Glycemic status as a lens into heterogeneity of the obesity-cardiovascular risk in chronic kidney disease

Abstract

In the course of chronic kidney disease, the relationship between cardiovascular outcomes and obesity is modified by blood glucose status. A national study has deepened our understanding of this complex interaction. The study found that among patients with chronic kidney disease without diabetes, low body weight and central obesity are risk factors. In contrast, for patients with diabetic kidney disease, relatively low waist circumference and low body mass index are associated with increased disease risk. These findings highlight the existence of an obesity paradox and underscore the need to recognize that patients with diabetic kidney disease are in a catabolic state, which is unfavorable for the development of protective factors. Therefore, cardiovascular prevention strategies should be adjusted according to blood glucose status, and both body composition and blood glucose status should be assessed concurrently. This paper reviews the above findings and analyzes the implications of risk stratification in the management of diabetic kidney disease.

Key Words: Chronic kidney disease; Cardiovascular disease; Obesity paradox; Body mass index; Waist circumference

Core Tip: In patients with chronic kidney disease, there is a close relationship between cardiovascular risk and obesity indices, and blood glucose level is an important modulator of this relationship. Even in patients with a relatively low body weight, cardiovascular risk may be increased, challenging the notion that “thin is safe”. In clinical assessment, attention should be paid to both body mass index and waist circumference, along with evaluation of muscle atrophy and malnutrition, to enable individualized risk stratification.

INTRODUCTION

In recent years, the increasing incidence of chronic kidney disease (CKD) has drawn global attention, as this disease is closely associated with cardiovascular disease and infection, and is also a contributor to increased mortality[1-3]. This is driven not only by the shared risk factors of diabetes mellitus and hypertension, but also by factors intrinsic to CKD itself, such as fluid overload and overactivation of the renin-angiotensin-aldosterone system[4,5]. Among the known causes of death in patients with end-stage renal disease, cardiovascular mortality accounts for a considerable proportion. In recent years, the prevalence of both diabetes and CKD has been rising steadily, and neither condition is rare. Moreover, 40% of diabetic patients have concurrent CKD, and the coexistence of these two conditions further increases the risk of cardiovascular disease[6]. In this regard, accurate risk assessment and appropriate interventions are warranted[2,7,8].

Traditionally, obesity is considered a risk factor for cardiovascular disease, while individuals with low body weight are regarded as being at relatively low risk[9]. In the evolving understanding of cardiovascular disease, the so-called “obesity paradox” has been proposed, challenging the traditional understanding. Specifically, some overweight patients with cardiovascular disease may exhibit better health status than their normal-weight counterparts[10]. This paradox is more complex in the development of type 2 diabetes[11]. Bae et al[12] published a study in which 1.7 million CKD patients in South Korea were selected as research subjects, and found that the relationship between obesity indicators and cardiovascular risk varies depending on patients’ glycemic status. These findings challenge the traditional view that “slenderness is safe” and provide a basis for risk stratification in diabetic kidney disease. In this paper, we analyze the conclusions drawn from the literature, and further explain the clinical significance of the research findings.

DIABETES AS A POWERFUL RISK AMPLIFIER

Cohort study results show that diabetic patients have relatively high mortality and a relatively high incidence of cardiovascular adverse events[12]. For patients with type 2 diabetes mellitus, regardless of the stage of CKD, cardiovascular risk is relatively high, and the risk of death from cardiovascular disease exceeds that from renal failure[13]. Thus, hyperglycemia profoundly impacts cardiovascular outcomes in patients with CKD. Moreover, the incidence of adverse cardiovascular events in patients with impaired fasting glucose is slightly increased, and their mortality is somewhat elevated. This conclusion is consistent with that of many epidemiological cohort studies, which indicate that even when blood glucose levels do not reach the diagnostic threshold for diabetes, the risk of cardiovascular mortality and all-cause mortality is still relatively high[12,14]. These observations are closely linked to the mechanisms identified in previous studies, including oxidative stress and advanced glycation end product formation, endothelial dysfunction, chronic low-grade inflammation, lipid metabolism disorders, imbalances in the coagulation-fibrinolysis system, activation of the renin-angiotensin-aldosterone system, and microvascular disease and diabetic cardiomyopathy, among others[15-18]. Collectively, these findings suggest that the impact of blood glucose on cardiovascular outcomes is continuous rather than a simple threshold effect, and patients with prediabetes has already face increased cardiovascular risk.

