Effect of statin therapy on renal and lipid outcomes in CKM syndrome stage 2: a meta-analysis of randomized controlled trials

Abstract

Cardiovascular–kidney–metabolic (CKM) syndrome is a recently defined multisystem disorder integrating metabolic, renal, and cardiovascular dysfunction. CKM syndrome stage 2 represents an early, potentially reversible phase that offers a critical window for intervention. This meta-analysis evaluated the effects of statin therapy on renal and lipid outcomes in this population. 7 randomized controlled trials involving 490 participants were included. In the primary analysis, statin therapy showed a directionally favorable but non-significant trend toward improved estimated glomerular filtration rate (eGFR) and reduced 24-hour urinary total protein excretion (24h UTP), with no significant change in serum creatinine (Scr). Statins significantly reduced LDL-C (MD = − 52.18) and total cholesterol (MD = − 52.70), while changes in HDL-C and triglycerides were not significant. Subgroup analyses indicated numerically greater renal and lipid benefits with high-intensity regimens, longer treatment duration (≥ 26 weeks), and lower baseline eGFR, though no significant subgroup interactions were detected. Sensitivity analysis including a borderline CKM syndrome 2–3 trial characterized by higher renal risk, longer duration, and high-intensity atorvastatin rendered both renal and lipid outcomes statistically significant without altering effect direction. These findings suggest that statin therapy confers robust lipid-lowering efficacy and potential renoprotective effects in early CKM syndrome stages, particularly under conditions of greater baseline metabolic or renal burden. Statins may therefore serve as an early metabolic–renal intervention, warranting further validation in larger, stage-specific clinical trials.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12882-025-04645-8.

Trial registration

This study was prospectively registered in the PROSPERO international prospective register of systematic reviews (CRD420251078940).

Supplementary Information

The online version contains supplementary material available at 10.1186/s12882-025-04645-8.

Clinical trial number

Not applicable.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12882-025-04645-8.

Introduction

Cardiovascular–kidney–metabolic (CKM) syndrome is a systemic disease construct defined by the coexistence of metabolic dysfunction, chronic kidney disease (CKD), and cardiovascular disease (CVD). First formally introduced by the American Heart Association (AHA) in 2023 [1], CKM syndrome is not merely the coincidental presence of three distinct conditions but a unified pathological entity, driven by metabolic toxicity and reinforced through complex, multisystem interactions. Its prevalence varies widely across populations, reaching up to 90% among certain groups, such as adults in the United States [2, 3].The pathogenesis of CKM syndrome involves more than the additive effects of its individual components. Instead, it reflects a synergistic cascade initiated by metabolic disturbances—such as lipotoxicity and glucotoxicity—that activate chronic inflammation, oxidative stress, and neurohormonal dysregulation. These interconnected mechanisms create a self-perpetuating cycle that destabilizes metabolic homeostasis, impairs renal function, and damages cardiovascular integrity, thereby accelerating end-organ injury [4, 5]. Within the CKM syndrome staging framework, stage 2 represents a particularly critical phase, accounting for over 40% of diagnosed cases [6–8]. Patients at this stage have not yet developed overt cardiovascular events but typically present with one or more metabolic abnormalities and/or moderate-to-high-risk CKD, reflecting early multisystem pathophysiological activation. Importantly, this phase is considered highly reversible and offers a favorable therapeutic window in which early intervention can produce meaningful clinical benefit [9]. Given its complex etiology and rising global burden, CKM syndrome poses a significant public health challenge. Addressing this condition requires integrated, multisystem management strategies that go beyond conventional single-disease frameworks and target its shared underlying mechanisms.

