An evaluation of canagliflozin for the treatment of type 2 diabetes: an update

Taichi Minami, Akiko Kameda & Yasuo Terauchi

To cite this article: Taichi Minami, Akiko Kameda & Yasuo Terauchi (2021): An evaluation of canagliflozin for the treatment of type 2 diabetes: an update, Expert Opinion on Pharmacotherapy, DOI: 10.1080/14656566.2021.1939675
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EXPERT OPINION ON PHARMACOTHERAPY https://doi.org/10.1080/14656566.2021.1939675

DRUG EVALUATION
An evaluation of canagliflozin for the treatment of type 2 diabetes: an update
Taichi Minamia,b, Akiko Kamedaa and Yasuo Terauchib
aDepartment of Diabetes and Endocrinology, Saiseikai Yokohamashi Nanbu Hospital, Konan-ku, Yokohama, Japan; bDepartment of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, Kanazawa-ku, Yokohama, Japan

ABSTRACT
Introduction
Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are proven to ameliorate kidney and heart failure in patients with type 2 diabetes (T2D), in addition to improving glycemic controls. Canagliflozin is a SGLT2i and has proved beneficial for kidney and heart diseases in addition to decreasing the incidence of the composite outcomes of cardiovascular diseases and stroke.
Areas covered
This paper reviews the development of canagliflozin and its effects on renal dysfunction, heart failure, and vascular diseases.
Expert opinion
Canagliflozin contributes to the inhibition of renal function, decline progression and, therefore, is effective for T2D patients with chronic kidney dysfunction and albuminuria. The Canagliflozin Cardiovascular Assessment Study (CANVAS) revealed that patients showed increased incidence of amputation via unknown mechanisms, which has not been observed in other studies that used real- world data. Moreover, canagliflozin has been proven effective for anemia-associated outcomes of chronic kidney failure. Meta-analyses have revealed that canagliflozin contributed to lower diastolic blood pressure when compared with other SGLT2is. A subanalysis of CANVAS data proved that canagliflozin reduced the risk of hemorrhagic stroke. Canagliflozin should be used for T2D patients with chronic kidney failure and/or albuminuria and those with vascular diseases, with monitoring for ulcers and/or the pulse on the lower limb.
ARTICLE HISTORY Received 29 December 2020 Accepted 3 June 2021
KEYWORDS
Amputation; canagliflozin; kidney disease; review

1.Introduction
An estimated 463 million people (9.3% of the world popula- tion) have diabetes worldwide. Moreover, 90% of diabetes cases were type 2 diabetes. Approximately 20% of people aged ≥60 years have diabetes [1,2]. Diabetes is a risk factor of chronic kidney disease (CKD) and heart failure (HF). When CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, 24.4% of patients with type 2 diabetes had CKD [3]. The Framingham Heart Study revealed that patients with diabetes had a two- to five-fold increase in the risk of HF as compared with age-matched controls [4]. Another study showed that 10–15% of diabetic patients had HF and 44% of inpatients with HF had diabetes [5].
Sodium-glucose cotransporter (SGLT-2) is expressed within the S1 and S2 segments of the proximal convoluted tubules, whereas SGLT-1 is distributed in proximal tubules’ S3 segment. SGLT-1 and SGLT-2 participate in glucose reabsorption across the apical membrane, followed by glucose transportation toward the plasma via glucose transporter 2 [6].
Sodium-glucose cotransporter-2 inhibitors (SGLT2is) block the glucose reabsorption in the proximal convoluted tubules and decrease blood glucose levels [7]. SGLT2is are reported to decrease the incidence of developing kidney diseases and HF. Canagliflozin, along with empagliflozin and dapagliflozin, is

one of the SGLT2is that have been shown to improve kidney disease and HF [8–13].

2.Overview of the market
Canagliflozin is used for patients with type 2 diabetes in ≥80 countries such as Europe, the United States, Japan, and Australia [14]. Although canagliflozin is not permitted for use in patients with type 1 diabetes (T1D), dapagliflozin is used for these patients in Europe. However, use of canagliflozin for type 1 diabetes is not permitted. As described earlier, many patients with type 2 diabetes have kidney diseases and HF, and SGLT2is such as canagliflozin are important agents for the prevention of the development of kidney diseases and HF [8– 13], and achieving better glycemic control.

