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

Cardiac sympathetic nervous dysfunction is linked to poor prognosis in heart failure with reduced ejection fraction (HFrEF), and patients with HFrEF complicated by type 2 diabetes mellitus (T2DM) represent a particularly high risk. Sodium-glucose cotransporter-2 (SGLT2) inhibitors reduce heart failure (HF) hospitalizations in patients with T2DM, but the mechanisms underlying these benefits are not fully understood; modulation of cardiac sympathetic activity has been proposed as one contributor. The TARGET-HF trial will investigate whether tofogliflozin improves cardiac sympathetic nerve activity, assessed by I-123 metaiodobenzylguanidine (MIBG) scintigraphy, along with other cardiovascular parameters in patients with HFrEF and T2DM. This single-arm prospective interventional study will enroll 50 patients with HFrEF (left ventricular ejection fraction < 40%), T2DM (hemoglobin A1c level, 6.5–10.0%), and estimated glomerular filtration rate ≥ 30mL/min/1.73 m². Participants will receive oral tofogliflozin (20 mg/day) for 24 weeks. The primary endpoint is the change in the heart-to-mediastinum ratio on delayed I-123 MIBG scintigraphy from baseline to 24 weeks. Secondary endpoints include changes in the early heart-to-mediastinum ratio, washout rate, echocardiographic parameters, and various biomarkers related to HF, inflammation, and metabolism. The TARGET-HF trial is the first interventional study to comprehensively evaluate the effects of tofogliflozin on cardiac sympathetic nerve activity using I-123 MIBG scintigraphy in patients with HFrEF and T2DM. By integrating nuclear imaging, echocardiography, and metabolic and biochemical biomarkers, this study aims to clarify the mechanisms underlying the cardioprotective effects of SGLT2 inhibitors. Improved understanding of these mechanisms may refine patient selection and guide targeted therapeutic strategies in HF management. Japan Registry of Clinical Trials; approval number: jRCTs041210022 (February 6, 2021).