As the cornerstone of lipid-lowering therapy, statins have been extensively used across the major components of CKM syndrome—including CVD, CKD, and type 2 diabetes mellitus (T2DM)—with well-established clinical benefits in each domain [5]. In addition to their potent lipid-lowering and cardioprotective effects, statins possess pleiotropic properties, including anti-inflammatory, antioxidant, and antifibrotic actions, which may contribute to slowing renal function decline in CKM syndrome patients. These multifaceted effects suggest that statins may serve as a central therapeutic agent targeting the shared pathophysiological axes of CKM syndrome. However, the complex interplay among metabolic, renal, and cardiovascular systems in CKM syndrome forms a non-linear, self-reinforcing network, where dysfunction in one system can amplify pathology in the others, leading to exponential increases in overall disease burden [9]. While the efficacy of statins is well documented in isolated conditions, it remains unclear whether these benefits translate into comparable multisystem synergy within the integrated framework of CKM syndrome. Currently, there is a lack of systematic evidence specifically evaluating statin efficacy in this context, highlighting an urgent need for integrated analyses and clinical validation within the CKM syndrome model.

Given the complex, multisystem nature of CKM syndrome, current treatment strategies emphasize multidisciplinary and integrative management—encompassing lifestyle modification, targeted therapy for underlying conditions, and comprehensive risk factor control [10]. However, research specifically addressing the CKM syndrome population remains in its infancy. To date, prospective clinical trials stratified by defined CKM syndrome stages are lacking, and most available evidence stems from studies focused on individual diseases in isolation. Consequently, there has been no systematic evaluation of therapeutic efficacy within the context of the CKM syndrome staging framework. In this context, the present study conducted a meta-analysis to evaluate the effects of statin therapy on renal function and lipid profile in patients with CKM syndrome stage 2. The primary objective was to clarify the clinical efficacy and therapeutic value of statins under the conditions of multisystem comorbidity that define CKM syndrome. By generating stage-specific, evidence-based insights, this study aims to inform early and comprehensive intervention strategies for CKM syndrome stage 2 patients, thereby advancing precision medicine approaches and supporting optimized clinical decision-making in this high-risk population.

Methods

This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines [11] (Supplementary Table 1). The study protocol was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO; Registration No. CRD420251078940).

Data sources and search strategy

A comprehensive literature search was conducted in PubMed, Embase, the Cochrane Library, and Web of Science from database inception to May 29, 2025. The search strategy employed a combination of Medical Subject Headings (MeSH) and free-text keywords, including but not limited to: “statin,” “Hydroxymethylglutaryl-CoA Reductase Inhibitors,” “hypertension,” “diabetes mellitus,” “metabolic syndrome,” “chronic kidney disease,” and “randomized controlled trial” (see Supplementary Table 2 for full search strategy). Additional sources were identified by manually screening the reference lists of relevant articles, clinical guidelines, conference proceedings, and trial registries.

Inclusion and exclusion criteria

Eligible studies were randomized controlled trials (RCTs) involving adults diagnosed with CKM syndrome stage 2, as defined by the AHA 2023 criteria. CKM syndrome stage 2 was characterized by the presence of one or more metabolic risk factors (e.g., hypertension, diabetes, hypertriglyceridemia, or metabolic syndrome) and/or moderate- to high-risk CKD without established cardiovascular disease; stage 3, subclinical CVD in CKM syndrome or risk equivalents (high predicted CVD risk or very high-risk CKD) [10].To be included, studies were required to compare a treatment group receiving statins alone with a control group receiving placebo. Only studies published in English were considered.

Inclusion further required the reporting of at least one relevant renal outcome. Studies were excluded if they were non-randomized, reviews, case reports, basic science studies, or retrospective in design. Trials with incomplete or missing outcome data, duplicate publications (with only the most recent or comprehensive version retained), or those lacking a control group or relevant outcomes were also excluded.

Data extraction and quality assessment

Two reviewers independently screened titles, abstracts, and full-text articles, and extracted data using a standardized form. Extracted information included study characteristics (e.g., first author, publication year, sample size), participant demographics, treatment and control protocols, and outcome measures. The primary renal outcomes were estimated glomerular filtration rate (eGFR), serum creatinine (Scr) and 24-hour urinary total protein excretion (24h UTP). eGFR was extracted as reported in each trial. When not specified, it was assumed that eGFR was calculated using a creatinine-based equation (MDRD or CKD-EPI). Secondary outcomes included serum creatinine levels and lipid parameters, such as total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). The methodological quality of included studies was evaluated using the Cochrane Risk of Bias 2.0 (ROB 2.0) tool [12]. Any discrepancies between reviewers were resolved through discussion with a third reviewer. The overall certainty of evidence for each outcome was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach [13].

