Diabetes mellitus causes significant harm through both macrovascular and microvascular complications (1, 2). A key macrovascular complication is ASCVD, which affects approximately 50% of individuals with diabetes. DKD, the primary microvascular complication affecting 30–40% of diabetic patients, significantly contributes to end-stage renal failure (3). These complications are major mortality factors in diabetes and create a vicious cycle due to shared pathological mechanisms such as vascular inflammation and endothelial dysfunction. ASCVD accelerates renal injury, whereas DKD exacerbates cardiovascular outcomes (4). The recently introduced “cardiovascular-kidney-metabolic (CKM) syndrome” highlights how cardiac, renal, and metabolic disorders form a pathological loop driven by oxidative stress, chronic inflammation, and neuroendocrine activation. This results in a lethal cycle known as the “metabolism-heart-kidney” triple hit (5, 6). Disrupting this cycle depends on identifying intervention targets with cross-organ protective effects.

Dyslipidemia is central to CKM syndrome due to its vascular toxicity (7), but lipid metabolism in CKM remains poorly defined. LDL-C drives atherosclerosis (8) and correlates with renal dysfunction in diabetes. It may directly damage kidney via glomerular deposition, activating TGF-βand promoting fibrosis (9, 10). However, Mendelian randomization suggests no direct causal link to eGFR decline, implying LDL-C nephrotoxicity requires specific pathological contexts (11). HDL-C inversely correlates with UACR (12), but its cardiorenal benefits may be reduced in diabetes or chronic inflammation due to altered functionality (13, 14). Elevated TG and TC contribute to cardiovascular risk and DKD progression (15, 16).Current lipid guidelines prioritize cardiovascular outcomes and LDL-C goals, lacking strategies for renal protection (17). Crucially, most studies fail to account for baseline lipid-lowering therapy. lipid-lowering therapy modify lipid profiles and renal inflammation, confounding observational studies and limiting the generalizability of findings on native lipids’ renal effects. Therefore, investigating lipid-DKD relationships in diabetic patients without lipid-lowering therapy is essential.

ASCVD may dynamically influence the lipid-DKD risk relationship by modifying the systemic inflammatory microenvironment and remodeling lipoprotein metabolism. However, the impact of diabetes accompanied by ASCVD on the progression of DKD remains insufficiently explored, and interactions among diabetic complications are inadequately considered. This gap hinders the establishment of customized lipid management.

This study aims to (1) elucidate the dose–risk relationships between specific lipid components and the risk of DKD and (2) assess whether the coexistence of ASCVD affects these associations. These findings provide evidence for personalized lipid management, facilitating a shift beyond isolated organ-focused treatments toward comprehensive strategies.

The study revealed no significant association between HDL-C and DKD risk in diabetic patients with ASCVD. LDL-C and TC levels were linearly related to DKD risk, whereas TG levels were significantly nonlinearly related. In diabetic patients without ASCVD, all four lipids were significantly associated with DKD risk, with significant threshold effects. Interaction analysis indicated that ASCVD significantly increased the DKD risk caused by TC and LDL-C. These findings support lipid management strategies for diabetic patients on the basis of ASCVD status. As a cross-sectional study, our findings identify associations but cannot establish causality. Relationships between lipids, ASCVD, and DKD require validation in longitudinal cohorts. Residual confounding like unmeasured genetic or dietary factors may also influence results.

By excluding lipid-lowering drug users, this study significantly reduced pharmacological confounding, enabling direct assessment of dyslipidemia-DKD associations. Second, RCS and threshold analysis revealed nonlinear lipid–DKD risk associations, enabling early high-risk identification. Importantly, ASCVD was shown to modify the relationship between lipids and DKD risk, suggesting a mechanistic link between systemic inflammation and lipid metabolism disorders.