DIABETES FUNDAMENTALLY ALTERS ASSOCIATIONS BETWEEN OBESITY INDICATORS (BODY MASS INDEX AND WAIST CIRCUMFERENCE) AND CARDIOVASCULAR RISK

For patients with CKD, even when blood sugar levels are normal or only impaired, the “obesity paradox” is still observed, and these patients tend to have a relatively low risk of death. Although the “obesity paradox” is most commonly discussed in the context of cardiovascular diseases, it also exists in other conditions, including most cancers (except for hepatobiliary and breast cancers), pulmonary diseases, and end-stage renal disease[9,19]. In exploring the underlying mechanisms, many scholars have proposed a series of plausible explanations. The potential pathways are diverse and include higher energy reserves to meet increased energy demands during illness, inflammatory preconditioning, and enhanced capacity for clearing endotoxins, among others[19-22]. Epidemiological studies have found in diabetic patients, a relatively high body mass index (BMI) is associated with a relatively low incidence of diabetic retinopathy, including vision-threatening forms. Several explanations for this protective effect have been offered. Some scholars suggest that a relatively high BMI is associated with elevated C-peptide levels, which may reduce the risk of diabetic retinopathy. Others argue that this phenomenon may simply reflect more intensive treatment received by individuals with obesity[23]. However, this view does not hold for some patients with severe obesity (BMI > 30 kg/m²)[24]. It should be emphasized that regardless of BMI, the mortality rate in diabetic patients remains relatively high[12]. This finding further suggests that for diabetic patients, particularly those with hyperglycemia, the protective effect of BMI is relatively weak, which may be related to chronic inflammation and insulin resistance[25]. The study also identified a direct relationship between cardiovascular disease and waist circumference, consistent with the findings of Bae et al[12]. Even when diabetic patients have a normal BMI, they may still present central obesity, which is more likely than general obesity to cause metabolic disorders and increase cardiovascular risk. Central obesity is directly associated with heart dysfunction and cardiac remodeling[26]. When diabetes is present, these factors interact with one another, leading to a marked increase in mortality risk. Nevertheless, it should be noted that even when waist circumference is relatively small, diabetic patients still face a relatively high mortality rate.

It should be noted that research on the obesity paradox has several limitations, the most typical being reverse causality and selection bias. Confounding factors (such as smoking) are not always adequately accounted for. In addition, the limitations of BMI in defining obesity should also be considered. BMI fails to quantify body fat distribution and does not reflect nutritional status or cardiorespiratory fitness. Nevertheless, regardless of whether the obesity paradox truly exists, the role of obesity as a risk factor for the development of cardiovascular and metabolic diseases should not be underestimated, and more comprehensive prevention and management strategies are therefore needed[11,14,21,27].

UNDERWEIGHT, OR CENTRAL UNDERWEIGHT, EMERGES AS THE FACTOR CARRYING THE HIGHEST RISK OF CARDIOVASCULAR EVENTS AND MORTALITY

In studies patients with diabetes and CKD, underweight individuals (BMI < 18.5 kg/m²) are known to have a higher risk of cardiovascular events and higher mortality rates[12]. Underweight is also a risk factor for die from infection in patients with CKD[28]. During the process of CKD, a higher BMI reflects better nutritional status, which confer a protective effect, yet it can also predispose to metabolic disorders[29]. In their review, Jaitovich and Hall[30] analyzed energy metabolism in critically ill patients and pointed out that the catabolism of muscle and fat tissue is not a passive depletion but rather an active adaptive response that can enhance the function of immune and inflammatory cells. They proposed that the body may exert a protective role during acute stress through immune cell infiltration and the provision of oxidative substrates (e.g., M2 macrophages). Moreover, the breakdown of muscle proteins supplies amino acid substrates for immune cell proliferation and hepatic gluconeogenesis, a mechanism that deepens our understanding of the “obesity paradox”. Adequate fat reserves may improve treatment outcomes by buffering inflammation and “sparing muscle”. In contrast, excessively low body weight indicates insufficient metabolic reserves, leading to impaired immune function and rapid muscle atrophy under stress.