Statistical analysis

Meta-analysis was conducted using RevMan version 5.4. For continuous outcomes, pooled effect estimates were expressed as mean differences (MD) or standardized mean differences (SMD), while dichotomous outcomes were analyzed using odds ratios (ORs), each with corresponding 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the chi-squared test and quantified with the I² statistic. A fixed-effects model was applied when heterogeneity was low (P >0.10 and I² < 50%); otherwise, a random-effects model was used to account for between-study variability [14]. Sensitivity analyses were performed by sequentially excluding individual studies to assess the robustness of the pooled results.

Publication bias was evaluated through visual inspection of funnel plots to detect potential small-study effects. In addition to subgroup analyses for outcomes with high heterogeneity, exploratory subgroup analyses were also conducted for outcomes with low statistical heterogeneity but high clinical relevance. Stratification variables included statin intensity (high vs. moderate), intervention duration (≥ 26 weeks vs. <26 weeks), presence of diabetes, and baseline eGFR (< 60 vs. ≥60 mL/min/1.73 m²), with the aim of comparing effect estimates across subgroups and exploring potential interactions.

Results

Literature screening and included studies

A comprehensive search of four English-language databases initially identified 11,849 records. After removing 4,706 duplicates, 7,143 records remained for title and abstract screening. Of these, 7,031 were excluded due to irrelevance to the study topic, target population, or intervention of interest. The full texts of the remaining 127 articles were retrieved and assessed for eligibility. A total of 120 studies were excluded for the following reasons: full text unavailable (n = 12); study population not meeting predefined inclusion criteria (n = 46); absence of relevant renal outcomes (n = 39); non-conforming intervention group (n = 7); inappropriate control group (n = 6); ineligible study design (n = 7); and duplicate publication (n = 3). Ultimately, six RCTs met al.l inclusion criteria and were included in the meta-analysis(Fig. 1). An additional study by Bianchi et al. [15]. was included only in sensitivity analyses to test result robustness. Although a subset of participants in that trial met criteria for CKM syndrome stage 3 due to very high–risk CKD, none had clinical or subclinical cardiovascular disease—the defining criterion separating stage 3 from stage 2. Therefore, the study was considered to represent a borderline CKM syndrome stage 2–3 population suitable for sensitivity testing.

Fig. 1.

Flowchart showing study retrieval and inclusion

Characteristics of included studies

This meta-analysis included 6 RCTs involving 434 participants as the primary analysis, and one additional borderline CKM syndrome stage 2–3 trial (Bianchi 2003; n = 56) for sensitivity analysis, yielding a total of 490 participants considered across analyses. These studies were conducted across diverse geographic regions, including the United States, Denmark, Italy, Japan, and Greece. All studies enrolled adult participants compared statin monotherapy (treatment group, T) with placebo (control group, C). Sample sizes per group ranged from 9 to 52 participants, with follow-up durations between 12 and 52 weeks. The mean age of participants across studies ranged from 35 to 74 years. Baseline eGFR varied from 42.3 to 72 mL/min/1.73 m², though one study did not report this parameter. Baseline BMI ranged from 19.19 to 29.6 kg/m², with BMI data unavailable in one study. Two trials had treatment durations shorter than 26 weeks, while the remaining five reported follow-up periods between 26 and 52 weeks. Of the seven included trials, three reported 2h UTP as a renal outcome, while one study (Abe 2011) measured urinary albumin-to-creatinine ratio (UACR); the latter was excluded from pooled analysis due to incompatibility with 24h UTP data. All included trials reported outcomes related to renal function and lipid profiles. The variation in sample size, follow-up duration, and baseline characteristics highlights the heterogeneity of the study populations and supports the need for subgroup and sensitivity analyses to ensure the reliability of pooled estimates (see Table 1).