These findings establish ASCVD as a key indicator for DKD risk stratification, guiding clinical approaches. For diabetic patients without ASCVD, maintaining LDL-C and TC levels near the identified threshold while avoiding extremes is recommended. Cardiovascular protection is paramount in diabetic patients with ASCVD. Guideline-directed lipid targets (e.g., LDL-C <1.8 mmol/L) should be strictly adhered to despite renal risk considerations, as ASCVD exacerbates lipid pathways contributing to DKD. TG management requires intervention below the threshold to reduce cumulative renal damage, transitioning to multifactorial risk control when the threshold is exceeded. HDL-C interventions should focus on enhancing function rather than merely increasing its concentration. Overall, this evidence shifts clinical practice from numerical lipid targets toward risk-stratified organ protection strategies, developing lipid management for DKD patients with coexisting ASCVD.

These four lipids revealed statistically significant relationships when analyzed via RCS modeling. This discrepancy likely stems from their nonlinear associations with DKD risk, which linear methods cannot detect. The RCS analysis overcomes this limitation by flexibly modeling threshold effects and nonlinear exposure–response relationships, thus revealing clinically meaningful links between blood lipids and DKD risk.

In diabetic patients without ASCVD, blood lipids may reflect the pathological mechanisms underlying DKD risk in a nonlinear manner. RCS analysis revealed that LDL-C and TC levels below certain thresholds were linked to increased DKD risk. This challenges the conventional “lower is better” rules, suggesting complex biological interactions: 1) Low LDL-C and TC may indicate systemic metabolic dysregulation, such as chronic inflammation or complications, serving as markers of disease severity rather than direct pathogenic factors. 2) Excessive lipid reduction could impair renal function by disrupting cellular membrane integrity or steroidogenesis. Conversely, elevated LDL-C and TC beyond thresholds can exceed renal metabolic capacity, leading to kidney injury via oxidative stress pathways.

These nonlinear relationships are supported by recent studies, including a cross-sectional analysis at Zhejiang University’s Affiliated Jinhua Hospital showing increased DKD risk at LDL-C <2.97 mmol/L (18) and Shanghai community data identifying TG (1.90 mmol/L) and HDL-C (1 mmol/L) thresholds (19). Importantly, these statistical inflection points represent population-level estimates rather than individualized targets. Significant interpatient variability in metabolic status, complications, and medications necessitates comprehensive clinical evaluation. Therefore, elevated DKD risk at low LDL-C levels should be interpreted cautiously, likely reflecting malnutrition or advanced comorbidities rather than direct LDL-C toxicity.

Limitations in the protective role of HDL-C align with European observations of the “HDL-C paradox” (20, 21). HDL-C showed significant protective effects against DKD only at concentrations below 1.64 mmol/L, with this association plateauing beyond that threshold. This attenuation may stem from insulin resistance and impaired particle functionality, which reduce cholesterol efflux capacity (22, 23). The threshold effect for TG likely reflects the free fatty acid metabolic balance. Below this threshold, moderate TG elevation may increase DKD risk through direct lipotoxic damage to glomerular endothelial cells. The above-threshold TG level was not significantly associated with DKD risk, possibly because severe insulin resistance in hypertriglyceridemic patients obscures the independent effects of TG, as hyperglycemia becomes the primary cause of renal damage (24, 25). These findings partially support Mendelian randomization studies establishing causal links in HDL-C, TG, and DKD risk (11), although complex pathophysiology of diabetes cannot be attributed exclusively to genetic influences.

In diabetic patients with ASCVD, LDL-C and TC were linearly associated with DKD risk, suggesting that ASCVD alters blood lipid-DKD risk relationships. The lipid thresholds in patients without ASCVD were similar to those in the overall cohort before subgroup analysis. This stability may indicate a critical point for renal injury due to metabolic imbalance, which is influenced by renal lipid metabolism capacity. Instead of changing this threshold, ASCVD likely exacerbates renal damage through inflammation and endothelial dysfunction. Additionally, the larger sample size of diabetic patients without ASCVD may limit the detection of differences in thresholds despite reflecting real-world distributions. Therefore, current observations on threshold consistency should be interpreted cautiously with respect to statistical power and clinical context, and subtle differences might go unnoticed owing to sample size limitations. Furthermore, the loss of the protective effect of HDL-C in ASCVD patients may be caused by functional impairment. The activity of myeloperoxidase (MPO), a proinflammatory oxidase, diminishes the antioxidant capacity of HDL-C. In atherosclerosis, increased serum MPO activity leads to oxidative modification of HDL-C (26, 27), potentially reducing its renoprotective function.

