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BACKGROUND & AIMS: It remains unclear whether sodium-glucose co-transporter-2 (SGLT2) inhibitors are effective for patients with underweight. This study aimed to elucidate the association between SGLT2 inhibitors use and prognosis in underweight patients with diabetes mellitus (DM) and HF.METHODS: This study was a post-hoc analysis of data from the Japanese Registry of Acute Decompensated Heart Failure, a prospective, multicenter, observational, nationwide registry. All hospitalized patients with HF decompensation requiring treatment were assessed for eligibility between April 2019 and April 2021. Patients with DM and body mass index (BMI) < 18.5 kg/m at discharge without a history of dialysis were included in this study. The patients were categorized into two groups based on SGLT2 inhibitor use at discharge. The main analysis relied on inverse probability of treatment weighting (IPTW) to balance the differences between the two groups, and the primary endpoint was 2-year all-cause mortality.RESULTS: Of the 4016 patients registered from 87 hospitals, 178 underweight patients with HF and DM (mean age: 77 years, 57 % men, and mean BMI: 16.9 kg/m) were analyzed. Of them, 59 patients were on SGLT2 inhibitors at discharge while 119 patients were not. Compared with the patients in non-SGLT2 inhibitor group, those in SGLT2 inhibitor group were younger, more often men, and had a lower left ventricular ejection fraction and higher albumin levels. After IPTW, the patient characteristics were well balanced with all the standardized mean difference <0.2. Kaplan-Meier curves showed that the SGLT2 inhibitor group had a significantly lower incidence of mortality than the non-SGLT2 inhibitor group (14.7 % versus 33.3 %), which was mainly driven by the difference in cardiovascular death (6.4 % versus 18.8 %). The association between SGLT2 inhibitor use and lower mortality was maintained even after IPTW with additional regression adjustment (hazard ratio, 0.40; 95 % confidence interval 0.17-0.93; P = 0.033).CONCLUSIONS: SGLT2 inhibitor use is associated with lower mortality in underweight patients with DM and HF.