Impact of luseogliflozin on metabolic health, lipid profiles, and cardiovascular outcomes in patients with type <scp>II</scp> diabetes: A systematic review and network meta‐analysis

Type II diabetes mellitus (T2DM) remains a major public health burden worldwide, with retinopathy and nephropathy contributing substantially to non-traumatic blindness and end-stage kidney disease. In the Philippines, around 4.3 million Filipinos had diabetes in 2021, equivalent to 1 out of 14 adults having the disease [1]. Beyond hyperglycemia, patients often present with other comorbidities such as hypertension, obesity, and dyslipidemia, components of metabolic syndrome that increase cardiovascular disease risk [2]. These overlapping conditions underscore the need for glucose-lowering therapies that also provide metabolic benefits. Sodium-glucose co-transporter 2 (SGLT2) inhibitors are a relatively new class of oral hypoglycemic agents that improve glycemic control while conferring additional benefits in weight reduction, blood pressure regulation, and lipid management [3]. Luseogliflozin, first approved in Japan in 2014, is a potent, widely accessible, and relatively more affordable agent within this class [4]. However, evidence regarding its effects on lipid profiles, liver enzymes, and cardiovascular markers has been inconsistent. Most available evidence is single-arm, and no network meta-analysis (NMA) has positioned luseogliflozin relative to other oral agents. Given the rising prevalence of T2DM and heterogeneity in metabolic outcomes across treatments, synthesizing comparative evidence is essential. This systematic review and meta-analysis, therefore, aims to evaluate the effects of luseogliflozin on lipid parameters, anthropometric indices, liver enzymes, and blood pressure relative to or in combination with other glucose-lowering therapies in adults with T2DM. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol was registered in PROSPERO (CRD42024605191). Comprehensive searches were conducted in PubMed, Scopus, and CINAHL from inception to April 2025 (Table S1), supplemented by citation searching. We included studies evaluating luseogliflozin, alone or combined with other glucose-lowering agents, that reported lipid, anthropometric, blood pressure, liver enzyme, or cardiovascular outcomes among adults with T2DM. Eligible designs included randomized controlled trials (RCTs) and observational studies. Exclusions were (1) single-arm trials, (2) non-English studies, and (3) those without approved comparators (e.g., metformin, DPP4 inhibitors, GLP-1 receptor agonists, other SGLT2 inhibitors). Two reviewers independently screened titles and abstracts, followed by full-text assessment to confirm eligibility. Disagreements were resolved through consensus or consultation with a third reviewer. Data were extracted by two independent reviewers using a standardized extraction form (Table S2). The Cochrane Risk of Bias Tool for Randomized Trials (RoB2) was used by two independent reviewers to assess methodological quality. Discrepancies were resolved by discussion. Furthermore, results were summarized graphically using the RobVis (https://mcguinlu.shinyapps.io/robvis/). A frequentist random-effects network meta-analysis (NMA) was conducted to compare luseogliflozin with placebo, metformin, DPP4 inhibitors, GLP-1 receptor agonists, and other SGLT2 inhibitors. Continuous outcomes were summarized using mean differences (MDs) with 95% confidence intervals (CIs). Random-effects modelling was applied to account for heterogeneity. Forest plots and network diagrams were generated, and inconsistency was evaluated using node-splitting analysis. All analyses were performed in MetaInsight (https://crsu.shinyapps.io/MetaInsight/). Nine clinical trials, mostly from East Asia and Russia, evaluated daily doses of 2.5–10 mg luseogliflozin over 12–52 weeks (Figure S1; Table 1) [5-13]. Most studies had low risk of bias, three had some concerns, and one was high risk due to non-randomized design (Figure S2). LFG 2.5 mg: 80 LFG 5 mg: 86 LFG 10 mg: 79 Total: 239 Control: 83 Week 12 Intervention: 204 Control: 202 Week 52 Intervention: 30 Control: 26 Week 8 Intervention: 83 Control: 82 Week 12 Intervention: 66 Control: 66 Week 24 Intervention: 17 Control: 17 Week 24 Metformin: median = 55 (47–62) LFG: median = 60 (53–66) Intervention: 16 Control: 16 Week 24 Intervention: 95 Control: 50 Week 24 Intervention: 150 Control: 71 Week 24 Glycemic