Apleway (tofogliflozin) / Kowa, Takeda - LARVOL DELTA

Impact of Sodium-Glucose Co-Transporter-2 (SGLT2) Inhibitors on Nocturnal Polyuria: A Cross-Sectional Study. (PubMed, Cureus) - "Tofogliflozin is less likely to exacerbate nocturnal polyuria compared to other SGLT2 inhibitors."

Journal • Observational data • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

The sodium-glucose cotransporter 2 inhibitor tofogliflozin induces vasodilation of rabbit femoral artery by activating Kv channels, the SERCA pump, and the sGC/cGMP pathway. (PubMed, Eur J Pharmacol) - "Furthermore, pretreatment with the voltage-dependent K+ (Kv) channel inhibitor 4-AP (3 mM) reduced the vasodilatory effects of tofogliflozin whereas pretreatment with the ATP-sensitive K+ channel inhibitor glibenclamide (10 μM) or the large-conductance Ca2+-activated K+ channel inhibitor paxilline (1 μM) did not...The vasodilatory effects of tofogliflozin were also significantly inhibited in femoral arterial rings pretreated with the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump inhibitors thapsigargin (1 μM) and cyclopiazonic acid (10 μM). Tofogliflozin-induced vasodilation was unaltered in arterial rings exposed to the adenylyl cyclase inhibitor SQ 22536 (50 μM), the protein kinase A (PKA) inhibitor KT 5720 (1 μM), and the protein kinase G inhibitor KT 5823 (1 μM) whereas it was effectively reduced by the soluble guanylyl cyclase (sGC) inhibitor ODQ (10 μM). These findings suggest that tofogliflozin-induced vasodilation is mediated by the activation of the SERCA..."

Journal • Preclinical • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Effect of administration and withdrawal of the sodium-glucose cotransporter 2 inhibitor, tofogliflozin, on renal protection in individuals with type 2 diabetes mellitus and diabetic nephropathy: A multicenter, single-arm study (RESTORE-nephropathy study). (PubMed, J Diabetes Investig) - "Urinary albumin improved during the administration of tofogliflozin and worsened during its withdrawal, suggesting the reversibility of its renoprotective effect. The administration of tofogliflozin should be continued to avoid the reversal of glycemic control, renoprotective effects, and other beneficial effects."

Journal • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Post-hoc analysis of the tofogliflozin post-marketing surveillance study (J-STEP/LT): Tofogliflozin improves liver function in type 2 diabetes patients regardless of BMI. (PubMed, J Diabetes Investig) - "Tofogliflozin reduced ALT levels without substantial body weight reduction among lean participants. These findings suggest that SGLT2 inhibitors may be a viable treatment option for non-obese patients with type 2 diabetes and SLD."

Journal • P4 data • Retrospective data • Diabetes • Hepatology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus

Sodium Glucose Cotransporter-2 Inhibitors Improve Endothelial Function and Arterial Stiffness in Diabetic Individuals: A Systematic Review and Network Meta-Analysis. (PubMed, Curr Vasc Pharmacol) - "SGLT2 inhibitors improve endothelial function and arterial stiffness in the diabetic population. Clinical studies evaluating the association between improvements in endothelial function with SGLT2is and reduced adverse cardiovascular and cardiorenal events and mortality are urgently needed."

Clinical • Journal • Retrospective data • Cardiovascular

Body fluid management as a treatment for obstructive sleep apnea: a new possibility for sodium-glucose cotransporter 2 inhibitors. (PubMed, Hypertens Res) - No abstract available

Journal • Cardiovascular • CNS Disorders • Congestive Heart Failure • Heart Failure • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Disorder

A retrospective study of seasonal variation in sodium-glucose co-transporter 2 inhibitor-related adverse events using the Japanese adverse drug event report database. (PubMed, Sci Rep) - "Six SGLT2 inhibitors prescribed in Japan (ipragliflozin, empagliflozin, luseogliflozin, canagliflozin, dapagliflozin, and tofogliflozin) were included. Healthcare providers should take adequate precautions against dehydration caused by SGLT2 inhibitors, not only in summer but also in winter. These findings are instructive and informational for health care professionals involved in diabetes care."

