Class effect for SGLT-2 inhibitors: a tale of 9 drugs

Abstract

The definition of class effect for SGLT-2 inhibitors may be based on three concepts: a similar chemical structure, a similar mechanism of action and similar pharmacological effects. We have also assumed that a class effect does exist when an effect on a particular outcome is present and is significant for each drug within the class of SGLT-2 inhibitors. For major cardiovascular events (MACE), there is no class effect for SGLT-2 inhibitors, as the 7% reduction of MACE risk observed with dapagliflozin in the DECLARE trial was not significant; on the other hand, a class effect is evident for both heart failure and diabetic kidney disease, as in all four trials so far completed (EMPAREG-OUTCOME, CANVAS, DECLARE, CREDENCE) the risk of hospitalization for heart failure and progression of diabetic kidney disease was significantly reduced by all SGLT-2 inhibitors.

The role of the kidneys in glucose homeostasis was first described more than a century ago. Under normal conditions, the tubular glucose reabsorption is mediated by a sodium-dependent transport system consisting of a family of active glucose transporters: sodium–glucose transporter-2 (SGLT-2) mediate the reabsorption of about 90% of the filtered glucose, with the remainder occurring through SGLT-1. Within the context of normal renal function and in condition of normoglycemia, the vast majority of daily filtered glucose (approximately 200 g) is reabsorbed, because the overall SGLT-2-mediated process of renal glucose reabsorption has high capacity [1].

SGLT-2 inhibitors are a new class of orally active drugs used in the management of type 2 diabetes (T2D) [2]. The glucoside phlorizin (a type of flavonoid) was isolated from the bark of apple trees in 1835 by French chemists, and later (1886) the German physician von Mering demonstrated that phlorizin might cause glycosuria. Further research on this topic identified the active glucose-transport system located on the luminal membrane of proximal tubular cells (brush border). In 1987, phlorizin demonstrated its efficacy to reduce glycemic level in diabetic rats and to restore insulin sensitivity; however, low oral availability, intestinal side effects and short half-life hampered phlorizin use as a therapeutic agent [3].

Dapagliflozin was the first SGLT-2 inhibitor approved for the treatment of T2D (in Europe in 2012 and in the United States in 2014), followed by empagliflozin, canagliflozin, and ertugliflozin. Nowadays, SGLT-2 inhibitors, also known as the “gliflozins”, include other drugs such as ipragliflozin, luseogliflozin, and tofogliflozin, all launched in Japan in 2014, sotagliflozin, which has been approved in Europe for certain patients with type 1 diabetes with a body mass index of 27 kg/m² or more, who could not achieve adequate glycemic control despite optimal insulin therapy, and lastly remogliflozin launched in India in April 2019 (Fig. 1). Given the unique mechanism of action, SGLT-2 inhibitors have potential for use as an adjunct therapy to enhance glucose lowering when used in combination with other glucose-lowering therapies.

Fig. 1

The class of SGLT-2 inhibitors with its founder phlorizin. Phlorizin-based analogs can be divided into O-glucoside analogs (the sugar group is bonded to another group via a glycoside bond, such the founder phlorizin and remogliflozin) or C-glucoside analogs (such as dapagliflozin and the many others); the latter have greater pharmacokinetic stability and selectivity for SGLT2. Inhibitor affinity is the result of a synergistic relationship between binding sites for sugar and the aglycone, with alterations in the sugar resulting in surprising differences in selectivity. All the nine SGLT-2 inhibitors showed in the figure are available in different parts of the world

On the basis of their ability to improve cardiovascular outcomes in high-risk individuals and slow the progression of diabetic kidney disease (DKD), SGLT-2 inhibitors should be considered reasonable second-line treatment options for individuals at risk of cardiovascular events or those with underlying nephropathy. Specifically, the American Diabetes Association [4] suggests to consider use of a SGLT-2 inhibitor in T2D patients with an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m² and particularly in those with > 300 mg/g albuminuria to reduce risk of diabetic kidney disease progression, cardiovascular events, or both. Adverse effects associated with SGLT-2 inhibitors include urinary frequency and dehydration. Other potential side effects include genitourinary tract infections and euglycemic diabetic ketoacidosis, while canagliflozin has been linked to lower-extremity amputations and bone fractures. In nationwide 2013–2016 registries from Denmark and Sweden, the use of SGLT-2 inhibitors, as compared with GLP-1 receptor agonists, was associated with an increased risk of lower limb amputation and diabetic ketoacidosis [5]. Moreover, the FDA warned about cases of necrotizing fasciitis of the perineum (i.e. Fournier’s gangrene which is a rare but potentially life-threatening affection) in patients treated with SGLT-2 inhibitors [6]. Although these adverse events [7] should not mask the overall cardiorenal benefits of SGLT-2 inhibitors [8], individuals at risk of these complications should be monitored closely and treatment should be reconsidered or discontinued if they occur.