3.Discovery and development of canagliflozin
Phloridzin is extracted from the root bark of the apple tree and reported to inhibit the expressions of sodium/glucose cotran- sporters 1 and 2 in the intestines (i.e. SGLT1) and kidneys (i.e. SGLT2) [15]. It is an O-glucoside SGLTi with a short half-life that is slightly absorbed from the intestine. Phloridzin was consid- ered inadequate for the treatment of type 2 diabetes due to

CONTACT Yasuo Terauchi [email protected] Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan
© 2021 Informa UK Limited, trading as Taylor & Francis Group

its gastrointestinal side effects (i.e., osmotic diarrhea due to poor glucose absorption in the gut). C-glucoside SGLTis as alternatives has been studied, whereby canagliflozin was developed [7].

4.Introduction to the compound
The SGLT-2 exists in the S1-2 segment of the proximal tubules and can transport glucose with sodium across the apical membrane [6]. SGLT2i can suppress glucose reabsorption in the renal tubules by blocking SGLT-2 [7]. It can also improve the HbA1c levels of patients with type 2 diabetes mellitus showing poor glycemic control. Canagliflozin as well as all SGLT2is reduce HbA1c more in patients with higher HbA1c levels [16].
In the early stages of diabetic nephropathy, the high amount of glucose in the proximal convoluted tubules is transported along with sodium to the intracellular compart- ments via SGLT2. Then, the sodium concentration in the distal tubular lumen is decreased, and the macula densa increases the glomerular filtration rate (i.e. hyperfiltration) via tubuloglo- merular feedback mechanisms. SGLT2i can inhibit the mechan- isms of and improve hyperfiltration, which leads to deceased intraglomerular pressure [17,18].
In addition, SGLT2i can contribute to lowering the blood pressure, partly because it blocks SGLT-2, leading to increased sodium excretion in the urine [19,20]. Sodium excretion might result in plasma and extracellular volume reduction and blood pressure lowering [21,22], although reports regarding this remain inconsistent [23–26]. Furthermore, SGLT2i can contri- bute to ketogenesis via elevated lipolysis and fatty acid oxida- tion because of a decreased serum insulin-to-glucagon ratio [27,28]. Lower blood pressure and increased ketone bodies were revealed to improve podocyte damage and proteinuria [29,30].
As described earlier, SGLT2i contributes to lower blood pressure in part via natriuresis, which can also reduce extra- cellular fluid volume and decrease the incidence of HF [31]. SGLT2i has been reported to increase ketone bodies, which can be catabolised into adenosine triphosphate by less con- sumption of oxygen than glucose and fatty acids in the myo- cardium. SGLT2i could switch myocardial energy consumption from glucose to ketone bodies. Thereby, infusion of ketone bodies has been reported to improve left ventricular ejection fraction and heart failure [32–35].
The Canagliflozin Cardiovascular Assessment Study (CANVAS) and Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study have revealed that canagliflozin improved HF and kid- ney disease and decreased the incidence of the composite outcomes of cardiovascular diseases and stroke [12,13], whereas the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) and Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events (DECLARE-TIMI58) revealed that empagliflozin and dapagliflo- zin also have the same effects (Table 1 and Figure 1) [10,12,13,36,37]. Canagliflozin was the first SGLT2i to