Adverse events • Journal • Retrospective data • CNS Disorders • Diabetes • Infectious Disease • Metabolic Disorders • Nephrology • Type 2 Diabetes Mellitus

Model-based meta-analysis of HbA1c reduction across SGLT2 inhibitors using dose adjusted by urinary glucose excretion. (PubMed, Sci Rep) - "This study was aimed to evaluate whether the dose-response relationship of the sodium glucose co-transporter-2 inhibitors (SGLT2is) in patients with type 2 diabetes mellitus (T2DM)-canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin, and tofogliflozin-can be explained in a unified manner based on their ability to promote urinary glucose excretion (UGE). Findings from this study would influence drug selection and adjustment in clinical practice. As with SGLT2is, in cases where the efficacy cannot be easily evaluated but an appropriate pharmacodynamic marker was assessed in early clinical trials, similar approaches for other drug classes can guide strategic and evidence-based dose selection in phase III trials."

Clinical • Journal • Retrospective data • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Effect of Baseline Values of Renal Prognosis-related Factors on Their Changes after Initiating Tofogliflozin Treatment: A Retrospective Study in Japanese Patients with Type 2 Diabetes and Renal Impairment. (PubMed, JMA J) - "None of the correlation coefficients between the normal- and low-eGFR groups showed a significant difference. Favorable changes in renal prognosis-related factors after tofogliflozin therapy may contribute to renoprotection in patients with type 2 diabetes and poor corresponding baseline values, despite the presence of renal impairment."

Journal • Retrospective data • Diabetes • Diabetic Nephropathy • Metabolic Disorders • Nephrology • Renal Disease • Type 2 Diabetes Mellitus

Tofogliflozin reduces sleep apnea severity in patients with type 2 diabetes mellitus and heart failure: a prospective study. (PubMed, Hypertens Res) - "A linear relationship was observed between the changes in body water content and AHI (r = 0.642, p = 0.045). Tofogliflozin reduced AHI, possibly associated with a reduction in body water content."

Journal • Cardiovascular • Congestive Heart Failure • Diabetes • Heart Failure • Metabolic Disorders • Obstructive Sleep Apnea • Respiratory Diseases • Sleep Apnea • Sleep Disorder • Type 2 Diabetes Mellitus

Branched-Chain Amino Acids Drive Mesangial Expansion in Diabetic Kidney Disease (KIDNEY WEEK 2024) - "Furthermore, these increases were reduced with SGLT2 inhibitor, Tofogliflozin... Mesangial expansion induced by diabetes improved with the accompanying decrease in serum leucine concentration due to BT2 treatment. BCAA enrichment diet in diabetes deteriorates albuminuria and mesangial expansion. These findings suggest that circulating BCAA levels modify DKD progression."

Chronic Kidney Disease • Diabetes • Diabetic Nephropathy • Genetic Disorders • Metabolic Disorders • Nephrology • Obesity • Renal Disease

TOFOGLIFLOZIN AMELIORATES PORTAL HYPERTENSION ALONG WITH LIVER FIBROSIS PROGRESSION BY INHIBITION OF SINUSOIDAL CAPILLARIZATION IN RATS WITH LIVER CIRRHOSIS (AASLD 2024) - "Our dataset demonstrates that tofogliflozin is useful to reduce portal hypertensin along with amelioration of liver inflammation and fibrosis in the rodent model. It may provide strong support for the efficacy of tofogliflozin against the progression of PH associated with liver cirrhosis."

Preclinical • Cardiovascular • Fibrosis • Gastroenterology • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Portal Hypertension • ACTA2 • CD34 • CD68 • COL1A1 • IL1B • IL6 • TGFBR1 • TNFA

Comparison of kidney and hepatic outcomes among sodium-glucose cotransporter-2 inhibitors: a retrospective study using multiple propensity scores. (PubMed, J Pharm Health Care Sci) - "Renoprotective and hepatoprotective effects are class effects of SGLT2i, and their effects are thought to be independent of kidney or liver status."

