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Introduction
Type 2 diabetes mellitus (T2DM) is a chronic metabolic condition characterized by a hyperglycemic state due to impaired insulin secretion and diminished insulin action in peripheral tissues [1]. Diabetes is the leading cause of blindness, non-traumatic limb amputations, and chronic kidney disease. It is strongly associated with an increased risk of life-threatening cardiovascular complications, such as myocardial infarction or stroke. Achieving optimal glycemic control remains a challenge due to several obstacles: the pathophysiology of diabetes, involving multiple deficiencies and/or resistances; low treatment adherence; clinical inertia; and resistance to implementing behavioral and lifestyle changes [2]. Adverse events (AEs), such as hypoglycemia or weight gain, also contribute to the challenge [3]. Traditional therapeutic approaches have been characterized by stimulating insulin secretion and/or improving peripheral insulin resistance. Sodium-glucose co-transporter 2 (SGLT2) inhibitors (dapagliflozin, canagliflozin, and empagliflozin in the USA and Europe, and ipragliflozin, luseogliflozin, and tofogliflozin in Japan) are a novel and attractive therapeutic approach for the treatment of T2DM [4].
Physiological Action of SGLT2 Inhibitors
SGLT2 inhibitors treat T2DM by selectively blocking SGLT2, a high capacity and low affinity glucose transporter expressed mainly in the S1 and S2 segments of the proximal tubule, inhibiting glucose reabsorption, lowering the renal glucose threshold, and inducing urinary glucose elimination (Fig. 1) [5]. SGLT2 activity seems to be upregulated in patients with T2DM, thereby increasing the renal glucose threshold and exacerbating the tendency to hyperglycemia. Inhibiting SGLT2 activity is accompanied by glycosuria and osmotic diuresis. Despite the fact that SGLT2 activity accounts for up to 90% of renal glucose reabsorption, in clinical practice SGLT2 inhibitors only block 30–50% of the filtered glucose load, even at higher doses [6]. An excess of 40–80 g of glucose and 200–600 mL urine per day are reported with the chronic administration of SGLT2 inhibitors [6]. Dosing and glomerular filtration rate cutoffs for SGLT2 inhibitors are shown in Table 1. The therapeutically induced glycosuria and osmotic diuresis lead to reductions in plasma glucose, body weight, and systolic and diastolic blood pressure [7]. These collateral effects are potentially beneficial because they may reduce the development of microvascular and macrovascular complications. On the basis of the efficacy demonstrated in clinical trials, SGLT2 inhibitors are recommended as second- or third-line agents for the management of patients with T2DM...