ORIGINAL RESEARCH article
Front. Nutr.
Sec. Nutrition and Metabolism
Volume 12 - 2025 | doi: 10.3389/fnut.2025.1660820
Glycemic Control Modifies LDL-C–DKD Risk: A U-Shaped Association in Well-Controlled Type 2 Diabetes
Provisionally accepted
- 1Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
- 2Taihe Hospital, Shiyan, China
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Background: The relationship between low-density lipoprotein cholesterol (LDL-C) levels and diabetic kidney disease (DKD) risk remains controversial, with limited evidence on its interaction with modifiable risk factors. This study aimed to investigate the dose-response relationship between LDL-C and DKD risk in patients with type 2 diabetes (T2D). Methods: A retrospective cohort of 3,040 patients with T2D and no baseline DKD was followed. Association between LDL-C and DKD risk was analyzed using Cox regression, interaction analysis and restricted cubic splines (RCS). Sensitivity analyses excluded lipid-lowering medication users, and threshold effects were validated using segmented regression and survival analysis. Results: 665 (21.9%) patients developed DKD during the follow up (median: 3.13 years). In the fully adjusted model, LDL-C as a continuous variable showed no significant association with DKD risk (P=0.061). When analyzed by quartiles, the hazard ratios (HR) displayed a non-monotonic pattern: compared to Q1, Q2 had the lowest risk (HR=0.69, P=0.001), followed by a partial rebound in Q3 (HR=0.80, P=0.046), and a subsequent decline in Q4 (HR=0.72, P=0.005), suggesting potential non-linearity. A significant LDL-C-by-glycemia control interaction was observed (Pinteraction =0.013). In the HbA1c ≤7% subgroup, RCS analysis demonstrated a U-shaped relationship between LDL-C and DKD risk (Pnonlinear <0.001), with nadir risk at 2.66–3.57 mmol/L. Risk increased below 2.66 mmol/L (HR=1.55, P=0.015) and trended upward above 3.57 mmol/L (HR=1.47, P=0.121). In this subgroup, sensitivity analyses excluding lipid-lowering drug users confirmed robustness, and survival curves showed lower DKD incidence in the intermediate LDL-C group (2.66–3.57 mmol/L) versus low/high groups (P=0.004). No associations were found in the HbA1c >7% subgroup. Conclusion: Glycemic control modulates the LDL-C-DKD risk association in patients with T2D, with a U-shaped relationship observed in those with good glycemic control, thereby emphasizing the necessity of integrating glycemic status into LDL-C target evaluations.
Keywords: Low-density lipoprotein cholesterol, Diabetes kidney disease, Type 2diabetes, U-shaped association, glycemic control
Received: 06 Jul 2025; Accepted: 19 Aug 2025.
Copyright: © 2025 Zheng, He, Chen, Wang and Ma. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Huabin Wang, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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