Impact of Remnant Cholesterol on the Risk for End-Stage Renal Disease in Type 2 Diabetes Mellitus: A Nationwide Population-Based Cohort Study (Diabetes Metab J 2025;49:1106–15)
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We appreciate Dr. Hong’s interest and comments on our article, entitled “Impact of remnant cholesterol on the risk for end-stage renal disease in type 2 diabetes mellitus: a nationwide population-based cohort study” [1].
Remnant cholesterol (remnant-C), which is calculated as total cholesterol minus low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol [2], primarily reflects cholesterol carried within triglyceride-rich lipoproteins and their remnants, including very-low-density lipoproteins and intermediate-density lipoproteins [3]. In type 2 diabetes mellitus (T2DM), overproduction and inefficient lipolytic processing of triglyceride-rich lipoproteins lead to increased formation of remnant-C. Remnant-C represents particles that are metabolically and biologically distinct from LDL-C (cholesterol transported by LDL particles), and differs in size, triglyceride content, and catabolic pathways [3]. Remnant-C is more likely to accumulate within the arterial wall and promote atherosclerosis [4]. In addition, remnant lipoproteins can be readily taken up by intimal macrophages without prior modification such as oxidation or glycation, thereby inducing low-grade inflammation even more potently than LDL-C [5].
In our study, elevated remnant-C levels were independently associated with higher risk of progression to end-stage renal disease (ESRD) in individuals with T2DM, suggesting that remnant-C may serve as an additional marker of renal vulnerability beyond LDL-C–mediated pathways [1]. This observation is consistent with a recent meta-analysis showing that, among individuals with T2DM-related chronic kidney disease (CKD), each one standard deviation increase in remnant-C was associated with a 24% increase in risk of progression to ESRD [6]. Moreover, the risk of ESRD across remnant-C quartiles showed a significant interaction with statin use, with a pronounced association observed in participants receiving statins compared with those not on statin therapy (P for interaction <0.0001) [1]. These findings support the hypothesis that remnant-C–driven residual risk can persist despite optimal LDL-C lowering.
Although the precise mechanisms through which remnant-C contributes to the pathophysiology of ESRD remain incompletely defined, accumulating evidence has implicated remnant-C in atherogenic and nephrotoxic processes—such as endothelial dysfunction, mesangial expansion, tubulointerstitial lipotoxicity, and low-grade inflammation—that may accelerate CKD progression [7–9]. Importantly, remnant-C–related nephropathy may develop even in individuals with apparently normal renal function, as elevated remnant-C levels are associated with increased risk of ESRD among those without dyslipidemia or CKD [1,6].
LDL-C remains the primary therapeutic target in lipid management for patients with T2DM, given its well-established role in reducing both cardiovascular and renal risk [10]. Nevertheless, we acknowledge that LDL-C–stratified analyses were not performed in our study, which limits our ability to delineate potential interactions between LDL-C and remnant-C in determining renal outcomes. Accordingly, our findings should be regarded as hypothesis-generating rather than confirmatory. Future investigations incorporating LDL-C–stratified analyses and applying standardized or more precise quantification methods for remnant-C will be essential to clarify whether remnant-C confers renal risk independent of LDL-C, as well as to determine whether therapeutic strategies aimed at remnant-C reduction can meaningfully improve kidney outcomes in T2DM.
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CONFLICTS OF INTEREST
Eun Roh has been an associate editor of the Diabetes & Metabolism Journal since 2023. She was not involved in the review process of this article. Otherwise, there were no conflicts of interest.