Tofogliflozin: the road goes ever on

Abstract

Several drugs are available for the treatment of type 2 diabetes mellitus (T2DM), but few patients achieve and maintain glycaemic control without weight gain and hypoglycaemias. Sodium glucose co-transporter 2 (SGLT-2) inhibitors are an emerging class of drugs with an original mechanism of action involving inhibition of renal glucose reabsorption. Two agents of this class, dapagliflozin and canagliflozin, have already been approved, although we need more data on cardiovascular outcomes along with bladder and breast cancer. Tofogliflozin is a further SGLT-2 inhibitor, which exhibits the highest selectivity for SGLT-2, the most potent antidiabetic action and a reduced risk of hypoglycaemia. Recently, a 52-week, multicentre, open-label, randomised controlled trial in Japanese T2DM patients has shown that tofogliflozin exhibits adequate safety and efficacy as monotherapy or as add-on treatment in patients suboptimally controlled with oral agents. Despite the very promising characteristics of this new drug, important questions remain to be answered, mainly additional data on safety outcomes and potential beneficial effects of tofogliflozin, for instance in prediabetes and diabetic nephropathy. Moreover, it would be welcome to examine the utility of its therapeutic use in combination with insulin and metformin.

Keywords::

• oral hypoglycaemic agents
• SGLT-2 inhibitors
• tofogliflozin
• treatment
• type 2 diabetes mellitus

Several drugs are available for the treatment of type 2 diabetes mellitus (T2DM), but the percentage of patients who achieve and maintain glycaemic control is still suboptimal [1]. Moreover, some oral antidiabetic agents are often associated with hypoglycaemia and weight gain [1]. Conversely, sodium glucose co-transporter 2 (SGLT-2) inhibitors, a relatively new class of oral hypoglycaemic agents, do not exhibit these two untoward effects [2]. Two agents are now commercially available, dapagliflozin in Europe and canagliflozin in United States and European Union, while several others are still in development [3]. They are characterised by selective and reversible inhibition of the SGLT-2 co-transporter, which is located on the proximal tubule of the kidney and is of paramount importance in glucose reabsorption [2] (Figure 1). As a result, these agents exhibit a novel mechanism of action, which involves removal of excess glucose in the urine [2]. This action is independent of insulin, and so SGLT-2 inhibitors can be used at any stage of T2DM, but, of note, it requires normal renal function [2]. Interestingly, for canagliflozin, no dose adjustment is needed in patients with mild renal impairment (estimated glomerular filtration rate [eGFR] ≥ 60 ml/min/1.73 m²), but the dose is limited in patients with eGFR 45 – 59 ml/min/1.73 m² [4]. Moreover, dapagliflozin is not recommended for use in patients with eGFR < 60 ml/min/1.73 m² [5].

Figure 1. Antidiabetic mechanism of SGLT-2 inhibitors.

Dapagliflozin has demonstrated safety and efficacy in reduction of fasting plasma glucose (FPG) (ranging between +2.4 to -84.3 mg/dl) and body weight (-2 to -4.5 kg) either as single agent or as add-on treatment [2]. Osmotic diuresis, caloric loss due to glycosuria and reduction in fat mass are considered the three main underlying mechanisms explaining weight loss [6]. Importantly, dapagliflozin improves FPG without increasing the risk of hypoglycaemia, as it promotes urinary glucose excretion by a glucose-dependent mechanism [7,8]. At the same time, this drug exerts beneficial metabolic actions: reduction in blood pressure (systolic blood pressure: -2.1 to -7.2 mmHg and diastolic blood pressure: -1 to -6.4 mmHg) [2,8], waist circumference (-1.7 to -2.7 cm), triglycerides (-2.4 to -6.2%) [2,8], serum uric acid (-0.018 to -0.07 mmol/l) [2,9] and highly sensitive C-reactive protein (-1.53 to -2.67 mg/l) and increase in high-density lipoprotein (HDL) cholesterol levels (+0.02 – +0.17 mmol/l) [2], without nephrotoxicity or electrolyte disorders [9]. Furthermore, despite inducing osmotic diuresis, dapagliflozin is not associated with clinically relevant hypotension or orthostatic hypotension [7].

