Apleway (tofogliflozin) / Kowa, Takeda - LARVOL DELTA

The examination of effects of adding on Tofogliflozin or not to add for type 2 diabetes controlled insufficiently by long-acting insulin glargine once daily with DPP-4 inhibitor or GLP-1 analog liraglutide with oral anti-diabetic agents (multicenter study) (clinicaltrials.gov) - P=N/A | N=15 | Completed | Sponsor: Toho University School of Medicine, Division of diabetes, metabolism and endocrinology | Unknown status ➔ Completed

Trial completion • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Distinct metabolomic signatures of SGLT2 inhibitor vs. sulfonylurea in a paired human liver biopsy study. (PubMed, Biochem Biophys Rep) - "In this 48-week randomized, open-label, parallel-group trial, Japanese participants with type 2 diabetes and biopsy-confirmed MASLD received either tofogliflozin or glimepiride. The metabolic signature of SGLT2 inhibitors in the human liver is characterized by starvation-induced glucose production and hypovolemia-induced aestivation-like response. Serum succinate emerged as a potential biomarker associated with MASLD severity and treatment-related improvements under SGLT2 inhibition."

Journal • Diabetes • Hepatology • Inflammation • Metabolic Disorders • Metabolic Dysfunction-Associated Steatotic Liver Disease • Type 2 Diabetes Mellitus

Long-term effects of tofogliflozin on renal function in patients with type 2 diabetes: A retrospective multicenter study. (PubMed, J Diabetes Investig) - "Real-world clinical data over 72 months suggested that tofogliflozin may slow estimated glomerular filtration rate decline."

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

Study Protocol for the TIGHTEN Study Comparing the Effects of Tofogliflozin and Glimepiride on Skeletal Muscle Mass in Patients with Type 2 Diabetes without Obesity: A Prospective, Multicenter, Open-Label, Randomized, Parallel Group Trial in Japan. (PubMed, Diabetes Ther) - "Japan Registry of Clinical Trials (jRCT) (No. jRCTs041240011); registered 10 April 2024, https://jrct.mhlw.go.jp/en-latest-detail/jRCTs041240011 ."

Journal • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Diabetes • Genetic Disorders • Heart Failure • Hypoglycemia • Metabolic Disorders • Nephrology • Obesity • Renal Disease • Sarcopenia • Type 2 Diabetes Mellitus

Association of Sodium-Glucose Cotransporter-2 Inhibitors With Fournier Gangrene: A Disproportionality Analysis Using the Japanese Adverse Drug Event Report Database. (PubMed, Am J Ther) - "All 5 SGLT2 inhibitors were associated with FG, with empagliflozin carrying the highest risk. Male patients exhibited elevated susceptibility. Continuous monitoring throughout treatment is essential. Further clinical trials are warranted to clarify causal relationships."

Adverse events • Journal • Genetic Disorders • Obesity

Effects of SGLT2 inhibitors on body composition and potential sarcopenia-related outcomes in type 2 diabetes mellitus: a network meta-analysis. (PubMed, Front Endocrinol (Lausanne)) - "For LM, empagliflozin (mean difference [MD] -1.22 kg, 95% CI -1.71 to -0.72), ipragliflozin (MD -0.99 kg, 95% CI -1.45 to -0.54), and canagliflozin (MD -0.80 kg, 95% CI -1.39 to -0.21) were associated with modest reductions in LM compared with placebo, whereas dapagliflozin and tofogliflozin showed neutral effects. Findings for LM should be interpreted cautiously, as LM does not directly reflect muscle mass. https://www.crd.york.ac.uk/prospero/, identifier CRD420261379719."

Clinical • Journal • Retrospective data • Review • Cardiovascular • Diabetes • Metabolic Disorders • Obesity • Sarcopenia • Type 2 Diabetes Mellitus

Temporal changes in obstructive sleep apnea severity and body composition parameters during 6-month tofogliflozin administration in patients with heart failure and type 2 diabetes mellitus: a TOPARDS-HF substudy. (PubMed, Sleep Breath) - "Tofogliflozin significantly improved OSA severity at 3 and 6 months; however, more improvements were observed at 3 months. These improvements were accompanied by gradual reductions in body water content, especially from baseline to 6 months. In contrast, body weight and fat mass reduction impacted the OSA severity in the early stages."