demonstrate diabetic nephropathy improvement in the CREDENCE trial [13]; subsequently, dapagliflozin demonstrated nephroprotective effects independent of the diabetic status, in the DAPA-CKD trial [38]. The European Association for the Study of Diabetes and American Diabetes Association recom- mend canagliflozin for type 2 diabetic patients with HF or diabetic kidney disease (DKD) in addition to empagliflozin and dapagliflozin. Especially SGLT2i, including canagliflozin, should be used for patients with decreased ejection fraction or DKD, such as those with albumin-to-creatinine ratios (ACR)
>30 mg/gCre [39,40]. An observational study proved that eGFR decreased by approximately 20 mL/min/1.73 m2 in 10 years [41]. Canagliflozin can contribute to slow progression of renal function decline in type 2 diabetes patients with ACR >30 mg/
gCre [42].
The main hypothesis for nephroprotection is that SGLT2i mitigates the tubuloglomerular feedback, which causes affer- ent arteriole vasoconstriction [18]. SGLT2i might also act on efferent arterioles, causing vasodilatation, which reduces glo- merular pressure [43]. Another hypothesis postulates that SGLT2i inhibits the sodium–hydrogen exchanger [44], though many recent data have contradicted this finding [45]. Moreover, SGLT2i activates lipolytic metabolism, which causes both weight loss and increased myocardial utilization of free acids, thereby elevating ATP production [46,47]. Canagliflozin does not exert its benefits exclusively via enhanced diuresis because of the following reasons. Firstly, the diuretic effect of SGLT2i disappears on day 3 after administration [24]. Secondly, SGLT2i benefits do not depend on patient’s congestion status [25]. Thirdly, pulmonary artery pressure reduction is negligible under the effect of SGLT2i; it might even reduce after cessa- tion of SGLT2i [26]; thus, ruling out the diuretic effect.
The CANVAS and EMPA-REG OUTCOME revealed that cana- gliflozin and empagliflozin contributed to improved primary composite cardiovascular outcomes (i.e. death from cardiovas- cular causes, nonfatal myocardial infarction, or nonfatal stroke) in patients with type 2 diabetes who were at high risk of cardiovascular diseases [9,12]. SGLT2is such as canagliflozin and empagliflozin are recommended for patients with athero- sclerotic cardiovascular disease [39,40].
CANVAS and CREDENCE trials reported that canagliflozin has reduced the incidence of heart failure associated hospita- lization by 30%–40% [12,13]. Dapagliflozin and empagliflozin can ameliorate the worsening of heart failure with reduced ejection fraction (HFrEF), independent of the diabetes status [48,49], partly because SGLT2i induces cardiac reverse remo- deling, with left ventricular (LV) volume reduction [50,51], LV hypertrophy regression [50,52] and LV ejection fraction improvement [50]. Some underlying mechanisms can explain the benefits of SGLT2i in heart failure. SGLT2i reportedly con- tributes to improvement in energetics via increased myocar- dial ketone consumption [33,34] and sodium–hydrogen exchanger inhibition [53], although some related data present conflicting results [45]. SGLT2i also causes diuretic effect [53], anti-inflammatory effect and improvement in myocardial fibrosis [54] and diastolic function in vitro and in vivo [55–57].
EMPEROR-PRESERVED and DELIVER trials studied the effect of SGLT2i on patients with heart failure with preserved ejec- tion fraction (HFpEF, 58, 59). The CHIEF-HE study investigated

Table 1. Baseline characteristics of the patients in the heart failure and kidney outcomes trials with SGLT2 inhibitors.
EMPA-REG outcome (n = 7020) [8] CANVAS (n = 10,142) [11] DECLARE-TIMI58 (n = 17,160) [10] CREDENCE (n = 4401) [12]
SGLT2 inhibitor Empagliflozin Canagliflozin Dapagliflozin Canagliflozin
Duration of follow-up, median, y 3.1 2.4 4.2 2.6 Patient characteristics
Men 5016 (71.5) 6509 (64.2) 10,738 (62.6) 2907 (66.1)
Age, mean (SD), y 63.1 (8.6) 63.3 (8.3) 63.9 (6.8) 63.0 (9.2) Diabetes characteristics
HbA1c, mean (SD), % 8.1 (0.8) 8.2 (0.9) 8.3 (1.2) 8.3 (1.3)
Diabetes duration, mean (SD), y 57% more than 10 years 13.5 (7.8) 11.8 (7.8) 15.8 (8.6) Comobidities

Established cardiovascular disease
7020 (100) 6656 (65.6) 6974 (40.6) 2220 (50.4)

History of heart failure 706 (10.1) 1461 (14.4) 1724 (10.0) 652 (14.8) Renal characteristics
Reduced kidney function 1819 (25.9) 2039 (20.1) 1265 (7.4) 2631 (59.8)
Urinary ACR ≥300 mg/gCre 769 (11.0) 760 (7.6) 1169 (6.8) 3874 (88.0)
Values are presented as number (%) unless otherwise specified. Abbreviations: ACR, albumin-to-creatinine ratio; CANVAS, Canagliflozin Cardiovascular Assessment Study; CREDENCE, Evaluation of the Effects of Canagliflozin on Renal and Cardiovascular Outcomes in Participants with Diabetic Nephropathy; DECLARE-TIMI58, Multicenter Trial to Evaluate the Effect of Dapagliflozin on the Incidence of Cardiovascular Events; EMPA-REG OUTCOME, Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; HbA1c, hemoglobin A1c; SGLT2, sodium-glucose cotransporter 2;

whether canagliflozin improves the symptom scores of heart failure via a mobile health platform [60], whereas the Canacardia-HF trial evaluated whether canagliflozin is benefi- cial on the myocardial uptake of dietary fatty acids via posi- tron emission tomography (NCT03298009). However, further studies are still warranted.