The most common adverse events of dapagliflozin (> 5% of patients) have been consistently shown both in monotherapy and in combination therapy. They involved urinary tract infections, genital infections, upper respiratory tract infections, influenza, cough, nasopharyngitis, hypertension, headache, back pain and diarrhoea [7,10]. However, the overall incidence of untoward effects was comparable between dapagliflozin and placebo [7]. Moreover, dapagliflozin was linked to an increase in haematocrit (+0.77 – +3.05%) [10] and serum parathyroid hormone levels (+0.6 – +0.7 pg/ml) [10]. Finally, results of a meta-analysis pertaining to cardiovascular outcomes along with bladder and breast cancer were inconclusive [11].

Canagliflozin has been studied as monotherapy and in conjunction with other agents, notably metformin, sulfonylurea, pioglitazone and insulin [12]. This drug is associated with a reduction in HbA_1c, body weight, blood pressure and triglycerides, while at the same time it increases HDL cholesterol and low-density lipoprotein (LDL) cholesterol [13]. Its foremost advantage is the low incidence of hypoglycaemias [12]. Similar to dapagliflozin, canagliflozin increases urinary tract infections, more so in females [13]. However, the lack of data on the safety profile for patients with increased cardiovascular risk is a major limitation of hitherto available trials [13].

Among the agents of its class, tofogliflozin harbours the highest selectivity for SGLT-2 and the most potent antidiabetic action without increasing untoward effects [14]. Another particularly promising advantage of tofogliflozin is the temporary interruption of tubular glucose secretion during hypoglycaemia, which improves the drug’s safety profile [14]. Recently, a 52-week, multicentre, open-label, randomised controlled trial in Japanese T2DM patients has looked at the long-term safety and efficacy of tofogliflozin [15]. The study included two study arms: a trial where tofogliflozin was used as monotherapy in patients insufficiently controlled with diet and exercise, and a trial in which tofogliflozin was used in addition to oral agents in patients not attaining adequate glycaemic control on the latter. Patients were randomised to 20 or 40 mg of tofogliflozin once daily [15]. The primary endpoint included untoward effects, laboratory values, vital signs, 12-lead electrocardiogram and self-monitoring of serum glucose. Secondary endpoints were changes in HbA_1c, FPG, body weight, waist circumference, insulin resistance and β-cell function, adiponectin, blood pressure and serum lipids in both trials, as well as 2-h postprandial glucose and insulin sensitivity in the single-agent trial. HbA_1c was significantly reduced (-0.3 to -0.8% in the single-agent trial and -0.7 to -0.9% in the 20 mg tofogliflozin dose as add-on treatment and -0.8 to -0.9% in the 40 mg tofogliflozin dose as add-on treatment) along with body-weight reduction (-1.6 to -3.2 kg in the single-agent trial and -1.6 to -3 kg in the 20 mg tofogliflozin dose as add-on treatment and -2 to -4 kg in the 40 mg tofogliflozin dose as add-on treatment) in both trials and with both tofogliflozin dosages. In the add-on trial, significant improvements were also observed in insulin resistance, β-cell function, waist circumference (-2.36 ± 3.51 cm in the 20 mg group and -2.50 ± 4.29 cm in the 40 mg group) and adiponectin, along with a significant reduction in blood pressure (-3.1 ± 14.2 mmHg in the 20 mg group and -5.2 ± 12.5 mmHg in the 40 mg group for systolic blood pressure and -2.1 ± 10.2 mmHg in the 20 mg group and -2.2 ± 9.2 mmHg in the 40 mg group in the diastolic blood pressure) and increase in HDL cholesterol (4 ± 9 mg/dl in the 20 mg group and 6.5 ± 9.8 mg/dl in the 40 mg group). In the single-agent trial, 2-h postprandial glucose (-59.6 ± 55.8 mg/dl in the 20 mg group and -59.1 ± 49.1 mg/dl in the 40 mg group) was significantly improved, in addition to insulin sensitivity and the aforementioned parameters [15].

In the single-agent trial, both tofogliflozin doses were well tolerated and only 3.1% of patients in each dosing group discontinued treatment due to adverse events. Adverse events with an incidence of 5% included nasopharyngitis, upper respiratory infections, pollakiuria, thirst and mild hypoglycaemias. Furthermore, mean serum uric acid, aminotransferases, γ-glutamyl transpeptidase and serum creatinine were decreased, whereas eGFR increased, with a documented dose-related elevation in blood ketones [15]. In the add-on trial, 5.7% of patients in the 20 mg group and 4.5% in the 40 mg group withdrew because of adverse events. Nasopharyngitis was the most common adverse event, followed by pollakiuria and thirst. Adverse event rates were comparable between the two dosing groups. Hypoglycaemias occurred in 4 and 4.8% of each dosing group, respectively, but moderate hypoglycaemia involved three patients, all of whom received tofogliflozin plus sulfonylurea. Genital and urinary tract infections were comparable between the two study arms and affected < 5% of patients [15].

