Glycemic status, adiposity indices and cardiovascular risk in chronic kidney disease: Core findings from a nationwide cohort study

Abstract

The studies highlights that diabetic patients who are underweight and have small waist circumference face the highest risk of cardiovascular disease. Among patients with normal glucose levels, being underweight and having central obesity increases risk, while low weight is a consistent risk factor for those with impaired fasting glucose. These findings offer valuable insights for personalized risk stratification in chronic kidney disease (CKD) patients. We cautiously suggest five recommendations: (1) Considering enhanced body composition assessments, such as measurement of body fat percentage and muscle mass via dual-energy X-ray absorptiometry; (2) Refining risk models according to CKD stages; (3) The integration of long-term glycemic control metrics, such as hemoglobin A1c; (4) Conducting intervention studies to develop targeted treatment strategies; and (5) Validating the findings across diverse ethnic populations. Furthermore, we synthesize recent evidence concerning sarcopenia, emerging adiposity indices, and the cardiovascular risk-modulating effects of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists in CKD. By addressing these existing knowledge gaps, this approach seeks to enhance the translation of epidemiological findings into clinical practice, thereby improving cardiovascular risk management within the expanding CKD patient population.

Key Words: Glycemic status; Waist circumference; Body mass index; Chronic kidney disease; Cardiovascular disease

Core Tip: This study found that diabetes patients with underweight and low waist circumference had the highest risk of cardiovascular disease. Normal blood sugar levels, low body weight and central obesity increase the risk, while low body weight is a persistent risk factor for individuals with impaired fasting blood sugar. These findings provide insights into personalized risk stratification for chronic kidney disease. We suggest using dual-energy X-ray absorptiometry to assess body composition, improving the risk model based on chronic kidney disease staging, adding long-term glycemic control metrics, conducting intervention studies and verifying the research results in different ethnic populations.

INTRODUCTION

This study[1], based on the Korean National Health Insurance Database, included 1714859 patients with chronic kidney disease (CKD), as summarized in Table 1. Through a large-scale cohort analysis, it systematically revealed the combined impact of glycemic status (normal glucose, impaired fasting glucose, and diabetes) and obesity indicators [body mass index (BMI), and waist circumference (WC)] on cardiovascular disease (CVD) and all-cause mortality, clarifying the risk differences of obesity indicators across different glycemic statuses. Among diabetic patients, those with low body weight (BMI < 18.5 kg/m²) and low WC (men < 80 cm/women < 75 cm) had the highest CVD risk [hazard ratio (HR) = 2.12/1.72]. In individuals with normal glucose levels, both low body weight (HR = 1.12) and central obesity (WC ≥ 100 cm for men and WC ≥ 95 cm for women, HR = 1.16) increased risk. For those with impaired fasting glucose, low body weight was a stable risk factor (HR = 1.25), and WC showed a linear correlation with CVD risk.

Table 1 Summary of limitations and optimization suggestions.

Core dimensions	Key points
Study subjects	Korean National Health Insurance Database, 1714859 patients with CKD
Study purpose	To analyze the combined effects of glycemic status (Normal, IFG, DM) and adiposity indices (BMI, WC) on CVD and all-cause mortality in patients with CKD
Core findings	Normal: Low body weight (HR = 1.12) and central obesity (men with WC ≥ 100 cm/women with ≥ 95 cm, HR = 1.16) both increase the risk. IFG: Low body weight is a stable risk factor (HR = 1.25). WC is linearly correlated with the risk of CVD, but not with mortality. DM: Those with low body weight (BMI < 18.5 kg/m2) and low WC (men < 80 cm/women < 75 cm) have the highest risk of CVD (HR = 2.12/1.72)
Core conclusions	It is necessary to combine glycemic status and obesity phenotype to conduct individualized cardiovascular risk stratification and intervention for patients with CKD
Study limitations	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.

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.