Table 1.

Baseline characteristics of included studies

Study	Country	Sample (T/C)	Age(year) (T/C)		BMI (T/C)		eGFR(mL/min/1.73m2) (T/C)		24h UTP (g/24 h) (T/C)		Intervention	Dose and frequeney	Follow-up	Risk factors	Outcome
Hommel 1992 [16]	Denmark	12/9	41 ± 9	35 ± 4	24.5 ± 4	23.6 ± 3	64 ± 30	72 ± 23	0.70 ± 0.39	0.76 ± 0.44	simvastatin	10 to 20 mg QD	12w	DM, CKD	①②,④-⑦
Imai 1999 [17]	Japan	26/17	58.5 ± 9.2	49.5 ± 11.4	22.27 ± 4.61	19.19 ± 5.22	68.5 ± 8.1	62.8 ± 9.9	1.1 ± 0.24	1.4 ± 0.29	pravastatin	5 to 10 mg QD	26w	HT, HTG, CKD	①-⑦
Bianchi 2003 [15]	Italy	28/28	55.6 ± 7.48	55.6 ± 7.48	27.6 ± 1.95	27.6 ± 1.95	47.18 ± 8.91	47.18 ± 8.91	2.5 ± 1.85	1.9 ± 1.48	atrorvastain	10 to 40 mg QD	52w	CKD	①②,④-⑦
Verma 2005 [18]	America	44/39	73 ± 10	74 ± 19	NA	NA	42.3 ± 11.1	49.4 ± 11.9	NA	NA	rosuvastatin	10 mg QD	20w	CKD	①②,④-⑦
kanaki 2011 [19]	Greece	25/25	59.7 ± 8.9	58.8 ± 10.8	29.4 ± 4.3	29.6 ± 3.8	NA	NA	NA	NA	atrorvastain	10 mg QD	26w	HT	②,④-⑦
Abe 2011 [20]	Japan	52/52	64.5 ± 9.6	64.9 ± 9.2	22.7 ± 2.3	22.9 ± 2.7	70.4 ± 11.9	69.3 ± 9.5	NA	NA	rosuvastatin	2.5 to 10 mg QD	26w	DM, CKD	①②,④-⑦
Takazakura 2014a [21]	Japan	35/43	60 ± 11	63 ± 11	23.8 ± 3.3	24.3 ± 3.2	64.0 ± 18.0	61.4 ± 16.0	NA	NA	atrorvastain	10 mg QD	52w	DM, CKD	①,④-⑦
Takazakura 2014b [21]	Japan	28/43	63 ± 11	63 ± 11	23.4 ± 3.0	24.3 ± 3.2	66.3 ± 17.0	61.4 ± 16.0	NA	NA	pravastatin	10 mg QD	52w	DM, CKD	①,④-⑦

Note: T: statins group; C: placebo group. Risk factors: DM: Diabetes Mellitus, HT: Hypertension, HTG: Hypertriglyceridemia, MS: Metabolic Syndrome, CKD: Moderate to high-risk CKD. Outcomes: ① estimated glomerular filtration rate (eGFR), ② 24-hour urinary total protein excretion (24h UTP), ③ serum creatinine(Scr), ④ total cholesterol (TC), ⑤ triglycerides (TG), ⑥ low-density lipoprotein cholesterol (LDL-C), ⑦ high-density lipoprotein cholesterol (HDL-C)

Risk of bias assessment

Risk of bias was assessed for all seven included RCTs using the RoB 2.0 tool. Detailed evaluations are presented in Figs. 2 and 3. Overall, only one study was judged to have a low risk of bias across all domains, while the remaining trials were rated as having “some concerns,” indicating a moderate level of methodological quality. All studies were deemed low risk in the domains of outcome measurement (Domain 4) and selection of the reported result (Domain 5), suggesting that outcome assessment and reporting were generally appropriate and consistent. However, frequent concerns were noted in the domains related to the randomization process (Domain 1) and deviations from intended interventions (Domain 2), primarily due to the use of open-label designs. In several cases, limited reporting on random sequence generation, allocation concealment, or blinding procedures contributed to the uncertainty in risk assessments. The predominant sources of bias arose from suboptimal implementation or insufficient reporting of key randomization and blinding procedures, potentially compromising internal validity and introducing performance or detection bias. These methodological limitations should be considered when interpreting the pooled effect estimates and underscore the need for sensitivity analyses to assess the robustness of the findings.