5.Chemistry
Phloridzin, extracted from the root bark of the apple tree, is the first SGLT2i that also inhibits SGLT1. It is a glucoside of phloretin, which has an O-glucoside-based structure. Therefore, phloridzin is catabolised by glucosidase in the intes- tine into phloretin [15]. Such characteristics cause the difficul- ties in the use of phloridzin as an oral hypoglycemic agent. Canagliflozin has a C-glucoside-based structure (Box) which cannot be catabolised by glucosidase. Canagliflozin can inhibit glucose absorption in renal proximal tubules via SGLT2.

6.Pharmacokinetics and pharmacodynamics
Canagliflozin is more selective for SGLT-2 by approximately 158-fold than for SGLT-1 [61] but less selective for SGLT-2 than for other SGLT2is. Empagliflozin and dapagliflozin are selective by 300- and 2000-folds, respectively [62]. The bioavailability of 300 mg of canagliflozin is 65%, and 99% of canagliflozin is tightly bound to plasma proteins [63].
The pharmacokinetics of canagliflozin was studied in non- diabetic patients with hepatic and renal impairments in the United States. Most of the patients were Caucasian. The patients with hepatic impairment received 300 mg of canagli- flozin once daily for 6 consecutive days, and those with renal impairment received 200 mg of canagliflozin in the same period. The mean time to peak plasma concentration (Tmax) was approximately 2 hours, the peak plasma canagliflozin concentration (Cmax) was 3000 ng/ml, and the area under the curve (AUC) was 27,000 ng•h/ml. All the values were similar across the different hepatic function groups. In non- diabetic subjects without kidney impairment (eGFR ≥80 mL/
min/1.73), the Tmax was 1.75 hours, Cmax was 1475 ng/ml, and AUC was 14,345 ng•h/ml. Moreover, among the patients with renal impairment (50 mL/min/1.73 ≥ eGFR ≥ 30 mL/min/
1.73), the Tmax was similar, whereas the Cmax and AUC increased by 29% and 63%, respectively. The amount of urin- ary glucose secretion declined as the eGFR decreased; how- ever, the renal threshold for glucose excretion did not change according to kidney function. The urinary glucose secretion increased by 50.7 g/day from baseline in the subjects without kidney impairment and 10.9 g/day in the patients with renal impairment [64].
The pharmacodynamic effects of canagliflozin were studied in patients with type 2 diabetes. The patients received canagli- flozin 30, 100, 200, or 400 mg once daily or 300 mg twice daily or placebo in the United States or 30 mg once daily or placebo in Korea. This study consisted of a single-day treatment fol- lowed by a washout day and then 14 consecutive days of treatment. Canagliflozin increased the urinary glucose secre- tion by approximately 80 to 120 g/day in the patients with doses ≥100 mg via decreased renal threshold for glucose excretion over the dosing period. Canagliflozin doses ≥100 mg decreased fasting and mean plasma glucose levels by 2.6 to 3.6 mmol/L and body weights by 1 to 2.5 kg during the treatment period [65].
Canagliflozin is metabolized into two metabolites, namely, M7 and M5, via glucuronide conjugation by uridine dipho- sphate-glucuronosyltransferases. These metabolites show no activity for SGLT-2. Approximately 60% of the administered canagliflozin is excreted in the feces (canagliflozin, M7 and M5: 41.5%, 3.2% and 7.0%, respectively), whereas 33% is excreted in the urine (<1%, 13.3% and 17.2%, respectively) [66].