Limitations	Core issues	Optimization suggestions
Obesity assessment index is too single	Unable to distinguish between body fat rate and muscle mass, ignoring the impact of muscle loss in patients with CKD	DXA or BIA could be used to evaluate body composition, including body fat rate and muscle mass index. Indicators such as BRI and VAI can enhance the accuracy of CVD assessment
Not stratified by eGFR	There are differences in metabolic status in different stages of CKD, and their risk models may also vary accordingly	When analyzing the risk association between blood glucose and obesity, CKD should be classified by stages according to eGFR
Lack of long-term glycemic control assessment	The regulatory effect of long-term blood glucose control on obesity-related CVD risk is not clear	TIR derived from CGM and HbA1c index (for long-term monitoring) could be included to analyze the correlation between the quality of blood glucose control and risk
Not studied targeted intervention	Clinical intervention programs corresponding to different risk stratification have not been studied	Intervention research should be carried out to verify the effectiveness of personalized nutrition, exercise, and drug intervention
Inadequate ethnic representation	The study was based on the data of the Korean population only, so universality was limited	A multi-ethnic, multi-center cohort study should be conducted to verify the cross-ethnic applicability of the risk model

CKD: Chronic kidney disease; DXA: Dual-energy X-ray absorptiometry; BIA: Bioelectrical impedance analysis; BRI: Body roundness index; VAI: Visceral adiposity index; CVD: Cardiovascular disease; TIR: Time-in-range; CGM: Continuous glucose monitoring; HbA1c: Hemoglobin A1c.

First, the assessment of body composition needs improvement. BMI and WC, while practical in large-scale epidemiologic studies, cannot distinguish between fat mass, lean mass, and fat distribution. In CKD patients, muscle wasting is prevalent and strongly linked to cardiovascular and all-cause mortality[4,16]. Sarcopenia (defined as low muscle mass, weakened strength or decline in bodily functions) significantly impacts the quality of life of patients with CKD and is associated with an increased risk of cardiovascular events[17,18]. Moreover, the combination of sarcopenia and obesity (sarcopenic obesity) may confer an exceptionally high risk, a finding recently confirmed by a cohort analysis of data from the China Health and Retirement Longitudinal Study[19]. Dual-energy X-ray absorptiometry, bioelectrical impedance analysis, and computed tomography can provide detailed body composition data[20,21]. Incorporating these measures into future studies may clarify whether the observed “protective” effect of low BMI in some CKD subgroups is attributable to preserved muscle mass or low adiposity[22]. Additionally, novel indices such as BRI[11], visceral adiposity index[23], and the conicity index[24] have demonstrated superior predictive value for cardiovascular and mortality outcomes in various populations. A recent nationwide retrospective analysis by Zhou and Liu[25] demonstrated that a higher BRI significantly increased the risk of type 2 diabetes, with a threshold identified at a BRI value reached 3.96; this suggests that BRI may serve as a valuable biomarker for assessing the risk of type 2 diabetes. Therefore, a prospective study is needed to verify the effectiveness of these indicators in CKD patients.

Second, the risk patterns for different stages of CKD need to be further refined. Bae et al[1] defined CKD as an epidermal growth factor receptor (EGFR) < 60 mL/minute/1.73 m² but did not further stratify by eGFR levels (such as stages 3a, 3b, and 4). Patients with CKD at different stages exhibit metabolic disorders of varying severity, and variable nutritional status, and risk of complications[26,27]. Patients with early CKD (stage 2) may have different risk patterns compared to those with advanced CKD (stage 4 or 5), where uremic milieu, inflammation, and malnutrition are more pronounced[28,29]. The Kidney Disease Improving Global Outcomes has clearly recommended stratifying CKD prognosis based on the urine albumin-to-creatinine ratio and eGFR[30]. The association between low body weight and the risk of end-stage renal disease has also been confirmed in large-scale studies[31,32]. Recent data from the Chronic Renal Insufficiency Cohort further suggest that the obesity paradox is most pronounced in advanced CKD stages[33]. It is recommended that future research analyze whether these risk patterns are consistent across different CKD stages to optimize risk assessment strategies for patients at various stages.

