Important knowledge gaps remain

The gap

Evidence profile

Sourced from the future work and limitations of the source papers, classified as general, spanning 4 journals.

Supporting evidence — 4 representative gaps

• Combination cardiometabolic therapy in type 2 diabetes: optimizing SGLT2 inhibitor and GLP‑1 receptor agonist use (2026) · Current Atherosclerosis Reports · doi

  Important knowledge gaps remain. Dedicated RCT data evaluating combination therapy on hard cardiovascular and kidney endpoints are limited, and optimal sequencing strate- gies have not been definitively established; PRECIDENTD is expected to provide the first randomized evidence [36]. In addition, the role of emerging dual incretin therapies in cardiometabolic care requires further investigation, par- ticularly regarding their cardiovascular and kidney benefits and their use alongside SGLT2is. Evidence is also sparse in advanced CKD, distinct HF phenotypes, and adults over 80 years [61–63]. Future research should prioritize pragmatic trials, comparative effectiveness studies, and precision med- icine approaches to identify individuals most likely to ben- efit from specific therapeutic combinations.

  generalfuture work
  Keywords: cardiovascular kidney evidence important knowledge gaps remain dedicated evaluating combination therapy hard endpoints limited optimal
• Glycemic instability in renal decline: a review of HbA1c variability and outcomes in chronic kidney disease (2026) · Diabetology & Metabolic Syndrome · doi

  The landscape of diabetes management in chronic kidney disease is shifting from a singular focus on achieving a target HbA1c to a more holistic appreciation of glycemic stability. Substantial evidence from observational studies and emerging data from CGM research converge on a central theme: long-term visit-to-visit HbA1c variability is a robust, independent correlate of adverse renal outcomes, cardiovascular events, and mortality in patients with diabetes and CKD (Table 1). This variability likely reflects a confluence of factors, including treatment adherence, therapeutic efficacy, underlying metabolic instability, and susceptibility to complications. The clinical implications are clear. Risk stratification in diabetic kidney disease should incorporate an assessment of glycemic variability, in addition to traditional markers like albuminuria and eGFR. Therapeutic strategies should prioritize treatment regimens that minimize wide glucose fluctuations and hypoglycemia, particularly in advanced CKD where the margin for error is narrow. The integration of CGM into the management toolkit offers an unprecedented opportunity to visualize and address glycemic instability in real-time, moving towards truly personalized care. However, important knowledge gaps persist. Much of the evidence is observational, and causality is not fully established. There is a pressing need for randomized controlled trials to determine whether interventions specifically designed to reduce glycemic variability (guided by CGM or sophisticated analytics of serial HbA1c) can improve hard renal and cardiovascular outcomes. The optimal frequency and mode of CGM use in dialysis patients, its cost-effectiveness, and long-term impact on patient- reported outcomes require further investigation. Similarly, the efficacy and safety of automated insulin delivery systems in this complex population are promising but require rigorous evaluation. Future research should also explore the biological mechanisms linking glucose fluctuations to tissue injury, particularly in the context of uremia. Furthermore, the development and validation of integrated risk scores that ARTICLE IN PRESSARTICLE IN PRESS ACCEPTED MANUSCRIPT combine variability in HbA1c, blood pressure, and other parameters could enhance bedside prognostication. Ultimately, advancing the care of patients with diabetes and CKD will depend on embracing the complexity of glycemic control, leveraging technology for better assessment, and individualizing therapy to achieve not just a lower average glucose, but a safer and more stable glycemic journey.

  generalfuture work
  Keywords: glycemic variability diabetes outcomes patients glucose management kidney disease evidence observational long term visit renal
• Editorial: Community series in: cardiovascular risks in cardiovascular-kidney-metabolic syndrome: mechanisms and therapies, volume II (2026) · Frontiers in Endocrinology · doi

