A novel and selective sodium‐glucose cotransporter‐2 inhibitor, tofogliflozin, improves glycaemic control and lowers body weight in patients with type 2 diabetes mellitus

Ikeda, Sachiya; Takano, Yasuki; Cynshi, Osamu; Tanaka, Reiko; Christ, Andreas D.; Boerlin, Viktor; Beyer, Ulrich; Beck, A.; Ciorciaro, Cornelia; Meyer, Markus; Kadowaki, Takashi

doi:10.1111/dom.12538

Cited by 62 publications

(66 citation statements)

References 26 publications

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“…Concomitantly, both fasting and postmeal plasma b-hydroxybutyrate concentrations were increased twofold to threefold; these changes were similar in time course, though attenuated in extent, in a group of nondiabetic volunteers receiving the drug. Similar results have been reported in Japanese patients with T2D with the use of empagliflozin, tofogliflozin, luseogliflozin, or canagliflozin (28)(29)(30)(31)(32). For example, in a 24-week phase III study of drug-naive patients with T2D (32), plasma ketones rose dose dependently with the administration of 100 or 200 mg canagliflozin versus placebo throughout the study period.…”

Section: Rationalesupporting

confidence: 69%

“…For example, in a 24-week phase III study of drug-naive patients with T2D (32), plasma ketones rose dose dependently with the administration of 100 or 200 mg canagliflozin versus placebo throughout the study period. Of note, though mean plasma ketone levels are only modestly elevated, in a sizeable proportion of subjects they rise into the millimolar range (27)(28)(29)(30)(31)(32), particularly in the more insulinopenic patients (27).…”

Section: Rationalementioning

confidence: 99%

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CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis

2016

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The striking and unexpected relative risk reductions in cardiovascular (CV) mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) observed in the EMPA-REG OUTCOME trial using an inhibitor of sodium-glucose cotransporter 2 (SGLT2) in patients with type 2 diabetes and high CV risk have raised the possibility that mechanisms other than those observed in the trialdmodest improvement in glycemic control, small decrease in body weight, and persistent reductions in blood pressure and uric acid leveldmay be at play. We hypothesize that under conditions of mild, persistent hyperketonemia, such as those that prevail during treatment with SGLT2 inhibitors, b-hydroxybutyrate is freely taken up by the heart (among other organs) and oxidized in preference to fatty acids. This fuel selection improves the transduction of oxygen consumption into work efficiency at the mitochondrial level. In addition, the hemoconcentration that typically follows SGLT2 inhibition enhances oxygen release to the tissues, thereby establishing a powerful synergy with the metabolic substrate shift. These mechanisms would cooperate with other SGLT2 inhibition-induced changes (chiefly, enhanced diuresis and reduced blood pressure) to achieve the degree of cardioprotection revealed in the EMPA-REG OUTCOME trial. This hypothesis opens up new lines of investigation into the pathogenesis and treatment of diabetic and nondiabetic heart disease.First among cardiovascular (CV) end point trials of glucose-lowering agents (1), the EMPA-REG OUTCOME trialdusing 10 or 25 mg/day sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin against placebo in 7,020 patients with type 2 diabetes (T2D) who were at increased CV riskdreported a 14% reduction in major CV events and marked relative risk reductions in CV mortality (38%), hospitalization for heart failure (35%), and death from any cause (32%) over a median time period of 2.6 years (2). Of note, all the pathologic categories of CV death (ischemic, pump failure, arrhythmic, embolic) contributed to the overall reduction in CV death in a patient cohort well treated with the use of renin-angiotensin-aldosterone inhibitors, statins, and acetylsalicylic acid. Furthermore, separation of the cumulative incidence functions between pooled-dose groups and placebo was already evident months after randomization. This unusual time course and the discrepancy between the relative risk reduction of the primary end point (nonfatal myocardial infarction, stroke, and CV mortality) and CV mortality itself suggests that active treatment affected case fatality rates more than event rates. In other words, empagliflozin treatment appeared mostly to rescue patients from impending cardiac decompensation. This interpretation is supported by the recent post hoc analyses of heart failure, documenting a large benefit in first and recurrent heart failure hospitalization across virtually every patient subgroup (3). Despite the fact that the diagnosis of heart failure was based on investigator reporting, th...

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Section: Rationalesupporting

confidence: 69%

Section: Rationalementioning

confidence: 99%

CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis

2016

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“…Overall, 56 randomized clinical trials were eligible for inclusion in the review. In Asian populations, 17 trials were included, among which two trials with dapagliflozin treatment compared with a placebo, three trials with canagliflozin treatment compared with a placebo, three trials with ipragliflozin treatment compared with a placebo, two trials with tofogliflozin treatment compared with a placebo, two trials with empagliflozin treatment compared with a placebo and five trials with luseogliflozin treatment compared with a placebo (shown in Table ). In non‐Asian populations, 39 trials were included, among which 18 trials with dapagliflozin treatment compared with a placebo, seven trials with canagliflozin treatment compared with a placebo, 10 trials with empagliflozin treatment compared with a placebo, two trials with ipragliflozin treatment compared with a placebo and one trial with ertugliflozin treatment compared with a placebo (shown in Table ).…”

