Letter to the Editor: Hepatic multi-omics insights into Jiangtang tiaozhi formula for glycolipid metabolic disorders

Abstract

Diabetic kidney disease (DKD) remains a major cause of chronic kidney failure despite advances in standard-of-care therapies. Emerging real-world evidence suggests that combination therapy with sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists may provide additive renal and metabolic benefits beyond single-agent approaches. However, DKD is a biologically heterogeneous condition, and treatment responses may vary substantially across disease stages and patient subphenotypes. In this commentary, we discuss the implications of recent clinical findings from a precision-oriented perspective, highlighting the importance of patient stratification, stage-specific evaluation, and mechanism-informed decision-making. We further emphasize the need to move beyond uniform treatment paradigms toward a layered, decision-driven therapeutic framework that integrates clinical phenotypes with emerging biological insights to optimize outcomes in DKD. The study by Miao et al published in the recent issue of the World Journal of Diabetes, aimed to clarify addressing the multifactorial pathophysiology of DKD.

Key Words: Diabetic nephropathy; Combination therapy; Sodium-glucose cotransporter 2 inhibitors; Glucagon-like peptide-1 receptor agonists; Precision medicine; Patient stratification

Core Tip: Diabetic kidney disease (DKD) is a biologically heterogeneous condition, and uniform treatment strategies may not yield equivalent benefits across patients. Recent real-world evidence supports the use of combined sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists as part of a layered therapeutic approach. This commentary highlights the importance of precision patient selection, stage-specific evaluation, and mechanism-informed decision-making to optimize combination therapy. Integrating clinical phenotypes with emerging biological insights may facilitate more individualized and effective management of DKD.

TO THE EDITOR

We read with great interest the in-press article by Miao et al[1], published in the recent issue of the World Journal of Diabetes, which evaluates the real-world renal outcomes of combination therapy with sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with diabetic nephropathy. This study provides timely and clinically relevant evidence supporting a layered therapeutic approach, in which SGLT2 inhibitors and GLP-1 RAs are prescribed on top of optimized background standard-of-care therapies, including renin-angiotensin system blockade, glycemic control, and blood pressure management, thereby addressing the multifactorial pathophysiology of diabetic kidney disease (DKD).

The major strength of this work lies in its real-world design and its focus on combination therapy, reflecting contemporary clinical practice. By demonstrating improved renal parameters in patients receiving combined SGLT2 inhibitor and GLP-1 RA treatment, the authors reinforce the concept that targeting complementary metabolic, hemodynamic, and inflammatory pathways may yield additive or synergistic renoprotective effects. These findings contribute meaningfully to the growing body of evidence supporting combination-based approaches in diabetic nephropathy management.

Nevertheless, several aspects of this study warrant further discussion, particularly with respect to patient selection, treatment individualization, and future research directions.

First, diabetic nephropathy, like other inflammatory conditions, is a highly heterogeneous disease, encompassing diverse metabolic, inflammatory, and hemodynamic phenotypes across different stages of progression[2]. Consequently, not all patients derive equivalent benefit from early combination therapy. Although the current study demonstrates overall renoprotective effects, it does not fully delineate which subgroups benefit most. Precision stratification based on baseline albuminuria burden, insulin resistance, obesity, and systemic inflammatory markers may help identify patients most likely to experience meaningful renal protection. In addition, incorporating baseline epidermal growth factor receptor slope may provide a dynamic measure of renal functional decline, while renal pathological severity-such as the extent of interstitial fibrosis and tubular atrophy-may further inform stage- and risk-adapted decision-making when biopsy data are available. Moreover, emerging circulating and urinary biomarkers, including tumor necrosis factor receptors and kallikrein-1, may capture inflammatory and tubular injury pathways beyond conventional clinical indices, thereby strengthening precision stratification for combination therapy. Importantly, integrating such clinically accessible features with underlying biological mechanisms may facilitate a shift from purely clinically guided management toward mechanism-based stratification.

Second, treatment responsiveness may vary across stages of diabetic nephropathy. Early disease characterized by hyperfiltration and metabolic stress may respond differently to combination therapy than advanced stages dominated by fibrosis and structural damage[2,3]. Longitudinal analyses examining stage-specific effects would help clarify the optimal timing for initiating combination therapy and avoid unnecessary exposure in patients with limited expected benefit.

Third, the single-center and retrospective nature of the study limits its generalizability[4]. Differences in patient demographics, comorbidity profiles, healthcare access, and treatment adherence across regions may influence observed outcomes. Multicenter, prospective studies across diverse populations and healthcare settings are therefore essential to validate these findings and establish robust clinical guidance.

Fourth, while the clinical outcomes are compelling, the mechanistic basis underlying differential treatment responses remains largely unexplored. Conventional clinical indices provide limited insight into the biological drivers of therapeutic efficacy across heterogeneous DKD phenotypes. Advanced molecular approaches, such as single-cell RNA sequencing and spatial transcriptomics, offer powerful tools to dissect cell-type-specific responses within the diabetic kidney, including metabolic and inflammatory programs in podocytes, proximal tubular epithelial cells, and infiltrating immune cells[5]. By resolving intercellular communication networks and regional heterogeneity, these techniques may help clarify how SGLT2 inhibitor and GLP-1 RA combination therapy exerts renoprotective effects at the cellular and molecular levels. Such analyses may ultimately uncover molecular signatures predictive of therapeutic responsiveness and support biologically guided patient selection and treatment optimization. In addition to transcriptomic and spatial profiling, emerging circulating and urinary biomarkers may further refine risk stratification and therapeutic decision-making in diabetic nephropathy. Biomarkers such as tumor necrosis factor receptors and kallikrein-1 have been associated with disease progression and treatment responsiveness, potentially capturing inflammatory and tubular injury pathways not reflected by conventional clinical indices. Moreover, microbial metabolomics has gained increasing attention as a contributor to systemic inflammation and metabolic dysregulation in DKD. Integrating microbiome-derived metabolic signatures with host molecular and clinical data may provide complementary insights into interindividual variability in therapeutic response and further support mechanism-based stratification strategies.

Finally, integrating multi-omics data with detailed clinical phenotyping represents a promising path toward precision medicine in diabetic nephropathy. Rather than applying uniform combination strategies, future frameworks may enable tailored therapeutic regimens that target dominant pathogenic pathways in individual patients, thereby maximizing efficacy while minimizing unnecessary treatment burden.

In summary, the study by Miao et al[1] provides valuable real-world evidence supporting the use of combined SGLT2 inhibitors and GLP-1 RAs as part of a layered therapeutic strategy in diabetic nephropathy. Importantly, the findings reinforce the concept that DKD is a heterogeneous condition and that treatment responses may vary across disease stages and biological subphenotypes. From a clinical perspective, these results underscore the need for precision patient selection, stage-specific evaluation, and the integration of mechanistic insights beyond conventional clinical markers to guide therapeutic optimization. Moreover, framing DKD management as a heterogeneous, decision-driven process may help translate combination therapy into more individualized and effective clinical practice. We commend the authors for their important contribution and believe that this work lays a strong foundation for advancing precision medicine-oriented approaches in the management of DKD.