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. 2025 Jun 7;24(1):205.
doi: 10.1186/s12944-025-02632-4.

Sex-specific and metabolic subgroup heterogeneity in high-density lipoprotein cholesterol associations with diabetic kidney disease risk: a retrospective cohort study

Huabin Wang #  1 , Xuanlin Jin #  2 , Fenfang Lin  3 , Guangming Chen  4 , Meili Lin  5 , Yongjun Ma  6
Affiliations

Sex-specific and metabolic subgroup heterogeneity in high-density lipoprotein cholesterol associations with diabetic kidney disease risk: a retrospective cohort study

Huabin Wang et al. Lipids Health Dis. .

Abstract

Background: The role of high-density lipoprotein cholesterol (HDL-C) in diabetic kidney disease (DKD) remains controversial. This study aimed to delineate the subgroup-specific relationships between the two by exploring cumulative and threshold effects.

Methods: 3,040 patients with type 2 diabetes and no baseline evidence of DKD were included. Cox proportional hazards regression models were performed to investigate the potential relationship between HDL-C level and DKD risk. To address subgroup heterogeneity, sex-stratified restricted cubic splines (RCS) were employed to model nonlinear relationships. The optimal threshold was identified through the maximum selected statistics and validated via 1,000 bootstrap iterations. Subgroup analyses stratified by sex, diabetes duration, and metabolic status were performed to evaluate heterogeneity. Survival analysis using Kaplan-Meier curves further validated these threshold effects.

Results: During a median follow-up of 3.13 years, 665 subjects (21.9%) progressed to DKD. Overall, each 1 mmol/L increase in HDL-C level independently reduced DKD risk by 43%. RCS analysis demonstrated an inverse correlation between HDL-C and DKD risk (P for overall = 0.025, P for nonlinear = 0.317), with increased risk reduction at lower concentrations, plateauing at higher levels. A robust threshold of 0.93 mmol/L was identified, showing significantly stronger protection against DKD progression (hazard ratio (HR) = 0.69, P < 0.001) compared to the traditional cutoff (HR = 0.86, P = 0.109). Females showed continuous protection (HR = 0.41, P = 0.009) without threshold dependency. The male and diabetes duration < 10 years subgroups exhibited threshold effects at > 0.93 mmol/L without continuous protection. The metabolically unstable (hypertension, poorly controlled glycemia, body mass index (BMI) > 28 kg/m2) and BMI < 24 kg/m² subgroups displayed dual effects (P < 0.05). Survival analysis confirmed lower cumulative DKD incidence with HDL-C > 0.93 mmol/L (P = 0.007).

Conclusions: This study reveals sex- and metabolic context-dependent heterogeneity in HDL-C-DKD associations: males and short-duration diabetes exhibited threshold effects (0.93 mmol/L), females showed continuous protection, and subgroups with hypertension, poorly controlled glycemia, or obesity (BMI > 28 kg/m²) exhibited both continuous protection and threshold effects. These findings may inform individualized risk stratification in specific populations.

Keywords: Diabetic kidney disease; Dual effects; High-density lipoprotein cholesterol; Metabolic context-dependent; Subgroup heterogeneity.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: The present study followed the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of Affiliated Jinhua Hospital, Zhejiang University School of Medicine (ethical approval number: (Res) 2024-Ethical Review-sb58). According to the regulations of the Ethics Committee, the consent for participation is not necessary for this retrospective study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
The participant flow chart. eGFR: estimated glomerular filtration rate; ACR: albumin-to-creatinine ratio; DKD: diabetic kidney disease; HbA1c: glycated hemoglobin
Fig. 2
Fig. 2
Association between HDL-C levels and DKD risk analyzed via RCS with Cox proportional hazards regression adjusted for age, sex, SBP, BMI, TG, LDL-C, HbA1c, TC, baseline ACR, and serum creatinine, hypertension status, diabetes duration, and SGLT2i/GLP-1RA use in the overall cohort (A), male subgroup (B) and female subgroup (C). DKD: diabetic kidney disease; RCS: restricted cubic spline; HDL-C: high-density lipoprotein cholesterol; SBP: systolic blood pressure; BMI: body mass index; HbA1c: glycated hemoglobin; TC: total cholesterol; LDL-C: low-density lipoprotein cholesterol; TG: triglycerides; ACR: albumin-to-creatinine ratio; SGLT2i: sodium-glucose cotransporter-2 inhibitors; GLP-1RA: glucagon-like peptide-1 receptor agonists
Fig. 3
Fig. 3
Determination of the optimal HDL-C threshold using the MSS method (A) and bootstrap validation (B) in the overall cohort. MSS: maximum selected statistics; HDL-C: high-density lipoprotein cholesterol
Fig. 4
Fig. 4
Subgroup analyses of HDL-C as a continuous variable (A) and as a threshold-defined (0.93 mmol/L) categorical variable (B) in relation to DKD risk across clinical subgroups showed significant heterogeneity. DKD: diabetic kidney disease; HDL-C: high-density lipoprotein cholesterol; BMI: body mass index
Fig. 5
Fig. 5
Adjusted Kaplan-Meier curves showed significantly reduced cumulative DKD incidence in the HDL-C ≥ 0.93 mmol/L group versus the lower HDL-C group in the overall cohort (P = 0.007). HDL group 0: subjects with HDL-C < 0.93 mmol/L; HDL group 1: subjects with HDL-C ≥ 0.93 mmol/L; DKD: diabetic kidney disease; HDL-C: high-density lipoprotein cholesterol
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