outcomes demonstrated consistent, but statistically borderline, improvements. Mean reduction for fasting glucose was −15.23 mg/dL (95% CI –34.11 to 3.66) for 5 mg and − 15.95 mg/dL (95% CI –34.73 to 2.83) for 10 mg; HbA1c reductions were −0.40% (95% CI –1.06 to 0.27) and −0.49% (95% CI –1.15 to 0.18) for 5 mg and 10 mg, respectively (Figure 1A,B). The lack of statistical significance is more plausibly attributable to heterogeneity in study outcomes, differing assessment periods, and the small number of contributing trials that widened the confidence intervals, rather than indicating a true lack of biological activity. Anthropometric effects were more consistent and reached statistical significance. Luseogliflozin produced dose-dependent reduction in weight (Figure 1C; 5 mg: MD –1.06 kg, 95% CI –1.81 to −0.31; 10 mg: MD –1.56 kg, 95% CI –2.32 to −0.80) and BMI (Figure 1D; 5 mg: MD –1.01 kg/m2, 95% CI –1.94 to −0.08; 10 mg: MD –1.51 kg/m2, 95% CI –2.41 to −0.61). These magnitudes are comparable to class effects seen with other SGLT2 inhibitors and are biologically plausible through mechanisms such as increased lipid oxidation and alterations in appetite-regulating peptides (e.g., des-acyl ghrelin), which may accelerate adipocyte lipid degradation [14]. Cardiovascular risk surrogates showed minimal change. Luseogliflozin blood pressure reductions were small and not statistically significant (Figure 1E,F). Lipid outcomes were heterogeneous and overall non-significant: LDL-C change was −1.40 mg/dL (Figure 1G; 95% CI −12.84 to 10.04), HDL-C + 0.80 mg/dL (Figure 1H; 95% CI −3.66 to 5.26), triglycerides +6.30 mg/dL (Figure 1I; 95% CI −19.08 to 31.68), and total cholesterol +6.30 mg/dL (Figure 1J; 95% CI −19.08 to 31.68). These variable lipid results mirror prior single-arm reports and suggest that luseogliflozin does not exert consistent lipid-modifying effects. Liver biochemistry suggests a trend toward improved hepatocellular integrity based on ALT (Figure 1K; MD –0.90 U/L, 95% CI –4.15 to 2.35) and AST (Figure 1L; MD –0.90 U/L, 95% CI –3.21 to 1.41) but did not reach statistical significance. Mechanistic studies propose that SGLT2 inhibition may reduce hepatic inflammation via modulation of IL-33 and TGF-β signalling and promote β-oxidation in hepatocytes, pathways that could plausibly underlie modest enzyme improvements and preliminary signals in NAFLD populations. Network geometry analysis revealed sparse connectivity in several treatment networks, with many comparisons lacking direct links to placebo (Figures S3–S5). This structural sparsity may limit the transitivity assumption since some indirect contrasts rely on a single shared comparator. Nevertheless, node-splitting tests found no significant inconsistency between direct and indirect evidence for comparisons where both were available (all p > 0.05) (Tables S3–S15). However, most contrasts lacked head-to-head trials, restricting formal local inconsistency assessment and tempering confidence in network-derived inferences. Key limitations temper interpretation. The evidence base is regionally concentrated (mostly Japan/East Asia), limiting generalizability to diverse genetic and lifestyle contexts. Heterogeneity in outcome definitions, assay methods, comparators, and follow-up durations (12–52 weeks) introduced imprecision and indirectness. Excluding single-arm studies reduced bias but also constrained the quantity of evidence. Finally, the short durations of most trials preclude conclusions about long-term cardiovascular or hepatic endpoints. Collectively, luseogliflozin demonstrates modest, statistically significant reductions in weight and BMI and trends toward improved glycemia and hepatic integrity but exhibits inconsistent effects on lipids and blood pressure. Given its lower cost relative to other SGLT2 inhibitors, luseogliflozin is a promising candidate for broader use, yet definitive conclusions about its metabolic and cardiorenal benefits require larger, multiethnic, longer-duration randomized trials with standardized outcome reporting and direct comparisons to established SGLT2 agents. None. None. The authors declare no conflicts of interest. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.70482. These data were derived from the following resources available in the public domain: PubMed (https://pubmed.ncbi.nlm.nih.gov/), Scopus (scopus.com), and CINAHL. Data S1. Data S2. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.