Section: Resultsmentioning

confidence: 99%

No disparity of the efficacy and all‐cause mortality between Asian and non‐Asian type 2 diabetes patients with sodium–glucose cotransporter 2 inhibitors treatment: A meta‐analysis

Cai

Gao

Yang

et al. 2017

J of Diabetes Invest

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Aims/IntroductionTo evaluate whether there is disparity of the efficacy and all‐cause mortality and other adverse effects between Asian and non‐Asian patients with sodium–glucose cotransporter 2 (SGLT2) inhibitors treatment.Materials and MethodsRandomized clinical trials publicly available before January 2017, comparing SGLT2 inhibitors treatment with a placebo in type 2 diabetes patients were identified. The association between treatment and outcomes was estimated by computing the weighted mean difference for glycated hemoglobin level, blood pressure level, lipid profile levels and bodyweight, and the odds ratios for adverse events.ResultsA total of 17 trials with Asian patients were included and 39 trials with non‐Asian patients were included. Comparison of the glycated hemoglobin decreases corrected by a placebo between Asian and non‐Asian patients showed that there was a non‐significant difference of 0.05% between groups (P > 0.05). Comparisons of the bodyweight changes and blood pressure changes corrected by a placebo between Asian and non‐Asian patients did not show a significant difference between groups (P > 0.05). The risk of all‐cause mortality was not increased when compared with a placebo both in Asian and non‐Asian populations, and the risk of genital infection in Asian and non‐Asian populations were both significant increased.ConclusionsOverall, according to the present meta‐analysis, comparison of the efficacy in SGLT2 inhibitors treatment between Asian and non‐Asian type 2 diabetes patients showed no significant difference in glycated hemoglobin reduction and bodyweight reduction. Furthermore, no disparity was found in the risk of all‐cause mortality or hypoglycemia in SGLT2 inhibitors treatment between Asian and non‐Asian patients.

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“…Tofogliflozin hydrate (Apleway ® ; Sanofi K.K., Tokyo, Japan; and Deberza ® ; Kowa Company, Ltd., Nagoya, Japan) is an SGLT2 inhibitor that was approved in Japan in 2014 for the treatment of type 2 diabetes mellitus. The safety and effectiveness of tofogliflozin have been shown in previous clinical trials and studies.…”

Section: Introductionmentioning

confidence: 99%

Safety and effectiveness of tofogliflozin in elderly Japanese patients with type 2 diabetes mellitus: A subanalysis of a post‐marketing study (J‐STEP/EL Study)

Kaku

Naito

Senda

et al. 2019

J of Diabetes Invest

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Aims/Introduction This subanalysis aimed to assess the safety and effectiveness of tofogliflozin by using data from the Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients in an Observational Study of the Elderly to categorize elderly Japanese patients with type 2 diabetes mellitus by the number of concomitant oral antidiabetic drugs (OADs) and insulin use at baseline. Materials and Methods Japanese Study of Tofogliflozin with Type 2 Diabetes Mellitus Patients in an Observational Study of the Elderly is a 1‐year prospective, observational and multicenter post‐marketing study that enrolled all patients with type 2 diabetes mellitus aged ≥65 years who started tofogliflozin during the first 3 months after its launch in May 2014 in Japan. Results The safety and effectiveness analysis sets included 1,497 and 1,422 patients, respectively. Overall, 18.10 and 2.20% of the patients experienced adverse drug reactions (ADRs) and serious ADRs, respectively. ADRs of special interest in the total, 0 OAD, one OAD, two OADs, three or more OADs and insulin groups occurred in 12.22, 10.04, 12.35, 13.32, 11.27 and 14.91% of patients, respectively. Volume depletion‐related events were the most frequently observed ADRs of special interest. Hypoglycemia occurred in 1.07% of patients. Overall, glycated hemoglobin and bodyweight were significantly decreased, but the estimated glomerular filtration rate was not significantly changed. Conclusions Our finding suggests that tofogliflozin could be safely and effectively used in elderly Japanese patients with type 2 diabetes mellitus, irrespective of the number of OADs and the use of insulin.

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A novel and selective sodium‐glucose cotransporter‐2 inhibitor, tofogliflozin, improves glycaemic control and lowers body weight in patients with type 2 diabetes mellitus

Abstract: A once-daily dose of tofogliflozin for 12 weeks was an effective, safe and well-tolerated treatment for T2DM.

Cited by 62 publications

References 26 publications

CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis

CV Protection in the EMPA-REG OUTCOME Trial: A “Thrifty Substrate” Hypothesis

No disparity of the efficacy and all‐cause mortality between Asian and non‐Asian type 2 diabetes patients with sodium–glucose cotransporter 2 inhibitors treatment: A meta‐analysis

Safety and effectiveness of tofogliflozin in elderly Japanese patients with type 2 diabetes mellitus: A subanalysis of a post‐marketing study (J‐STEP/EL Study)

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