Fig. 2.

Risk of bias graph

Fig. 3.

Risk of bias summary

Renal outcomes

This meta-analysis evaluated three renal outcomes to assess the effects of statin therapy on kidney function in patients with CKM syndrome stage 2: eGFR, 24h UTP and Scr. Given the relatively low heterogeneity observed for these outcomes (eGFR: I² = 0%; 24 h UTP: I² = 0%; Scr: I² = 37%), fixed-effects models were applied throughout. Statin therapy did not significantly improve eGFR (MD = 2.00; 95% CI [− 0.87, 4.87]) or reduce 24h UTP (SMD = − 0.18; 95% CI [− 0.70, 0.34]) compared with placebo. Scr showed a slight but non-significant trend toward reduction (SMD = − 0.11; 95% CI [− 0.34, 0.12]) (Fig. 4). These findings suggest that, within strictly defined CKM syndrome stage 2 populations, the renoprotective effects of statin therapy did not reach statistical significance during the study periods examined.

Fig. 4.

Forest plots comparing renal outcomes. (A) eGFR, estimated glomerular filtration rate; (B) 24h UTP, 24-hour urinary total protein excretion; (C) Scr, serum creatinine levels

Subgroup analyses were conducted for eGFR based on statin intensity (high vs. moderate), intervention duration (≥ 26 weeks vs. <26 weeks), and diabetes status (Supplementary Table 3). Across all comparisons, statin therapy showed a consistent but non-significant trend toward eGFR improvement. Effect directions were similar between high and moderate-intensity statins, short (< 26 weeks) and longer (≥ 26 weeks) treatments, and patients with or without diabetes. No significant subgroup interactions were observed (all P > 0.05), although the direction of effects remained consistent across subgroups.

Lipid profile

In the primary CKM syndrome stage 2 analysis, statin therapy improved all four lipid metabolism parameters compared with placebo, although not all changes reached statistical significance. Due to substantial heterogeneity observed in LDL-C (I² = 88%), TC (I² = 82%), and TG (I² = 57%), random-effects models were applied for these outcomes, whereas HDL-C (I² = 7%) was analyzed using a fixed-effects model (Fig. 5). Pooled estimates demonstrated significant reductions in LDL-C (MD = − 52.18; 95% CI [–66.33, − 38.04]) and TC (MD = − 52.70; 95% CI [–66.21, − 39.19]), while improvements in HDL-C and TG did not reach statistical significance. These findings indicate that statin therapy confers a favorable lipid-lowering trend in CKM stage 2 populations, with significant effects primarily on LDL-C and TC.

Fig. 5.

Forest plots comparing lipid profile. (A) LDL-C, low-density lipoprotein cholesterol; (B) HDL-C, high-density lipoprotein cholesterol; (C) TC, total cholesterol; (D) TG, triglycerides

Marked heterogeneity in LDL-C and TC prompted subgroup analyses to explore potential effect modifiers (Supplementary Table 3). These analyses were stratified by statin intensity, treatment duration, diabetes status, and baseline renal function. Across all strata, statin therapy consistently reduced LDL-C and TC levels, indicating a robust lipid-lowering effect. High-intensity statin therapy yielded greater reductions in LDL-C and TC than moderate-intensity regimens, but subgroup differences were not statistically significant. Comparable lipid improvements were also observed across treatment durations, diabetes status, and baseline eGFR categories, indicating consistent lipid-lowering efficacy regardless of clinical characteristics. Collectively, these findings suggest that while statin intensity and patient profile may influence the magnitude of response, the overall lipid-lowering effect of statins in CKM syndrome stage 2 remains broadly stable across clinical subgroups.