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

Tofogliflozin alters amino acid metabolism in gut microbiota linked to hepatic transcriptomic signatures in MASLD. (PubMed, J Gastroenterol) - P4 | "Gut microbial amino acid metabolism, particularly phenylalanine metabolism, is closely linked to liver fibrosis and molecular pathways in MASLD. Modulation of microbial metabolic functions may represent a promising therapeutic strategy beyond changes in microbial composition."

Journal • Diabetes • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease • 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 | Completed | Sponsor: Kowa Research Institute, Inc. | Active, not recruiting ➔ Completed

Trial completion • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis

Correspondence: Effects of short-term tofogliflozin treatment on insulin secretory capacity in type 2 diabetes: Insights and future directions. (PubMed, J Diabetes Investig) - No abstract available

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

When Antidiabetic Therapy Affects the Skin – case report and literature review. (EADV-Sp 2026) - "Initial dermatological management included systemic antihistamines and topical triamcinolone combined with tetracycline spray...The patient was maintained on metformin monotherapy...This drug class includes canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, luseogliflozin, and tofogliflozin [3]...Conclusions In the present case, blistering lesions developed after more than one year of empagliflozin therapy and showed partial remission following drug substitution and complete resolution after discontinuation of SGLT2 inhibitor treatment , suggesting a possible association with a non-autoimmune bullous reaction. This observation highlights the importance of considering SGLT2 inhibitors (flozins) in the in the differential diagnosis of bullous or blistering skin eruptions in patients with type 2 diabetes mellitus."

Case report • Clinical • Review • Bullous Pemphigoid • Cardiovascular • Dermatopathology • Diabetes • Hypotension • Immunology • Infectious Disease • Metabolic Disorders • Nephrology • Pruritus • Psoriasis • Type 2 Diabetes Mellitus

Stereocontrolled spirocyclization of exo-glycals with arylamines for the synthesis of (1S)-spiro-tetrahydroquinoline glycosides. (PubMed, Org Biomol Chem) - "An excellent diastereomeric ratio is observed in reactions involving either exo-glucal or exo-galactal substrates, and only the S-isomers were obtained. This methodology can be applied to alkyl-, F-, Br-, Cl-, NO2- and ester-substituted anilines, as well as sterically congested 1-aminoanthraquinone and 4-benzylaniline, for the synthesis of spiro-4-tetrahydroquinoline glycosides as SGLT2 inhibitor tofogliflozin mimics."

Journal

Do SGLT2 Inhibitors Influence Parkinson’s Disease Risk? A Meta-analysis of Randomized Trials (AAN 2026) - "No eligible data were found for ertugliflozin, enavogliflozin, henagliflozin, ipragliflozin, luseogliflozin, or tofogliflozin...Subgroup analyses showed no significant effect for individual agents: empagliflozin 10 mg (OR 0.64, 95% CI 0.17–2.43), empagliflozin 25 mg (OR 0.33, 95% CI 0.01–8.15), dapagliflozin 10 mg (OR 0.33, 95% CI 0.09–1.23), sotagliflozin (OR 0.25, 95% CI 0.03–2.24), canagliflozin 100 mg (OR 3.00, 95% CI 0.31–28.81), and bexagliflozin (OR 1.50, 95% CI 0.06–36.99)...Conclusions SGLT2 inhibitors do not significantly alter the risk of PD. These findings support their neurological safety, though longer follow-up and dedicated neurodegenerative outcome trials are warranted."

Retrospective data • Cardiovascular • Chronic Kidney Disease • CNS Disorders • Congestive Heart Failure • Diabetes • Heart Failure • Metabolic Disorders • Movement Disorders • Nephrology • Parkinson's Disease • Renal Disease • Type 2 Diabetes Mellitus

Effects of individual sodium-glucose cotransporter-2 inhibitors on all-cause mortality in patients with diabetic kidney disease. (PubMed, Clin Exp Nephrol) - "Comparable effects of SGLT2is on all-cause mortality risk were observed in patients with DKD using the Asian real-world data. This apparent class effect on all-cause mortality suggests that different agents may confer comparable short-term mortality benefits when selected according to patient characteristics."

