Objective <p>This study aimed to evaluate the effects of tofogliflozin, a sodium-glucose cotransporter 2 inhibitor, on health issues in patients with type 2 diabetes (T2DM) and overweight or obesity in real-world clinical practice.</p> Methods <p>This post-hoc sub-analysis of the UTOPIA trial, a randomized prospective study, included 210 patients (102 in the tofogliflozin group and 108 in the conventional treatment group) with a body mass index of ≥ 25.0&#xa0;kg/m². The primary outcome was the percentage of patients achieving a weight loss of ≥ 3% at 26 and 104&#xa0;weeks. Secondary outcomes included improvements in obesity-related health problems.</p> Results <p>At 26&#xa0;weeks, 46.4% of the tofogliflozin group (95% confidence interval [CI] 36.2–56.8%) achieved a weight loss of 3% of more, significantly higher than 14.4% in the conventional treatment group (95% CI 8.3–22.7%, p &lt; 0.001). At 104&#xa0;weeks, 62.0% of the tofogliflozin group (95% CI 51.2–71.9%) achieved this outcome compared with 29.3% in the conventional treatment group (95% CI 20.6–39.3%, p &lt; 0.001). The tofogliflozin group also showed greater improvements in glycated hemoglobin, fasting blood glucose, blood pressure, liver indices, high-density lipoprotein-cholesterol, serum uric acid, and quality of life (QOL). Additionally, arterial stiffness progression was significantly reduced (p &lt; 0.05) and the increase in urinary albumin tended to be attenuated (p = 0.056) in the tofogliflozin group.</p> Conclusions <p>In Japanese patients with T2DM and obesity, tofogliflozin effectively promotes weight loss and has a positive impact on various obesity-related health problems and QOL. These findings suggest its potential as a therapeutic option for improving both metabolic and cardiovascular health in this population.</p> Trial registration <p>UMIN000017607 (<a href="https://www.umin.ac.jp/icdr/index.html">https://www.umin.ac.jp/icdr/index.html</a>).</p>