Sensitivity analysis, publication bias, and evidence certainty

Sensitivity analyses were conducted for all seven outcomes assessed in this meta-analysis. Sequential exclusion of individual studies resulted in minimal changes in pooled effect sizes or directions, indicating good robustness and consistency of the overall findings (Supplementary Fig. 1).

For both renal and lipid outcomes, inclusion of Bianchi 2003 study—a borderline CKM syndrome stage 2–3 trial—modified the statistical significance of the pooled estimates while maintaining consistent effect directions. In the primary analysis, neither eGFR nor 24h UTP showed significant improvement. After inclusion of the Bianchi trial, both outcomes reached statistical significance (eGFR: MD = 2.68; 95% CI [0.33, 5.04]; 24h UTP: SMD = − 0.48; 95% CI [− 0.86, − 0.10]) (Supplementary Fig. 3).

Similarly, for lipid parameters, the addition of this study increased the magnitude and significance of the lipid-lowering effects. Reductions in LDL-C and TC became more pronounced, while improvements in HDL-C and TG, previously non-significant, achieved statistical significance (HDL-C: MD = 1.95; 95% CI [0.09, 3.81]; TG: SMD = − 0.24; 95% CI [− 0.42, -0.07]) (Supplementary Fig. 3). Collectively, these findings suggest that inclusion of borderline high-risk CKM syndrome populations may amplify the detectable therapeutic benefits of statins across both renal and metabolic domains.

Funnel plot analyses showed relatively symmetrical distributions for eGFR, TG, and LDL-C, suggesting a low risk of publication bias. However, mild asymmetry was observed for Scr, 24h UTP, and TC, likely influenced by small-sample studies. Moreover, several outcomes were derived from a limited number of trials, necessitating cautious interpretation of potential bias (Supplementary Fig. 2). According to the GRADE framework, the overall certainty of evidence for the primary outcomes was rated as low. This assessment was primarily due to concerns regarding risk of bias, small sample sizes, and substantial heterogeneity across studies (Supplementary Table 4).

Discussion

Primary findings

This meta-analysis systematically synthesized evidence from 7 randomized controlled trials evaluating the effects of statin therapy in CKM syndrome stage 2 populations. Statin therapy did not produce statistically significant improvements in any renal outcomes, including eGFR, 24h UTP, and Scr, although all showed modest trends toward renal benefit. Subgroup analyses yielded consistent effect directions across statin intensity, treatment duration, and diabetes status, with no significant interactions observed.

For lipid outcomes, statin therapy significantly reduced TC and LDL-C, while TG and HDL-C showed favorable but non-significant improvements. Subgroup analyses similarly revealed consistent lipid-lowering trends across treatment intensities, durations, and baseline renal function, without statistically significant subgroup interactions.

Renal outcomes

In this meta-analysis, statin therapy did not produce statistically significant improvements in eGFR, 24h UTP, or Scr among patients with CKM syndrome stage 2, although all three indicators showed directionally favorable trends. These findings suggest that while statins may exert renoprotective effects, the magnitude of benefit in early CKM syndrome populations is limited. This likely reflects the reversible nature of CKM syndrome stage 2, in which renal injury is primarily functional rather than structural, and the narrow baseline variability that constrains detectable between-group differences. Therefore, the observed non-significance may indicate subclinical therapeutic activity that falls below the statistical threshold for detection in early-stage disease.

Sensitivity analysis incorporating Bianchi et al. [15].—a trial enrolling patients at the CKM syndrome stage 2–3 boundary—altered the statistical significance of the pooled renal estimates while maintaining consistent effect directions. Methodologically, this study contributed substantial analytic weight due to its longer treatment duration (52 weeks) and use of high-intensity atorvastatin (40 mg), thereby increasing statistical power. Clinically, a subset of participants exhibited very high-risk CKD features (mean eGFR ≈ 47 mL/min/1.73 m²; proteinuria >1.5 g/day) without subclinical cardiovascular disease, representing a renal-severity–driven transition between CKM syndrome stages 2 and 3 rather than a typical stage 3 profile. The shift to statistical significance therefore likely reflects enhanced detectability of statin-related renal benefits in populations with greater baseline renal and metabolic burden, highlighting that disease severity and treatment intensity are key modifiers of measurable response.