Journal • Retrospective data • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Dyslipidemia • Heart Failure • Metabolic Disorders • Nephrology • Renal Disease

Multicenter, open label, randomized controlled superiority trial for availability to reduce nocturnal urination frequency: The TOP-STAR study. (PubMed, J Diabetes Investig) - "The frequency of nocturia after tofogliflozin did not increase. Tofogliflozin reduced nocturia when combined with salt restriction. Furthermore, daytime urine volume and frequency showed an increasing trend, suggesting a shift in urine production to daytime hours due to the short half-life of tofogliflozin. Dietary modifications can enhance the therapeutic benefits of tofogliflozin in managing nocturia in people with type 2 diabetes."

Head-to-Head • Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Transient elevation of minerals and bone resorption during 48-week treatment with an SGLT2 inhibitor tofogliflozin in people with type 2 diabetes (EASD 2024) - P4 | "The present study comprehensively evaluated the effects of tofogliflozin and glimepiride on serum and urinary levels of electrolytes and bone metabolism in an open-label, randomized, parallel trial in patients with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). Tofogliflozin elevated transiently Ca, P, and bone resorption marker TRACP-5b levels and persistently Mg levels without affecting urinary excretion of these minerals in people with type 2 diabetes. However, the tofogliflozin-mediated elevation in Ca and TRACP-5b converges until 48 weeks of treatment. Indeed, no fracture events were identified in the tofogliflozin group, supporting some meta-analyses reporting no bone mineral density (BMD) reduction or increased risk for fracture by SGLT2 inhibitors."

Diabetes • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Type 2 Diabetes Mellitus • TRAP

Tofogliflozin attenuates renal lipid deposition and inflammation via PPARα upregulation mediated by miR-21a impairment in diet-induced steatohepatitic mice. (PubMed, Endocr J) - "Notably, the expression of PPARα, which has been known to be negatively regulated by miR-21, was significantly increased, leading to enhancing β-oxidation genes, Acox1 and Cpt1 in the Tofo group. Tofogliflozin decreased renal cholesterol and NEFA levels and improved inflammation through the regulation of PPARα and miR-21a."

Journal • Preclinical • Chronic Kidney Disease • Dermatitis • Hepatology • Inflammation • Metabolic Disorders • Nephrology • Renal Disease • ACOX1 • MIR204 • MIR21 • PPARA

Update on evidence-based clinical application of sodium-glucose cotransporter inhibitors: Insight to uncommon cardiovascular disease scenarios in diabetes. (PubMed, World J Diabetes) - "According to our review, certain SGLTis (empagliflozin, dapagliflozin, canagliflozin, and tofogliflozin), but not sodium-glucose cotransporter 1 inhibitor (SGLT1i), exhibit relatively superior clinical safety and effectiveness for treating the abovementioned diseases. However, clinical trials involving SGLTis for certain diseases have relatively small sample sizes, brief intervention durations, and conclusions based on weak evidence, necessitating additional data. These findings are significant and valuable for providing a more comprehensive reference and new possibilities for the clinical utilization and scientific exploration of SGLTis."

Journal • Review • Atherosclerosis • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Diabetes • Dyslipidemia • Heart Failure • Metabolic Disorders • Myocardial Infarction • Type 2 Diabetes Mellitus

Study to Evaluate the Efficacy and Safety of K-877-ER and CSG452 in Participants With NASH With Liver Fibrosis (clinicaltrials.gov) - P2 | N=200 | Recruiting | Sponsor: Kowa Research Institute, Inc. | N=300 ➔ 200 | Trial completion date: Jun 2025 ➔ Mar 2026 | Trial primary completion date: May 2025 ➔ Feb 2026

Combination therapy • Enrollment change • Trial completion date • Trial primary completion date • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis

Safety and effectiveness of tofogliflozin in Japanese people with type 2 diabetes: A multicenter prospective observational study in routine clinical practice. (PubMed, J Diabetes Investig) - "Tofogliflozin was associated with only mild or moderate ADRs characteristic of SGLT2 inhibitors, with no unpredictable, new, serious, or high-incidence adverse events or ADRs. This independent study confirmed the safety and effectiveness of tofogliflozin in adult type 2 diabetes patients."