These findings further clarify that thinness does not necessarily imply safety for patients with diabetes and CKD. Instead, it may be associated with chronic inflammation and sarcopenia—conditions commonly observed in both diseases—which can lead to poor prognosis. This conclusion serves a warning to clinicians, underscoring the need for close monitoring of such patients, as they are in a high-risk state (Figure 1).

Figure 1 Clinical stratification and management strategy for patients with chronic kidney disease based on glycemic status and body composition. CKD: Chronic kidney disease.

THE IMPORTANCE OF A “DUAL-COMPONENT” APPROACH IN ASSESSMENT INDICATORS

BMI reflects overall obesity but fails to capture visceral fat distribution[27,31-33]. In contrast, waist circumference reflects visceral fat, which is closely associated with metabolic risk[34-38]. In individuals without diabetes, increased waist circumference (men ≥ 90 cm, women ≥ 85 cm) is an independent risk factor. Among diabetic patients, however, both low waist circumference and low BMI are associated with relatively high risk. Therefore, rather than rigidly analyzing a single index, we should integrate both indicators to identify subgroups requiring intervention[39]. For diabetic patients with both low BMI and low waist circumference, further evaluation of nutritional status and frailty is necessary (Figure 1). This evaluation should include a questionnaire for sarcopenia screening, analysis of dietary records, and measurements of handgrip strength (men < 28 kg, women < 18 kg) and gait speed (6-meter walk < 1.0 m/second)[40-44].

CLINICAL IMPLICATIONS AND FUTURE DIRECTIONS

From the epidemiological point of view, the obesity paradox exists in the development of CKD. However, recent therapeutic advances have reduced cardiovascular risk in diabetic patients[45-47]. Sodium-glucose cotransporter 2 inhibitors significantly reduce cardiovascular death and heart failure, with updated indications[48-51]. Glucagon-like peptide 1 receptor agonists slow the decline of estimated glomerular filtration rate and reduce the incidence of atherosclerotic cardiovascular events[52-56]. Finerenone, a non-steroidal mineralocorticoid receptor antagonist, reduces the incidence of cardiovascular events and delay the progression of CKD[57-61]. The cardiovascular benefits with these agents challenge the conclusion that being “slightly overweight” is protective. Rather than focusing solely on weight loss, patients should aim to adjust their body composition and receive treatment with multiple drug classes, which may yield better outcomes. The mechanisms underlying these benefits are clearly superior to the harm caused by weight reduction. It should be noted that the “obesity paradox” observed in epidemiological studies reflects relatively robust metabolic and nutritional reserves, which is distinctly different from intentional weight loss achieved through pharmacologic or lifestyle interventions—the latter being effective for controlling blood pressure and blood sugar.

Going forward, in-depth research is needed in the following areas. First, we should determine the optimal weight range for each patient’ based on their glycemic status. Second, targeted intervention strategies should be developed for different phenotypes. Most critically, body composition should be into risk prediction models and to better characterize the distribution of fat and muscle mass. In clinical research, we should appreciate the obesity paradox from an epidemiological perspective while recognizing through clinical trials that weight loss confers cardiovascular benefits. Both body composition optimization and weight loss regarded as primary therapeutic goals.

CONCLUSION

In summary, a consensus has emerged among scholars that the cardiovascular risk profile of patients with CKD is more complex than previously understood. In the management of cardiovascular disease, it is essential to fully recognize the impact of diabetes, which significantly modifies the relationship between obesity indicators and clinical outcomes. On the one hand, this understanding helps explain the “obesity paradox” observed in studies of non-diabetic patients. On the other hand, it eliminates the purported advantages of mild obesity, while identifying low body weight as a key indicator of poor prognosis. In recent years, therapeutic advances have yielded meaningful results. The use of finerenone and other agents has been shown to reduce cardiovascular risk, thereby challenging previous conceptions.