Journal • Diabetic Nephropathy • Nephrology • Renal Disease

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. | Trial completion date: Mar 2026 ➔ Jun 2026 | Trial primary completion date: Feb 2026 ➔ May 2026

Trial completion date • Trial primary completion date • Fibrosis • Hepatology • Immunology • Liver Cirrhosis • Metabolic Dysfunction-Associated Steatohepatitis

THE EFFECT OF ALTERED BRANCHED-CHAIN AMINO ACID METABOLISM ON DIABETIC KIDNEY DISEASE (ISN-WCN 2026) - "This study investigated the impact of BCAA metabolic regulation on the development and progression of DKD.Methods SGLT2 inhibitor, Tofogliflozin (5mg/kg/day) was given to the db/m and db/db mice for 8 weeks...Because BCAAs are known activators of mTORC1, MES13 was stimulated with BCAAs to evaluate the expression of Col IV and mTORC1-related proteins. BCAA stimulation enhanced phosphorylation of S6 (pS6) and S6 kinase (pS6K) as well as Col IV expression, all of which were abrogated by mTOR inhibition.Conclusion These findings indicate that elevated BCAAs promote glomerular mesangial matrix expansion and albuminuria via activation of the mTORC1 signaling pathway, providing mechanistic insight into the link between altered amino acid metabolism and DKD progression.I have potential conflict of interest to disclose.Commercial Support - Kowa Company, Ltd.I did not use generative AI and AI-assisted technologies in the writing process."

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

Tofogliflozin and glimepiride on liver and serum metabolites in persons with metabolic dysfunction-associated steatotic liver disease and type 2 diabetes mellitus: a post hoc analysis (EASL-SLD 2026) - "Conclusion The metabolic signature of the SGLT2 inhibitor was associated with starvation-induced glucose production and hypovolemia-induced aestivation-like response in the liver. The serum succinate level may be a biomarker reflecting MASLD pathology."

Retrospective data • Metabolic Disorders • Metabolic Dysfunction-Associated Steatohepatitis • Metabolic Dysfunction-Associated Steatotic Liver Disease

Effect of Tofogliflozin on Skeletal Muscle Mitochondrial Function in Male Diabetic Mice With Muscle Atrophy. (PubMed, J Endocr Soc) - "Because Tofo is a highly selective SGLT2 inhibitor with distinct pharmacokinetic properties, these results are specific to Tofo and should not be generalized to all SGLT2 inhibitors. Further studies are warranted to determine whether similar effects are observed with other agents in this class."

Journal • Preclinical • Cardiovascular • Chronic Kidney Disease • Congestive Heart Failure • Heart Failure • Metabolic Disorders • Muscular Atrophy • Nephrology • Obesity • Ocular Inflammation • Renal Disease • Sarcopenia • Type 2 Diabetes Mellitus • AMPK • GDF15 • OPA1

Effects of short-term tofogliflozin treatment on the insulin secretory capacity of people with type 2 diabetes: A randomized controlled trial, the TOP-ELM study. (PubMed, J Diabetes Investig) - "Short-term tofogliflozin therapy did not improve the insulin secretory capacity of treatment-naïve people with type 2 diabetes. However, tofogliflozin may facilitate the early recovery of insulin secretory capacity in individuals with poor glucose tolerance."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus

Tofogliflozin attenuates liver steatosis and fibrosis in non-diabetic non-alcoholic steatohepatitis mice. (PubMed, BMC Gastroenterol) - "Tofo may be a potential candidate for inhibiting liver steatosis and fibrosis via an alternative pathway, unlike glucose metabolism, in NAFLD patients without diabetes."

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

Effect of tofogliflozin on cardiac sympathetic nerve activity in type 2 diabetes mellitus patients with heart failure (TARGET-HF): rationale and design of the single-arm intervention trial. (PubMed, Cardiovasc Diabetol Endocrinol Rep) - No abstract available

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

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