Eun Roh; Ji Hye Heo; Kyung-Do Han; Jun Goo Kang

doi:10.4093/dmj.2025.1052

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Response 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): Eun Roh¹, Ji Hye Heo², Kyung-Do Han³, Jun Goo Kang²; Diabetes & Metabolism Journal 2026;50(1):203-204.
DOI: https://doi.org/10.4093/dmj.2025.1052
Published online: January 1, 2026

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¹Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul National University College of Medicine, Seoul, Korea

²Department of Internal Medicine, Hallym University Sacred Heart Hospital, College of Medicine, Hallym University, Anyang, Korea

³Department of Statistics and Actuarial Science, College of Natural Sciences, Soongsil University, Seoul, Korea

Corresponding author: Jun Goo Kang

Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University Sacred Heart Hospital, College of Medicine, Hallym University, 22 Gwanpyeong-ro 170beon-gil, Dongan-gu, Anyang 14068, Korea E-mail: kjg0804@empas.com

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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See the letter "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)" on page 190.

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.

REFERENCES

1. Roh E, Heo JH, Jung HN, Han KD, Kang JG, Lee SJ, et al. 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.PubMed PMC
2. Castaner O, Pinto X, Subirana I, Amor AJ, Ros E, Hernaez A, et al. Remnant cholesterol, not LDL cholesterol, is associated with incident cardiovascular disease. J Am Coll Cardiol 2020;76:2712-24.PubMed
3. Ginsberg HN, Packard CJ, Chapman MJ, Boren J, Aguilar-Salinas CA, Averna M, et al. Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies: a consensus statement from the European Atherosclerosis Society. Eur Heart J 2021;42:4791-806.Article PubMed PMC PDF
4. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35.Article PubMed
5. Tomono S, Kawazu S, Kato N, Ono T, Ishii C, Ito Y, et al. Uptake of remnant like particles (RLP) in diabetic patients from mouse peritoneal macrophages. J Atheroscler Thromb 1994;1:98-102.Article PubMed
6. Karakasis P, Patoulias D, Rizzo M, Fragakis N, Mantzoros CS. Association between remnant cholesterol and chronic kidney disease: systematic review and meta-analysis. Diabetes Obes Metab 2025;27:2573-83.Article PubMed PMC
7. Navarro-Gonzalez JF, Mora-Fernandez C, Muros de Fuentes M, Garcia-Perez J. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy. Nat Rev Nephrol 2011;7:327-40.Article PubMed PDF
8. Varbo A, Benn M, Tybjaerg-Hansen A, Nordestgaard BG. Elevated remnant cholesterol causes both low-grade inflammation and ischemic heart disease, whereas elevated low-density lipoprotein cholesterol causes ischemic heart disease without inflammation. Circulation 2013;128:1298-309.Article PubMed
9. Wang K, Wang R, Yang J, Liu X, Shen H, Sun Y, et al. Remnant cholesterol and atherosclerotic cardiovascular disease: metabolism, mechanism, evidence, and treatment. Front Cardiovasc Med 2022;9:913869.Article PubMed PMC
10. Yang YS, Kim HL, Kim SH, Moon MK. Lipid management in Korean people with type 2 diabetes mellitus: Korean Diabetes Association and Korean Society of Lipid and Atherosclerosis Consensus Statement. Diabetes Metab J 2023;47:1-9.Article PubMed PMC PDF

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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)

Diabetes Metab J. 2026;50(1):203-204. Published online January 1, 2026

DOI: https://doi.org/10.4093/dmj.2025.1052

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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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Roh E, Heo JH, Han KD, Kang JG. 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). Diabetes Metab J. 2026;50(1):203-204.

DOI: https://doi.org/10.4093/dmj.2025.1052.

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