Subgroup analyses showed consistent but nonsignificant trends toward eGFR improvement across statin intensity, treatment duration, and diabetic status. High-intensity regimens and longer exposure (≥ 26 weeks) produced numerically greater benefits, suggesting a possible dose–time–response relationship [22, 23]. The attenuated renal response observed in diabetic participants contrasts with findings from some previous studies [24, 25]. This discrepancy may be explained by the dominant influence of glucotoxicity and advanced glycation end-products in diabetic kidney injury, which are less responsive to the lipid-lowering and anti-inflammatory actions of statins [24]. Moreover, emerging evidence supports the mortality-reducing efficacy of statins even in advanced CKD and dialysis populations, suggesting a spectrum-wide benefit extending beyond early CKM syndrome stages [26, 27]. However, the absence of significant subgroup interactions (all P >0.05) indicates that these trends remain exploratory and require validation in larger, stratified trials.

Mechanistically, the renoprotective potential of statins is supported by multiple complementary actions, including NF-κB inhibition and suppression of pro-inflammatory cytokines (IL-6, TNF-α) [28, 29], eNOS-mediated improvement of endothelial function [30, 31], and attenuation of TGF-β/Smad-driven fibrotic remodeling [32]. These processes collectively reduce oxidative stress, glomerular injury, and proteinuria progression. Notably, their clinical manifestation may follow a “threshold effect,” becoming apparent only when cumulative metabolic and inflammatory stress surpass a certain level—as in patients with higher baseline renal burden or prolonged, high-intensity statin exposure. This phenomenon explains why significant renoprotective effects emerged after inclusion of the Bianchi 2003 study, while remaining subclinical in strictly defined CKM syndrome stage 2 populations. Collectively, these results suggest that statins act on key renal injury pathways, but observable functional improvement may require both sufficient disease severity and cumulative pharmacologic exposure.

Lipid profile

In this meta-analysis, statin therapy significantly reduced LDL-C and TC, while modest, non-significant trends toward improvement were observed for HDL-C and TG. These findings indicate a predominant lipid-lowering benefit focused on atherogenic fractions, consistent with the expected pharmacological profile of statins. The limited significance of HDL-C and TG likely reflects the small sample sizes, short treatment durations, and heterogeneity among the included trials.

Sensitivity analyses further demonstrated that the inclusion of the Bianchi 2003 study strengthened both the magnitude and statistical significance of the lipid-lowering effects. This enhancement is attributable to the study’s higher-risk population, longer follow-up, and use of high-intensity atorvastatin, all of which increased the cumulative drug exposure and statistical power. These observations suggest a metabolic “threshold effect,” whereby the benefits of statins become more readily detectable in patients with greater baseline metabolic burden or under higher-intensity interventions—an effect that parallels the pattern seen for renal outcomes.

Subgroup analyses revealed directionally consistent reductions in LDL-C and TC across statin intensity, treatment duration, diabetes status, and baseline renal function, though no significant interactions were observed. Patients receiving high-intensity statins or treated for ≥ 26 weeks tended to achieve larger lipid reductions, supporting a potential dose–time–response trend [33]. These findings reinforce that statins provide robust lipid-lowering efficacy across diverse CKM syndrome stage 2 populations, even if statistical significance for subgroup differences was not achieved.

Mechanistically, the lipid-lowering action of statins results from HMG-CoA reductase inhibition, upregulation of hepatic LDL receptors, and enhanced clearance of circulating LDL particles [34, 35]. In addition, their pleiotropic effects—such as anti-inflammatory, antioxidant, and endothelial-protective actions—may further mitigate lipid-induced renal and vascular injury, thereby linking metabolic correction to renal stabilization [36, 37]. This integrative metabolic–renal improvement highlights statins’ potential as a cornerstone therapy for early CKM syndrome stage 2, when interventions remain most reversible and impactful.