Interaction analysis revealed that ASCVD modifies the relationship between blood lipids and DKD risk in type 2 diabetic patients, highlighting complex interactions between dyslipidemia and renal injury. ASCVD significantly enhances the nephrotoxic effects of TC and LDL-C, with both multiplicative and additive interactions showing statistical significance. The presence of these two interactions represents a strong form of interaction (28). The additive interaction results indicate that lowering LDL-C and TC may reduce DKD risk more effectively in ASCVD patients than in those without ASCVD. The inconsistent multiplicative interaction among different gender and age populations indicates that at the relative risk level, ASCVD does not significantly change the intensity of the effect ratio of blood lipids on the risk of DKD. However, the additive interaction among people of different genders and ages is significant, which has important public health significance, especially when assessing the hazards of combined exposure. It indicates that simultaneous exposure to two factors can lead to an excessive increase in risk, which may be more dangerous than exposure alone.

ASCVD amplifies lipid-driven renal injury through synergistic pathways:systemic inflammation promotes LDL oxidation to pro-atherogenic ox-LDL (29, 30), activating pro-fibrotic TGF-β signaling in glomerular cells. Endothelial dysfunction impairs renal vascular integrity, enhancing subendothelial retention and oxidation of atherogenic lipoproteins like oxidized LDL (31, 32), which directly induce podocyte injury, mesangial cell apoptosis, and tubular epithelial cell damage via lipid peroxidation and ER stress. Atherosclerotic renal hypoperfusion activates the renin-angiotensin-aldosterone system (RAAS) (33, 34), accelerating proteinuria and tubulointerstitial fibrosis.

Limitations include: first, the cross-sectional design limits causal inference and risks reverse causation. Second, residual confounding from unmeasured variables such as dietary patterns and genetic polymorphisms in lipid metabolism genes like APOE or PCSK9 cannot be ruled out. Such factors may independently modulate systemic lipid exposure and renal lipid metabolism. Lack of medication data (e.g., RAAS inhibitors) and diabetes duration may introduce residual confounding. Future studies should incorporate these variables. Future research should validate lipid thresholds through multicenter studies, assess the impact of threshold-directed lipid management on DKD incidence via interventional trials, and define optimal lipid target ranges. Additionally, mechanistic studies should clarify ASCVD-lipid metabolism interactions, especially concerning oxidative stress and RAAS pathways, for comprehensive pathophysiological insights. Despite these limitations, this work provides significant evidence for early DKD prevention by emphasizing nonlinear risk patterns and ASCVD in lipid management. It shifts lipid management from universal numerical targets to precision threshold-based approaches, ultimately facilitating personalized lipid control and organ-specific protection.

This research explores the link between blood lipids and DKD risk, highlighting the effect of ASCVD on these associations. Key findings indicate that in diabetic patients with ASCVD, LDL-C and TC were linearly related to DKD risk; and only TG exhibited a significant nonlinear association. In contrast, diabetic patients without ASCVD displayed significant nonlinear threshold effects for all four lipids on DKD risk. Importantly, interaction analysis revealed that ASCVD accelerated the nephrotoxic effects of TC and LDL-C. These results emphasize distinct clinical implications: diabetic patients with ASCVD need strict control of TC and LDL-C levels to reduce DKD risk, whereas those without ASCVD benefit from threshold-based lipid management. This work provides essential evidence for personalized clinical decision-making and suggests the need for future research into synergistic ASCVD-lipid mechanisms and targeted therapies.