Apleway (tofogliflozin) / Kowa, Takeda - LARVOL DELTA

Effect of Tofogliflozin on Urinary Albumin-to-Creatinine Ratio vs. Metformin in Diabetic Kidney Disease: Rationale and Study Protocol of the TRUTH-DKD Trial. (PubMed, Diabetes Ther) - P2 | "If tofogliflozin demonstrates a superior reduction in albuminuria, SGLT2 inhibitors may be considered an alternative first-line therapy in selected patients with type 2 diabetes and DKD. jRCTs031210339; Clinicaltrials.gov (NCT05469659)."

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

Effect of Oral Hypoglycaemic Agents on Carotid Artery Intima-Media Thickness in Patients With Cardiovascular Disease and/or Diabetes-A Systematic Review. (PubMed, Endocrinol Diabetes Metab) - "The study suggests that prolonged use of Pioglitazone, Repaglinide and Alogliptin may significantly slow CIMT progression, improving cardiovascular risk management in patients with diabetes and/or cardiovascular disease. Further research is needed to understand the benefits and optimise oral hypoglycaemic treatment strategies for these patients."

Journal • Review • Atherosclerosis • Cardiovascular • Diabetes • Hypoglycemia • Inflammation • Metabolic Disorders • Type 1 Diabetes Mellitus

A Meta-Analysis of Type 2 Diabetes Mellitus Treatments for MASLD (ACG 2025) - "Heterogeneity of fibrosis data was low with I2 of 0% and significant fixed and random effects models (p < 0.001). Out of the seven trials only Takahashi et al. (ipragliflozin) and Loomba et al."

Retrospective data • Diabetes • Fibrosis • Genetic Disorders • Hepatology • Immunology • Inflammation • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Obesity • Type 2 Diabetes Mellitus

Tofogliflozin ameliorates cardiotoxin induced skeletal muscle injury and fibrosis in obesity. (PubMed, Sci Rep) - "Tofo activates fibro-adipogenic progenitors (FAPs) in skeletal muscle, leading to upregulated follistatin (Fst) expression and boosting the recovery process after acute injury. Mechanistically, Tofo prevented the obesity-induced decline in AMPK phosphorylation, rescued the impairment of lipid metabolism, and improved skeletal muscle function, which led to increased exercise tolerance, activation of FAPs, facilitation of skeletal muscle repair, and reduction of fibrosis."

Journal • Diabetes • Fibrosis • Genetic Disorders • Immunology • Inflammation • Metabolic Disorders • Obesity • AMPK • Myogenin • PAX7

Effect of tofogliflozin on obesity-related health problems in patients with type 2 diabetes and overweight or obesity-a post-hoc sub-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/s13340-025-00845-7."

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

Effects of Progranulin Deficiency on Inflammation and Fibrosis in the Kidneys and Liver of Diabetic Mice Fed a High-Fat Diet. (PubMed, Endocrinol Metab (Seoul)) - "Three diabetic mouse models were used: high-fat diet and nicotinamide/streptozotocin-induced diabetic wild-type (WT) and PGRN-knockout (KO) mice (WT-diabetes mellitus [DM] and KO-DM, respectively) and WT-DM mice treated with an SGLT2 inhibitor (tofogliflozin; WT-DM/Tofo)...Kidney inflammation and fibrosis were ameliorated in WT-DM/Tofo mice, but these improvements were limited by autophagy insufficiency in KO-DM mice. Additionally, both WT-DM/Tofo and KO-DM mice demonstrated improved liver inflammation and fibrosis; in the former, this was associated with enhanced fatty acid oxidation via PPARα activation, while in the latter, it appeared to result from improved insulin sensitivity and anti-inflammatory effects through PPARγ activation."

Journal • Preclinical • Diabetes • Fibrosis • Immunology • Inflammation • Metabolic Disorders • MAP1A • PPARA • PPARG

Differential Effects of SGLT-2 Inhibitors on Liver Function and Nocturia in Patients with Type 2 Diabetes: A Randomized Controlled Trial. (PubMed, Diabetes Metab Syndr Obes) - "A total of 135 patients with type 2 diabetes and MASLD were randomly assigned to receive tofogliflozin (20 mg/day), dapagliflozin (5 mg/day), or empagliflozin (10 mg/day). Tofogliflozin, likely due to its shorter half-life, has the most favorable nocturia profile and may be preferable for patients at risk. The UMIN Clinical Trial Registry number for this study is UMIN000054278; Clinical Trials Registry date 28/04/2024."

Journal • Diabetes • Fibrosis • Hepatology • Immunology • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Type 2 Diabetes Mellitus • LGALS3BP

Sodium-glucose co-transporter 2 inhibitor-induced increase in adenosine promotes lipolysis and weight reduction by activating reno-adipose autonomic neurocircuitry. (PubMed, Hypertens Res) - "The results indicated that renal autonomic nerves mediated lipolysis in mice fed a high-fat diet following treatment with tofogliflozin, an SGLT2 inhibitor...These findings uncover a novel reno-adipose neurocircuitry linking renal energy depletion to systemic fatty acid oxidation, providing insights into the sustained weight-reducing effects of SGLT2 inhibitors. A scheme illustrating SGLT2 inhibitor-induced activation of reno-adipose autonomic neurocircuitry, which promotes lipolysis and weight reduction."

Journal • Diabetes • Metabolic Disorders • 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=228 | Active, not recruiting | Sponsor: Kowa Research Institute, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis

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