Third, the regulatory role of blood glucose control levels remains unclear. This study stratified participants exclusively by baseline blood glucose status, without considering the quality or duration of glycemic control. Hemoglobin A1c (HbA1c) levels, which reflect chronic glucose exposure, are critical modifiers of cardiovascular risk in diabetes[34,35]. Poor glycemic control may exacerbate obesity-related inflammation and endothelial dysfunction, while good control could mitigate these effects[36,37]. Among patients with CKD, the relationship between HbA1c and outcomes is complex due to factors such as anemia, erythropoietin use, and altered red blood cell lifespan[38,39]. Research indicates that in patients with severe CKD, maintaining HbA1c levels between 6.7% and 7.1% can reduce long-term adverse vascular events[40]. Moreover, time-in-range derived from continuous glucose monitoring has emerged as a superior metric for assessing glycemic control and predicting cardiovascular outcomes[41,42]. Incorporating time-updated HbA1c or continuous glucose monitoring data in future studies could elucidate whether glycemic control modifies the adiposity-CVD relationship.

Fourth, the clinical translation of targeted intervention strategies requires further in-depth exploration. Identifying high-risk subgroups is only the first step; translating these findings into effective interventions is paramount. This study clarified the risk stratification of different combinations of blood glucose and obesity but did not provide corresponding intervention recommendations. For underweight diabetic CKD patients with low WC, interventions should focus on nutritional support, resistance exercise, and prevention of protein-energy wasting[43,44]. In contrast, patients with central obesity and normal glucose may benefit from weight loss strategies that preserve kidney function, such as dietary modification, physical activity, and, where appropriate, bariatric surgery[45,46]. Pharmacologic interventions present significant therapeutic opportunities. Sodium-glucose cotransporter 2 inhibitors have demonstrated robust cardiorenal protective effects across the spectrum of CKD and diabetes, reducing major adverse cardiovascular events, heart failure hospitalizations, and CKD progression[47-50]. The landmark Empagliflozin in Patients with CKD trial confirmed the benefits of empagliflozin in a broad CKD population regardless of diabetes status[51]. Glucagon-like peptide-1 receptor agonists similarly confer cardiovascular and renal benefits while promoting weight loss[52-54]. The Flow Research on Renal Outcomes with Semaglutide trial specifically evaluated semaglutide in patients with type 2 diabetes and CKD, demonstrating significant reductions in major cardiovascular events and kidney failure[55]. Tirzepatide have shown superior weight loss efficacy in real-world studies[56]. It is recommended that future interventional studies be conducted to verify whether individualized interventions based on the risk model from this study can reduce the incidence of CVD.

Fifth, attention should be paid to the impact of racial differences on the generalizability of research findings. While this study utilizes data from the Korean population, it is important to note that obesity phenotypes in Asian populations (such as high body fat percentage at low BMI and preferential visceral fat accumulation) differ from those in Western populations. Asian populations tend to have higher body fat percentages at lower BMI and are more prone to visceral adiposity[57,58]. WC cutoffs for defining central obesity in Asians are generally lower than those used in Western populations[59]. Moreover, the prevalence and impact of sarcopenia, dietary patterns, and genetic factors exhibit significant variation across ethnic groups and sexes[60-62]. The Global Burden of Disease Study highlights significant regional heterogeneity in CKD burden and risk factor profiles[63]. A recent study comparing cohorts from South Korea and the United States revealed significant racial differences in the progression of CKD and the risk of mortality[64]. Therefore, findings from a single ethnic group may not be directly generalizable to other populations. Multi-ethnic, multi-center cohort studies are urgently needed to validate whether the risk patterns observed in Koreans remain applicable in other populations, including Caucasians, African Americans, Hispanics, and South Asians. Such efforts will enhance the global applicability of risk stratification models and provide a reference basis for prevention strategies in regions with different income levels.

CONCLUSION

The study by Bae et al[1] significantly advances our understanding of the combined effects of glycemic status and adiposity on cardiovascular risk in CKD. By revealing distinct risk patterns across glycemic strata, it challenges the simplistic view that obesity uniformly increases risk and underscores the importance of personalized risk assessment. However, as noted above, several critical gaps persist, including the need for more precise body composition measures, CKD stage-specific analyses, integration of glycemic control indicators, translation into targeted interventions leveraging novel cardiorenal agents, and validation across diverse populations. We commend the authors for their innovative work and contend that addressing these gaps will advance the field. Ultimately, a more nuanced approach to cardiovascular risk assessment in CKD - one that incorporates body composition, metabolic control, and individual patient characteristics - will enable clinicians to move beyond uniform strategies and provide truly personalized care. We look forward to future research that builds upon these findings and accelerates their translation into clinical practice.