SGLT2 Inhibitors: Background and Mechanism of Action
In addition to the core pathologic defects of beta-cell failure and insulin resistance, a number of other factors contribute to disease progression in T2DM. Together, these have been termed the 'ominous octet', as shown in Figure 1. The dysregulation of kidney-mediated maintenance of glucose homoeostasis is one component of the ominous octet. Renal glucose resorption capacity is increased in individuals with diabetes, and the kidneys continue to reabsorb glucose even when plasma glucose concentrations are high, with levels that usually exceed the transport maximum of glucose of healthy individuals. This leads to the continuous movement of glucose from the kidneys into the circulation, even in the presence of hyperglycaemia, thus perpetuating hyperglycaemia and increasing the risk for diabetes-associated complications. In addition, renal gluconeogenesis is elevated in patients with T2DM, resulting in increased glucose release in these individuals. Renal gluconeogenesis is negatively regulated by insulin and renal glucose production increases with increasing insulin resistance, with 40% of the increased endogenous glucose release in patients with T2DM attributable to increased renal gluconeogenesis.
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Figure 1.
The ominous octet. In addition to the insulin resistance in the muscle and liver, and impaired insulin secretion in the β-cell, the fat cell (accelerated lipolysis), gastrointestinal tract (incretin deficiency/resistance), α-cell (hyperglucagonaemia), kidney (increased glucose reabsorption) and brain (insulin resistance) all play important roles in the development of glucose intolerance in type 2 diabetic individuals (3). Reproduced with permission from DeFronzo R et al. Diabetes, 2009; 58:773–795. Copyright ©2009 American Diabetes Association. All rights reserved
SGLT2 is a low-affinity, high-capacity glucose transporter located in the early part of the proximal tubule, involved in the reabsorption of the vast majority (~90%) of glucose in the kidney. As the actions of SGLT2 promote glucose conservation and the maintenance of plasma glucose concentrations, inhibition of SGLT2 may have the opposite effect; namely, to reduce hyperglycaemia by stimulating urinary glucose excretion. Observations in individuals with SGLT2 gene alterations suggest that functional depletion of SGLT2 may not have long-term deleterious effects, at least in the individuals followed up to date. The resulting disorder, known as familial renal glucosuria, causes urinary glucose excretion, with the amount of glucose excreting ranging from < 10 g/day to > 200 g/day. Affected individuals are usually otherwise asymptomatic, and the condition is not known to be associated with T2DM or other pathological sequelae.
As the action of SGLT2 is independent of insulin, its inhibition should not be influenced by pancreatic beta-cell mass or function, or by the degree of insulin resistance present. Therefore, SGLT2 inhibitors have the potential to be used at any stage of T2DM. They may even have the potential to show efficacy as the disease progresses, unlike some other types of antidiabetes agents that show a decline in glucose-lowering potential caused by their dependence on beta-cell function (e.g. sulfonylureas or glinides). Additionally, the non–insulin-dependent mechanism of action of SGLT2 inhibitors gives them the potential to be used in combination with any of the existing classes of glucose-lowering agents, including insulin. Other metabolic characteristics of SGLT2 inhibitors may also be anticipated. For example, SGLT2 inhibitors should not increase the risk of hypoglycaemia, as inhibition of SGLT2 does not affect endogenous glucose production, does not stimulate insulin release when glucose levels decline and does not cause urinary glucose excretion when plasma glucose levels fall below threshold values. SGLT2 inhibitors should also promote some weight loss, resulting from the reduction in available calories caused by urinary glucose excretion. This ability to induce weight loss, along with the ability to act as a diuretic, would also suggest a potential BP-lowering effect for SGLT2 inhibitors.