Association of High-Density Lipoprotein Cholesterol and Wound Healing in Patients with Diabetic Foot Ulcers

Diabetic foot ulcers (DFUs) represent a significant complication of diabetes mellitus, contributing to substantial morbidity and healthcare burden. With a prevalence of 4%–10% and a lifetime incidence of 19%–34% among individuals with diabetes, DFUs are notoriously challenging to treat due to their multifactorial pathophysiology and frequent resistance to conventional therapies. Emerging evidence suggests that dyslipidemia, particularly alterations in high-density lipoprotein cholesterol (HDL-C), may play a role in modulating wound repair processes. This study investigates the association between HDL-C levels and wound healing outcomes in patients with DFUs, providing novel insights into potential therapeutic targets.

Study Design and Participant Characteristics

This observational cohort study was conducted at the Diabetic Foot Care Center of West China Hospital, Sichuan University, between July 2013 and June 2019. A total of 167 adult patients with DFUs classified as Wagner grade 2–4 were enrolled. Exclusion criteria included non-diabetic ulcers (e.g., malignant ulcers, gout-related ulcers), active medical conditions such as diabetic ketoacidosis or severe systemic infections, and use of immunosuppressive therapies. The cohort had a mean age of 64 ± 11 years, with 30% female participants. The average duration of diabetes was 12.8 ± 7.8 years, and the median wound duration prior to enrollment was 2 months (interquartile range [IQR]: 1–5 months). The mean hemoglobin A1c (HbA1c) level was 8.4% ± 2.0%, reflecting suboptimal glycemic control in the study population.

Interventions and Outcome Measures

All participants received standardized multidisciplinary care, including metabolic optimization (glucose, blood pressure, and lipid control), infection management, and local wound therapies such as offloading, debridement, negative pressure wound therapy, and autologous platelet-rich gel applications. Surgical interventions, including amputations and endovascular procedures, were performed as clinically indicated. Patients were followed for 12 weeks, with the primary outcome defined as time to complete wound healing.

HDL-C Levels and Baseline Characteristics

Over half of the cohort (53%) exhibited reduced HDL-C levels, defined as <1.03 mmol/L (40 mg/dL). Participants with lower HDL-C levels had significantly higher Wagner grades ((P < 0.05)) and lower serum albumin levels compared to those with higher HDL-C ((geq)1.03 mmol/L). These findings suggest that HDL-C deficiency may correlate with more severe ulcer presentations and poorer nutritional status.

Association Between HDL-C and Wound Healing

Within the 12-week follow-up period, 106 ulcers (63.4%) achieved complete healing, with a median healing time of 50 days (IQR: 30–84 days). Kaplan-Meier survival analysis revealed a significant divergence in healing trajectories between HDL-C subgroups ((P = 0.016)). Patients with HDL-C (geq)1.03 mmol/L demonstrated faster healing rates, with a 12-week healing probability of 70%, compared to 45% in the low HDL-C group.

Cox proportional hazards regression models were employed to quantify this relationship. When analyzed as a categorical variable (using 1.03 mmol/L as the cutoff), low HDL-C was associated with delayed healing in unadjusted analyses (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.45–0.95, (P = 0.025)). However, after adjusting for age, sex, Wagner grade, and wound duration, this association lost statistical significance (HR: 0.82, 95% CI: 0.55–1.22, (P = 0.303)), likely due to confounding by ulcer severity.

In contrast, when HDL-C was treated as a continuous variable, each standard deviation (SD) increase in HDL-C (0.13 mmol/L) correlated with a 30% higher likelihood of healing (HR: 1.30, 95% CI: 1.07–1.60, (P = 0.010)) in fully adjusted models. Quartile analysis further supported this dose-response relationship: participants in the highest HDL-C quartile ((geq)1.30 mmol/L) had nearly double the healing rate of the lowest quartile (HR: 1.89, 95% CI: 1.03–3.46, (P = 0.040)).

Mechanistic Insights and Clinical Implications

The observed association between HDL-C and wound healing aligns with emerging evidence on the pleiotropic functions of HDL beyond lipid metabolism. HDL particles exhibit anti-inflammatory properties by inhibiting endothelial adhesion molecule expression and neutralizing pro-inflammatory oxidized lipids. In the context of DFUs, chronic inflammation impedes tissue repair; thus, HDL-C deficiency may exacerbate inflammatory damage and delay healing.

Additionally, HDL enhances angiogenesis—a critical process in wound repair—by promoting endothelial progenitor cell (EPC) mobilization and incorporation into neovessels. Preclinical studies demonstrate that HDL stimulates EPC proliferation and secretion of pro-angiogenic factors like vascular endothelial growth factor (VEGF). Impaired angiogenesis is a hallmark of diabetic wounds, suggesting that HDL-C restoration could mitigate microvascular dysfunction.

HDL also facilitates cholesterol efflux from macrophages, preventing foam cell formation and maintaining tissue homeostasis. In diabetic patients, glycation and oxidative modification of HDL particles impair this function, leading to intracellular lipid accumulation and cellular dysfunction in ulcer beds.

Limitations and Future Directions

This study has several limitations. First, its single-center design and modest sample size limit generalizability. Second, HDL-C quantification did not account for qualitative aspects such as apolipoprotein composition or paraoxonase activity, which influence HDL functionality. Third, residual confounding by unmeasured variables (e.g., dietary patterns, physical activity) cannot be excluded.

Prospective studies are needed to validate these findings and explore causality. Interventions targeting HDL-C, such as exercise, niacin, or cholesteryl ester transfer protein (CETP) inhibitors, should be evaluated in randomized trials. Additionally, mechanistic studies investigating HDL’s effects on diabetic skin fibroblasts, keratinocytes, and immune cells could elucidate novel therapeutic pathways.

Conclusion

This study provides compelling evidence that reduced HDL-C levels are independently associated with impaired wound healing in patients with DFUs. The findings underscore the importance of dyslipidemia management in diabetic wound care and highlight HDL-C as a potential biomarker and therapeutic target. Future research should focus on optimizing HDL function to improve outcomes in this high-risk population.

doi.org/10.1097/CM9.0000000000001544

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