7.Phase II studies, phase III studies, and post-marketing surveillance
A 12-week phase 2, randomized, double-blind, placebo- controlled, multicentre, dose-ranging trial was conducted worldwide, including Great Britain, the United States, Poland, and India. Four hundred fifty-one patients with poor glycemic

Figure 1. SGLT2i trials on hospitalization for heart failure and composite renal outcome, using data from CANVAS [11],CREDENCE [12], DECLARE-TIMI58 [9] and EMPA-REG [7,8] trials.

control who were receiving metformin were enrolled in this study and divided into the following groups: those who received placebo and those who received canagliflozin 50, 100, 200, or 300 mg daily, or 300 mg twice daily and sitagliptin 100 mg daily. As baseline characteristics, the mean HbA1c levels in the respective groups ranged from 7.6% to 8.0%. Canagliflozin increased renal glucose excretion from 35.4 to 61.6 mg/mg creatinine and decreased HbA1c levels by 0.70% to 0.95%, with the greatest reductions observed in the 300 mg once- and twice-daily groups. Adverse events related to urin- ary tract infections were reported at an incidence of 5.0% in the canagliflozin group and 3.0% in the control group, show- ing no significant difference [67].
In the phase 3 trial conducted in 19 countries, 1450 patients were randomized into three groups, the single-dose glimepiride and canagliflozin 100 and 300 mg groups. At baseline, the mean age was 56.2 years; HbA1c level, 7.8%; and body mass index, 31.0 kg/m2. The patients consisted of 67% Caucasians, 4% Black and African Americans, and 20% Asians. In the patients who were receiving glimepiride or 100 mg of canagliflozin, the reduction in HbA1c level was non- inferior. The HbA1c level in the canagliflozin 100 mg group decreased by 0.82%, whereas that in the glimepiride group decreased by 0.81% at 52 weeks. The HbA1c level in the canagliflozin 300 mg group decreased 0.93% more than those in the other two groups significantly [68].
A post-marketing surveillance was conducted 1 year after canagliflozin was launched in the market. The incidence of adverse drug reactions was 9.09%. The incidence rates of the events were as follows: dehydration, 0.73%; constipation, 0.73%; thirst, 0.65%; pollakiuria, 0.51%; cystitis, 0.44%; eczema, 0.44%; pruritus, 0.44%; and rash, 0.44%. Serious adverse drug reactions were reported in 1.02% of the cases, including urin- ary tract infection in 0.15%, dehydration in 0.15%, and hypo- glycemia in 0.15%. Canagliflozin administration decreased the HbA1c level by 0.77% in 12 months after treatment. The safety and efficacy profiles of canagliflozin were proved among the type 2 diabetic patients in the post-marketing surveil- lance [69].

8.Safety and tolerability
As described earlier, adverse events such as dehydration, urinary tract infections, and skin disorders were reported [69]. Moreover, amputation was taken into consideration, reported in the
CANVAS [12]. However, increased risk of amputation was not observed in the CREDENCE trial [13]. The difference in the inclu- sion criteria between the two studies might have contributed to the elevated risk of amputation. Patients with a history or high- risk factors of cardiovascular disease were recruited in the CANVAS, whereas those with urinary albumin-to-creatinine ratios ≥300 were recruited in the CREDENCE study. Therefore, the CANVAS had more patients with cardiovascular diseases than the CREDENCE study (65.6% vs 50.4%). No cases of periph- eral artery disease (PAD) was reported in the CREDENCE study, whereas a 20.8% incidence of PAD was reported in the CANVAS. The differences in baseline characteristics might result in the risk of amputation. However, in a real-world meta-analysis based on large US claims databases, no increased risk of amputation was observed in 142,500 new users of canagliflozin as compared with 110,897 new users of other SGLT2is or 460,885 new users of non-SGLT2is [70]. EMPA-REG OUTCOME and DECLARE-TIMI58 revealed that empagliflozin and dapagliflozin did not contribute to the increased risk of amputation, although the patients in the EMPAREG OUTCOME had higher incidence rates of cardiovascu- lar diseases than those in the CANVAS (Table 1) [9,10,12]. The underlying mechanism thereby canagliflozin increased the inci- dence of amputation in the CANVAS is unknown [71]. Further studies are required.
Canagliflozin was reported to contribute to the elevated risk of bone fracture in the CANVAS, but not in the CREDENCE study [12,13]. Empagliflozin and dapagliflozin did not affect the incidence of fracture [9,11]. A study investigated and described the effects of canagliflozin on bone fracture risk on the basis of the CANVAS (n = 4327) and a pooled popula- tion of eight non-CANVAS studies (n = 5867). Canagliflozin administration did not affect the incidence of bone fracture in the non-CANVAS studies. The incidence of bone fracture was observed immediately after canagliflozin administration in the CANVAS. Therefore, the underlying mechanism might not consist of metabolic factors. The patients in the CANVAS were older, with lower eGFR and higher diuretic use, than those in the non-CANVAS study. Wobbling was thought to be a candidate for correlation with fractures as observed in the patients included in the CANVAS, although the increased inci- dence of falls was not observed in the CANVAS unlike in the non-CANVAS studies [72]. Bone fractures should be taken into consideration when initiating treatment with canagliflozin for older patients with kidney diseases.

