Practical Approach to Initiating SGLT2 Inhibitors in Type 2 Diabetes

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 [8]. This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.

In randomized phase 2 and 3 clinical trials, the use of SGLT2 inhibitors as monotherapy (only indicated when intolerance to metformin or side effects exist) has been shown to significantly improve glycemic control in patients with T2DM. A systematic review of 45 randomized clinical studies comparing SGLT2 inhibitors to placebo (11,232 patients implicated) and 13 studies comparing SGLT2 inhibitors to active comparators (5175 patients using metformin, sitagliptin, or sulfonylurea) reported a reduction in HbA1c of −0.66% (95% confidence interval (CI) −0.73% to −0.58%) compared with placebo and −0.06% (95% CI −0.18% to 0.05%) with respect to active comparators [7]. Greater HbA1c reductions (0.44%, 0.54%, and 1.01%) have been observed in patients with high baseline HbA1c levels, i.e., HbA1c less than 8.0% (64 mmol/mol), HbA1c = 8.0–9.0% (64–75 mmol/mol), and HbA1c greater than 9.0% (75 mmol/mol), respectively [9]. In addition, SGLT2 inhibitor therapy as monotherapy or in combination with metformin has been described to induce stable weight loss [10, 11]. In a systematic review, in comparison with other agents, SGLT2 inhibitors reduced mean body weight by −1.80 kg (95% CI −3.50 to −0.11 kg) [7]. In this vein, SGLT2 inhibitors have also been associated with a reduced systolic blood pressure of −4.45 mmHg (95% CI −5.73 to −3.18 mmHg) from baseline. A meta-analysis involving 27 randomized clinical trials and 12,960 individuals (follow-up period ranging from 4 to 52 weeks) recently demonstrated that SGLT2 inhibitors achieve a reduction of systolic and diastolic blood pressure of −4.0 and −1.6 mmHg, respectively [12]. Finally, the EMPA-REG OUTCOME trial, which aimed to evaluate long-term effects of empagliflozin on renal and cardiovascular outcomes in T2DM patients (3.1 years of median follow-up period), has demonstrated that, in addition to standard care, empagliflozin reduced the rate of incident or worsening nephropathy (approximately 39% reduction), serum creatinine doubling (44%), initiation of renal replacement therapy (55%), the risk of death from cardiovascular disease (38%), hospitalization for heart failure (35%), and all-cause death (32%) in patients with T2DM and high cardiovascular risk [13, 14]. Separation of event curves started very early in the study and is a matter of debate. The mechanisms involved in cardiovascular and renal benefits of empagliflozin are multifactorial. Hemodynamic effects, specifically reduced blood pressure and extracellular volume, driven by the direct drug class mechanism of action (osmotic diuresis), seems to be the main explanation for such a rapid effect, especially applied to the reduction in cardiovascular mortality and heart failure-related events. Many other factors including changes in weight, cardiac function, and metabolic actions could also be implied. A possible class effect should be confirmed in upcoming cardiovascular outcomes trials using other SGLT2 inhibitors.

The overall incidence of AEs using dapagliflozin, canagliflozin, or empagliflozin varies between 57.3% and 83.0% in different clinical trials, which is similar to other antidiabetic drugs (e.g., with metformin it ranges between 36.6% and 81.0%) [15]. Most frequent AEs are infections of the genitourinary tract (including vulvovaginitis in women or balanitis in men), with a frequency between 3.6% and 9.0%. Patients usually experience only a single episode, mild in intensity, and that responds to standard treatment [4].

SGLT2 inhibitors, when used in monotherapy, are associated with a low risk of hypoglycemia owing to their insulin-independent mechanism of action [7]. Additionally, long-term use of SGLT2 inhibitors has been associated with a rise in plasma glucagon levels and increased hepatic glucose production [16]. Interestingly, SGLT2-induced glucagon secretion is prevented by administering sulfonylureas concomitantly, thus explaining the risk of hypoglycemia with the use of these agents [11, 17‐19]. The frequency of hypoglycemia increases significantly when SGLT2 inhibitors are used with a background therapy that includes sulfonylureas [11, 17‐19] or insulin [20‐23], compared to placebo. Reported frequencies of hypoglycemia using SGLT2 inhibitors vary greatly, from 6.9% [11] to 43.2% [12] with sulfonylureas, and from 29.2% [20] to 60.4% [21] with insulin. AEs are more likely to occur during the first few days or weeks of treatment [24].

Reducing the insulin dose has also been associated with euglycemic diabetic ketoacidosis [25]. The US Food and Drug Administration (FDA) issued a warning in May 2015 about the potential risk of diabetic ketoacidosis in patients receiving SGLT2 inhibitors and, in February 2016, the European Medicines Agency (EMA) established recommendations to reduce the risk of diabetic ketoacidosis reported in these patients [26, 27]. Nevertheless, the warning and recommendations come from case series with few patients, mainly those with type 1 diabetes who are insulin deficient [28]. To date, the cause of the higher frequency of diabetic ketoacidosis in patients with T2DM is unclear and requires further investigation. Recent studies have reported that SGLT2 inhibitors in pancreatic alpha cells trigger glucagon secretion [16]. The resulting hyperglucagonemia might contribute to ketogenesis under conditions of low insulin concentration. The osmotic diuresis induced by SGLT2 inhibitors can lead to dehydration, reduction in intravascular volume, and orthostatic hypotension.

The reported frequency of volume depletion-related events ranges between 1.2% and 1.5% [24, 29]. The risk of postural hypotension and dehydration is higher among patients receiving diuretics (2.2–2.7%) than those who do not (0.9–1.0%) [4, 30]. This risk is particularly increased when combined with thiazides and loop diuretics as a result of their mechanism of action, enhancing the removal of sodium and water. Patients over the age of 75 years have shown an up to 4.4% increased frequency of postural hypotension [20, 21, 31]. Gastrointestinal AEs, such as nausea, vomiting, and diarrhea, are main AEs of incretin drugs (DPP4 inhibitors and GLP-1 receptor agonists, GLP1ra), and metformin [32‐34]. While in most cases these symptoms are intermittent and insidious, in some cases they can lead to dehydration and an added risk of SGLT2 therapy-associated volume depletion.

SGLT2 inhibitors might also affect bone metabolism given the increased number of bone fractures reported in some clinical trials [35]. Indeed, the FDA released a warning for the use of canagliflozin for this regard in 2005 [36, 37]. Nevertheless, a recent meta-analysis of 38 randomized controlled trials (involving 30,384 patients, and a follow-up period between 24 and 160 weeks) has questioned the harmful effect of SGLT2 inhibitors on bone fractures [38]. A pooled analysis of 10 randomized trials has also suggested that the risk of fractures with canagliflozin might be caused by falls, potentially related to volume depletion-related AEs [39].

Furthermore, the FDA and EMA recently warned about a potential increased risk of lower limb amputation, mainly toes, in patients receiving canagliflozin [40, 41]. This warning is based on the interim analysis of the ongoing Canagliflozin Cardiovascular Assessment Study (CANVAS) clinical trial, in which the incidence of lower limb amputation was 7, 5, and 3 cases every 1000 patients with 100, 300 mg canagliflozin, and placebo, respectively. Further studies are required to corroborate the implication of SGLT2 inhibitors in bone fractures and lower limb amputations.