Strengths and limitations

The present study refines, rather than challenges, existing guideline-based evidence. Statin therapy is already recognized as standard care for metabolic and cardiovascular risk reduction across the CKD spectrum, and the AHA 2023 specifically recommends its use in CKM syndrome stage 2 as part of comprehensive cardiometabolic management. By focusing on a strictly defined CKM syndrome stage 2 population, our meta-analysis provides the first quantitative evaluation of statin efficacy within this early, potentially reversible phase, thereby addressing a key evidence gap at the metabolic–renal interface. The lack of statistically significant renal improvement likely reflects stage-specific characteristics—short follow-up, limited sample size, and the functional rather than structural nature of renal injury—rather than contradiction of prior evidence. Methodologically, the inclusion of a borderline CKM syndrome 2–3 sensitivity analysis and predefined subgroup stratifications further enhance interpretability and robustness, distinguishing this work from previous single-system or mixed-stage CKD meta-analyses.

Nonetheless, several limitations warrant consideration. First, the small number of included trials and limited sample sizes for several outcomes reduce statistical precision and may limit generalizability. Second, statistical significance in sensitivity analyses was partially driven by a high-risk cohort, indicating that detectable benefits may depend on baseline disease severity and cumulative statin exposure rather than uniform population-wide effects. Third, substantial heterogeneity in statin types, dosages, and treatment durations may have influenced pooled estimates despite consistent effect directions. In addition, incomplete reporting of randomization, allocation concealment, or blinding in several trials introduced potential risks of bias. Finally, most included studies had relatively short follow-up periods, restricting the ability to assess long-term renal or cardiovascular outcomes.

Given these limitations, the present results should be viewed as exploratory yet hypothesis-generating evidence, providing mechanistic and methodological guidance for future large-scale, long-duration RCTs designed to clarify the stage-specific benefits of statin therapy in CKM syndrome populations.

Conclusion

In conclusion, this study provides the first integrated meta-analytic evidence exploring the effects of statin therapy in CKM syndrome stage 2. Statin treatment was associated with significant lipid-lowering benefits and a trend toward renal protection, suggesting potential dual metabolic–renal effects during the early, reversible phase of CKM syndrome. However, given the small number of trials, moderate risk of bias, and dependence of statistical significance on higher-risk subgroups, these findings should be interpreted as hypothesis-generating rather than practice-changing.

Statins may nonetheless represent a promising therapeutic option for early metabolic modulation, when functional renal alterations remain reversible. Future large-scale, long-duration RCTs are warranted to confirm these effects and to identify stage-specific phenotypes or biomarkers that predict therapeutic responsiveness.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

Shuai Lin and Ruxin Liu contributed equally as co–first authors. They designed the study, collected data, and performed the analyses. Wenrui Huang assisted with data extraction and quality assessment. Li Liu and Bing Zhang contributed to literature search and data verification. Juan Xu helped with manuscript drafting and figure preparation. Yanlin Li supervised the study, revised the manuscript critically, and approved the final version. All authors read and approved the manuscript and agree to be accountable for the work.

Funding

This work was supported by the National Demonstration Pilot Project for the Inheritance and Development of Traditional Chinese Medicine -Construction project between Guangzhou University of Chinese Medicine and Zhongshan Hospital of Traditional Chinese Medicine (No. GZYZS2024U19); National Demonstration Pilot Project for the Inheritance and Innovative Development of Traditional Chinese Medicine - Research Project on Traditional Chinese Medicine at Zhongshan Hospital of Traditional Chinese Medicine (No.YN2024A007); National Key Specialty of Traditional Chinese Medicine Program (Nephrology Department, Zhongshan Hospital of Traditional Chinese Medicine); Research Project of Guangdong Provincial Administration of Traditional Chinese Medicine (20251436); Zhongshan Social Welfare Science and Technology Research Project (2021B3006).

Data availability

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/Supplementary Material.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.