  Read together, these twelve contributions support a view of CKM cardiovascular risk as a linear yet self-reinforcing pathway. Composite metabolic–inflammatory markers (TyG index, IRD-PS, CLR) appear to outperform isolated measurements for risk predic- tion (Zhang et al., Zhu et al., Yang et al.). The vascular–renal axis — RAAS activity, arterial stiffness, and NO–sGC–cGMP signaling — deserves recognition as a modifiable intermediate target (Zhu et al., Li et al., Zhang et al.). Inflammation should be treated as an adjustable amplifier across the whole spectrum (Liu et al., Yang et al., Zhu et al.). And both exercise and pharmacotherapy exhibit stage-dependent, pleiotropic effects that favor individualized, phe- notype-driven prescribing (An et al., Sun et al.). The principal limitation is methodological: most evidence remains cross-sec- tional, retrospective, or post hoc, so prospective multicenter studies with standardized staging and longitudinal follow-up are required, together with deeper mechanistic work on aldosterone’s non- genomic signaling and the pathways from inflammation to podocyte and endothelial damage. We hope this second volume encourages continued investigation and, ultimately, evidence-based care that interrupts the chain before it reaches its end.

  generalfuture work
  Keywords: together risk zhang yang signaling ammation evidence read twelve contributions support view cardiovascular linear self
• Glycemic status, adiposity indices and cardiovascular risk in chronic kidney disease: Core findings from a nationwide cohort study (2026) · World Journal of Diabetes · doi

  Lack of dynamic data on body composition, failure to consider gender differences, and it was an observational study that could not draw causal relationships CKD: Chronic kidney disease; IFG: Impaired fasting glucose; DM: Diabetes mellitus; BMI: Body mass index; WC: Waist circumference; CVD: Cardiovascular disease; HR: Hazard ratio. Open in New Tab Full Size Table The large sample size and rigorous study design provide important clinical evidence for personalized cardiovascular risk stratification and intervention strategies in CKD patients, highlighting significant academic value and practical implications. However, as with any landmark study, it raises several critical questions that merit further exploration. By synthesizing recent literature, including landmark trials such as Flow Research on Renal Outcomes with Semaglutide, Dapagliflozin in Patients with CKD, and Empagliflozin in Patients with CKD, alongside emerging data on novel obesity metrics and muscle atrophy, we present a forward-looking perspective designed to advance cardiovascular risk management within this heterogeneous population. THE COMPLEX INTERPLAY BETWEEN GLYCEMIC STATUS AND ADIPOSITY IN CKD The findings of Bae et al[1] underscore the intricate interplay between body composition, glycemic status, and cardiovascular outcomes in CKD. The observation that underweight diabetic patients exhibit the highest risk of CVD is consistent with the well- documented “obesity paradox” in CKD, where a higher BMI is often associated with better survival[2,3]. However, this paradox ⌃ may be attributed to the limitation of BMI in distinguishing between fat mass and lean mass. Within the context of CKD, malnutrition[4], sarcopenia[5], and underweight[6] are prevalent conditions that are independently associated with adverse  outcomes. Muscle loss may promote insulin resistance and systemic inflammation, which in turn exacerbates cardiovascular risk[7,8]. In contrast, the finding that central obesity elevates CVD risk among normoglycemic individuals highlights the critical role of fat distribution. Visceral adiposity is metabolically active and contributes to inflammation, endothelial dysfunction, and insulin resistance[9,10]. Recent research indicates that measures such as the body roundness index (BRI)[11] and visceral adiposity index[12] may more accurately reflect this risk than BMI alone[13]. Large-scale studies have further demonstrated that BRI surpasses BMI in predicting both all-cause and cardiovascular mortality in general and CKD populations[14,15]. Consequently, a key remaining challenge is determining how to incorporate advanced body composition metrics into risk stratification protocols for patients with CKD. UNRESOLVED ISSUES AND FUTURE DIRECTIONS In this opinion review, we seek to build upon the findings of Bae et al[1] by discussing unresolved issues and proposing future directions. Specifically, we address five key areas: (1) The limitations of traditional adiposity indices; (2) The need for CKD stage- specific risk stratification; (3) The role of long-term glycemic control; (4) The translation of risk stratification into targeted interventions; and (5) The ethnic considerations in generalizing findings. We respectfully offer a few additional reflections, hoping to provide a reference for subsequent research and clinical translation in the related fields, as summarized in Table 2. Table 2  Summary of limitations and optimization suggestions.

  generallimitationsevidence 5/5
  Keywords: risk cardiovascular body patients stratification adiposity composition mass index outcomes obesity glycemic disease size large

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