Journal • Observational data • Diabetes • Hypoglycemia • Infectious Disease • Metabolic Disorders • Type 2 Diabetes Mellitus

Effects of 6-month administration of tofogliflozin on cardiac function in elderly patients with heart failure with preserved ejection fraction: A retrospective study of a patient cohort. (PubMed, Medicine (Baltimore)) - "The interaction with time was significant in high/low eGFR. Tofogliflozin was shown to improve E/e', a measure of diastolic function, while maintaining EF, with hypoglycemic effects and no clinical side effects."

Journal • Observational data • Retrospective data • Cardiovascular • Congestive Heart Failure • Diabetes • Heart Failure • Metabolic Disorders • Type 2 Diabetes Mellitus

Changes in serum levels of liver-related parameters, uric acid, and hemoglobin in patients with type 2 diabetes mellitus under treatment with tofogliflozin-a post-hoc analysis of the UTOPIA study. (PubMed, Diabetol Int) - "UMIN000017607 (https://www.umin.ac.jp/icdr/index.html). The online version contains supplementary material available at 10.1007/s13340-024-00693-x."

Journal • Retrospective data • Atherosclerosis • Cardiovascular • Diabetes • Dyslipidemia • Genetic Disorders • Metabolic Disorders • Obesity • Type 2 Diabetes Mellitus

Impact of Salt Reduction on Nocturia in Patients with Type 2 Diabetes—The TOP-STAR Study (ADA 2024) - "Our findings indicate no significant superiority of salt restriction in reducing the frequency of nocturnal urination. However, tofogliflozin therapy was not associated with an increase in nocturia frequency and may contribute to a decrease in nocturnal urine volume. Notably, a subset of patients adhering strictly to salt reduction showed a trend towards reduced nocturia, suggesting potential individual benefits."

Clinical • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Effects of Switching From Another Sodium-Glucose Cotransporter 2 Inhibitor to Tofogliflozin on Nocturia in Patients With Type 2 Diabetes. (PubMed, Cureus) - "The switch from another SGLT2 inhibitor to tofogliflozin may reduce the frequency of nocturnal urination, implying that it may have a positive impact on the quality of life of patients with type 2 diabetes."

Journal • Diabetes • Genito-urinary Cancer • Metabolic Disorders • Oncology • Prostate Cancer • Solid Tumor • Type 2 Diabetes Mellitus

Cardioprotective Effects of Sodium-Glucose Cotransporter Subtype Inhibition on Ischemic and Pharmacological Preconditioning. (PubMed, Cureus) - "The cardioprotective effect of IPC was attenuated by strong SGLT1 inhibition, but the effect was preserved under a clinical dose of highly selective SGLT2 inhibitor. Olprinone exerts a cardioprotective effect even under strong SGLT1 inhibition."

Journal • Cardiovascular • Diabetes • Metabolic Disorders • Reperfusion Injury • Type 2 Diabetes Mellitus

Rationale and Design of Prospective, Multicenter, Double-Arm Clinical Trial to Investigate the Efficacy of Tofogliflozin on Left Ventricular Diastolic Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction and Type 2 Diabetes Mellitus (TOP-HFPEF Trial). (PubMed, Cardiovasc Drugs Ther) - "The TOP-HFPEF trial will clarify the efficacy of an SGLT2 inhibitor, tofogliflozin, on LV diastolic function in patients with HFpEF and type 2 diabetes mellitus."

Journal • Atrial Fibrillation • Cardiovascular • Congestive Heart Failure • Diabetes • Heart Failure • Metabolic Disorders • Type 2 Diabetes Mellitus