependent on glycosuria and can, therefore, be considered diuretics with a "hybrid" mechanism. A slightly lower osmotic effect is seen in non-diabetic individuals, due to their lower plasma glucose levels (estimated average glycosuria is 75 g and 45e72 g per day for diabetic and non-diabetic subjects, respectively) [9,10]. SGLT2 is responsible for up to 97% of glucose reabsorption and for about 5% of total renal Na þ reabsorption.…”

“…In addition to the energy loss linked to glycosuria (about 300 kcal/d), partly offset by the increased caloric intake, SGLT2 inhibition modulates multiple metabolic pathways. For example, insulin levels are reduced, while glucagon levels are increased, resulting in hepatic glycogenolysis and gluconeogenesis [9]. Moreover, insulin in the presence of high glycaemic levels is a potent inducer of the NPs clearance receptor (NPRC) [47].…”

“…Therefore, SGLT2i could enhance NPs activity by reducing insulin levels. Furthermore, lipolysis is stimulated leading to higher levels of circulating free fatty acids for lipid oxidation and ketogenesis [9], a metabolic change that can have a role in CV benefits, especially improving the cardiac metabolism [48]. Finally, several studies showed also a reduction in arterial stiffness, likely due to a direct effect of SGLT2i on the arterial vessel and oxidative stress, although not all evidences are in agreement [49,50].…”

Effects of sodium‐glucose cotransporter inhibitors on cardiorenal and metabolic systems: Latest perspectives from the outcome trials

“…The articles published in the special supplement issue of Diabetes, Obesity and Metabolism this month covered the efficacy and safety of SGLT2 inhibitors and of an SGLT2/1 co‐inhibitor in type 2 diabetes (T2D) and type 1 diabetes (T1D): Wilding and colleagues reviewed the mechanism of action of SGLT2 inhibitors focusing on their metabolic and haemodynamic effects; Nassif and Kosiborod dissected the effects of SGLT2 inhibitors on heart failure; Scholtes and colleagues reviewed the major CV outcome trials of SGLT2 inhibitors, which showed cardiorenal and metabolic benefits; Fitchett summarized the recent update in the safety issues of SGLT2 inhibitors; Dominguez Reig and Rieg described the rationale and prospects of SGLT2 and SGLT1 dual inhibition; Biester et al reviewed the potential role of SGLT inhibition in T1D …”