9.Regulatory affairs
Canagliflozin is not recommended for patients with type 1 diabetes and ketoacidosis. The initiated dose of canagliflozin is 100 mg once daily before the first meal. The dose can be increased to 300 mg once daily in patients who could tolerate canagliflozin 100 mg once daily with an eGFR ≥ 60 mL/min/
1.73 m2. In Europe and the United States, patients with eGFRs of 30 to 60 mL/min/1.73 m2 are not recommended to receive 300 mg of canagliflozin [73].

10.Conclusion: an analysis of the data presented in the review
Canagliflozin has been proved to protect the kidneys especially in patients with ACR >30 mg/gCre [13,42] and to ameliorate HF in the CANVAS [12]. The CREDENCE and other studies revealed that canagliflozin can contribute to the slow renal function decline progression in type 2 diabetes patients with kidney dysfunction and albuminuria [13,42]. Moreover, canagliflozin has been proved to be cost-effective as compared with dipepti- dyl peptidase-4 inhibitors worldwide, partly because it post- pones the hemodialysis introduction and reduces the incidence of hospitalization for HF [74]. However, the patients in the CANVAS showed a higher incidence of amputation, although the underlying mechanism remains obscure. Therefore, monitoring for ulcers and/or the pulse on the lower limb is necessary when initiating treatment with canagliflozin.

11.Expert opinion
Canagliflozin is recommended for patients with kidney diseases and HF. Moreover, SGLT2is containing canagliflozin are benefi- cial for patients with kidney failure from multiple perspectives. First, canagliflozin administration also decreased acute kidney injury and adverse renal events in a meta-analysis [75]. Another study reported that canagliflozin improved hemoglobin and hematocrit levels in the observation period and reduced ane- mia-associated outcomes in type 2 diabetes patients with CKD [76]. This was partly because of the increased erythropoiesis via suppression of hepcidin leading to utilization of iron [77]. Canagliflozin was thought to be effective for patients with kidney dysfunction from various points of view.
Canagliflozin has been shown to be beneficial for prevent- ing nonfatal stroke and cardiovascular diseases [12,13]. Canagliflozin was reported to reduce the risk of hemorrhagic stroke, presumably because it lowers blood pressure. Empagliflozin had no effect on the incidence of stroke [78]. In meta-analyses that investigated the effects of SGLT2i for lowering blood pressure, canagliflozin reduced systolic blood pressure better than dapagliflozin and diastolic blood pressure better than dapagliflozin and empagliflozin [79,80], partly because canagliflozin has moderate SGLT-2 selectivity [62]
and blocks intestinal SGLT-1 in the intestine in addition to inhibiting SGLT-2 activity in the proximal tubule [79,80].
In conclusion, the CANVAS showed that canagliflozin admin- istration decreased the incidence of the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke and the incidence of hospitalization for HF [12].

The CREDENCE study also revealed a decreased incidence rate of the composite of dialysis, transplantation, or sustained eGFR
<15 mL/min/1.73 m2 [13]. Although the patients in the CANVAS showed higher incidence rates of amputation and bone fracture via unknown mechanisms, canagliflozin showed strong evidence of efficacy for improving kidney diseases, prolonging the initiation of dialysis, and lowering blood pres- sure, and cost-effectiveness. Canagliflozin is especially recom- mended for type 2 diabetic patients with kidney failure.

Funding
This manuscript was not funded.

Declaration of interest
The author(s) have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures
One referee declares that they are working on a collaborative project with Taisho Pharma who provided them with luseogliflozin and Tanabe- Mitsubishi who provided canagliflozin. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Drug summary

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•• highlights differences between canagliflozin and other SGLT2is.
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Canagliflozin
•• highlights differences between canagliflozin and other SGLT2is.