The strengths of this trial include the relatively large number of patients, longer follow-up, comprehensive assessment by experienced personnel and robust analysis. However, the number of patients cannot exclude less common side effects, such as cardiovascular events and cancer. Moreover, as the vast majority of patients were men, the incidence of urinary tract infections may not reflect the real-world situation [15]. Further limitations include the open-label design, which might lead to bias in the interpretation of the results, and the exclusion of insulin and glucagon-like peptide-1 analogues from the add-on trial [15].

1. Conclusion

Tofogliflozin has recently demonstrated safety and efficacy as monotherapy or add-on treatment [15]. This is very important, granted our expectations of SGLT-2 inhibitors as useful alternative oral hypoglycaemic agents. Although important questions remain to be answered, the results of the new trial add to the importance of SGLT-2 inhibitors as a useful new class of oral hypoglycaemic agents.

2. Expert opinion

Tofogliflozin appears to be a useful new agent with adequate efficacy in improving glycaemic control and reducing body weight along with a favourable safety profile including low hypoglycaemia rates [15]. This outcome notwithstanding, a number of issues await further clarification.

First, given that moderate hypoglycaemias occurred only among patients receiving tofogliflozin plus sulfonylurea, it would be useful to know what to expect from the combination of tofogliflozin with insulin in terms of hypoglycaemic events and a potential reduction in insulin dose. Interestingly, in a very recent study, another SGLT-2 inhibitor, empagliflozin, was used in the treatment of type 1 diabetes mellitus patients and significantly reduced HbA_1c, enabling a reduction in insulin dose [16]. Furthermore, it would be important to know if tofogliflozin can provide an alternative treatment option in the American Diabetes Association/European Association for the Study of Diabetes algorithm [1], which suggests the use of different drug categories as add-on treatment to metformin. Thus, it has already been suggested that dapagliflozin may be used in combination with metformin in T2DM patients [2], and it is reasonable to assume that SGLT-2 inhibitors might be combined with all agents currently used as adjuncts to metformin in the second therapeutic step.

Second, additional data on the incidence of genital infections, urinary tract infections, renal impairment and risk of malignancy along with cardiovascular safety outcomes and effect on LDL cholesterol would be desirable. Moreover, caution is needed in the presence of renal failure, dehydration and urinary tract infections [2,11]. Furthermore, it was shown that blood ketones increased in a dose-related manner among patients receiving tofogliflozin [15]. This effect was ascribed to increased metabolism of fatty acids into ketones in the liver, which, in turn, was due to glucose secretion in the urine [15]. Reassuringly, patients with elevated blood ketones had no clinical symptoms [15]. Nonetheless, in patients whose ability to secrete insulin is severely impaired, we should probably refrain from using SGLT-2 inhibitors without insulin due to the risk of increased blood ketones.

Additionally, it would be interesting to explore the potential delay in the onset of T2DM with tofogliflozin administration in prediabetes. Indeed, this drug may reduce, especially postprandial, glucose excursions, thereby decreasing glycaemic load in high-risk patients. Finally, given the early evidence that empagliflozin mitigated renal hyperfiltration in type 1 diabetes [16], it is reasonable to explore the potential effects of this class of agents on incipient diabetic nephropathy.

Interestingly, the journey to discover insulin-independent antidiabetic agents actually began as early as 1800 with phlorizin, the first SGLT inhibitor encountered in apple trees, but it was only in the 1980s that its mechanism of action was realised [2]. More recently, tofogliflozin represents one step forward [15] on the road towards improved antidiabetic treatment.

Declaration of interest

N Papanas has been an advisory board member of TrigoCare International; has participated in sponsored studies by Novo Nordisk and Novartis; has received honoraria as a speaker for Astra-Zeneca, Eli-Lilly, Novo Nordisk and Pfizer; and attended conferences sponsored by TrigoCare International, Novo Nordisk, Sanofi-Aventis and Pfizer. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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