INTRODUCTION
Statins are fungus-derived compounds. Since lovastatin was commercialized, seven statins have become available, excluding cerivastatin, which the company withdrew because of fatal myopathy [1-4]. The successful development of statins has led to remarkable reduction in the cardiovascular (CV) mortality rates. Lowering low-density lipoprotein cholesterol (LDL-C) to 2 to 3 mmol/L (approximately 76 to 116 mg/dL) can reduce 40% to 50% of myocardial infarction (MI), coronary death, stroke, or coronary revascularization [5]. Studies support the use of statins for the primary prevention of CV cardiovascular diseases (CVD), including MI risk reduction (odds ratio [OR], 0.72; 95% confidence interval [CI], 0.66 to 0.78), stroke reduction (OR, 0.8; 95% CI, 0.72 to 0.89), and reduced death from all CVD (OR, 0.83; 95% CI, 0.76 to 0.91), emphasizing that their absolute benefits across various clinical trials [4]. However, statins do not completely prevent every CVD event. Despite guideline-based drugs use and risk stratification, 10% of patients still experience CV mortality [6]. This is called that ‘residual CV risk,’ a persistent risk of CV events even after LDL-C target optimization. Additional therapeutic options including ezetimibe and new drugs including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors would have potential role for better CVD management [7,8]. First of all, in this paper, we will focus on statins in chronic kidney disease (CKD). CKD and metabolic syndrome can directly contribute to CVD, lipid metabolism abnormalities can arise from kidney dysfunction itself.
According to clinical guidelines for dyslipidemia treatment in CKD, CKD is considered a risk factor for CVD risk factor [9,10]. Specifically, when the estimated glomerular filtration rate (eGFR) falls below 60 mL/min/1.73 m² and LDL-C levels are elevated, statin therapy is recommended, as clearly noted in the Korean dyslipidemia guidelines [11]. High LDL-C levels are not only a risk factor for CVD but also contribute to CKD progression [12,13]. Similarly, elevated triglyceride (TG) levels are associated with CKD progression and an increased risk of CVD [14]. However, statins cannot control every single component of dyslipidemia. Therefore, the role of statins in CKD must be understood from a pathophysiological perspective. To explore this, it is important to examine lipid profile components.
DYSLIPIDEMIA IN CKD AND END-STAGE KIDNEY DISEASE
It is important to note that high serum LDL-C levels are not just the prominent feature of uremic dyslipidemia [15]. First, patients with CKD often exhibit mixed dyslipidemia, characterized by elevated TG and reduced high-density lipoprotein cholesterol (HDL-C) levels, requiring different treatment strategies from those used in the general population. The imbalanced part of lipid metabolism including increased TG and decreased HDL-C levels and their ratio, TG/HDL-C ratio has been proposed as a biomarker for CVD risk prediction [16]. HDL-C is generally considered cardioprotective. However, in patients with CKD, excessively high or low HDL-C levels have been reported to accelerate renal function detorioration [17]. Compared to the general population, where HDL-C is traditionally considered protective, this study found a U-shaped association between HDL-C levels and CKD progression. Low (< 30 mg/dL) and high (≥ 60 mg/dL) HDL-C levels are linked to an increased risk of adverse renal outcomes, including a 50% decline in eGFR and progression to end-stage kidney disease (ESKD). Patients with CKD often present with dyslipidemia, characterized by low HDL-C levels and elevated TG levels and oxidized LDL-C levels. However, HDL dysfunction is a critical issue in CKD, as inflammation and oxidative stress modify its composition, leading to reduced cholesterol efflux and proinflammatory properties, explaining why high HDL-C levels in patients with CKD might not be beneficial and instead reflect dysfunctional HDL particles.
Second, altered pharmacokinetics of statins in patients with CKD raised concerns regarding drug efficacy and safety. Reduced renal function affects drug metabolism and excretion, necessitating careful dose adjustments to avoid adverse effects. Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I) study, not powered for a direct comparison between the two statins, showed a different renal profile in CKD population [18]. These two statins have differential impact on renal damage supported by proteinuria as well as eGFR based on cystatin C. The atorvastatin 80 mg group showed proteinuria-protective effect (OR, 0.87; 95% CI, 0.77 to 0.99; P= 0.033) and the rosuvastatin 40 mg group showed eGFR decline—9.5 mL/min/1.73 m2 at week 52 (95% CI, –16 to –3; P= 0.0045). Drug-specific characteristics and dosages are associated with an increased risk of hematuria, proteinuria, and the even need for kidney replacement therapy [19]. Shin et al. [19] reviewed the natural course of statin use based on real-world data. The effects of rosuvastatin and atorvastatin were compared revealing that rosuvastatin users have a slightly higher risk of hematuria, proteinuria, and ESKD than atorvastatin users, despite similar CV benefits. A dose-related risk was observed, particularly in patients with severe CKD, among whom nearly 45% were on rosuvastatin doses exceeding the U.S. Food and Drug Administration recommendations (maximum rosuvastatin dose of 10 mg/day for CKD patients). Mechanistically, high-dose statins may impair protein uptake in kidney tubules and induce mitochondrial dysfunction. Rosuvastatin is accumulating more in CKD due to higher renal excretion, as noted in preapproval trials at a dose-dependent risk of proteinuria with rosuvastatin ≥ 40 mg. High-potency statins were also linked to increased acute kidney injury (AKI) risk.
Another consideration is the potential impact of inflammation and oxidative stress on lipid metabolism in patients with CKD. Chronic inflammation, prevalent in CKD, alters lipid profiles and contributes to CV risk. Moreover, protein-energy wasting, a common phenomenon in advanced CKD, may influence lipid levels and complicate treatment decisions. Hemodialysis patients with LDL-C levels below 100 mg/dL exhibit higher mortality rates [12]. This observation predated the widespread statin use, suggesting that malnutrition and inflammation played a significant role in increasing mortality risk. Besides malnutrition and inflammation, complicated comorbidities including frailty, sarcopenia, general poor performance status, and chronic disease burdens also contribute to lower LDL-C levels. Malnutrition remains one of the strongest risk factors for mortality, significantly affecting overall health and survival. It weakens the immune system, increases vulnerability to infections, and exacerbates chronic diseases. Malnutrition is often associated with higher complication rates and poorer outcomes in hospitalized patients and those with severe illnesses. In older adults and individuals with chronic conditions, such as cancer or kidney disease, inadequate nutrition accelerates disease progression and increases the risk of death. Addressing malnutrition through early intervention and proper nutritional support is essential for improving patient outcomes and reducing mortality rates. Hypocholesterolemia is a risk factor of poor outcomes, particularly in patients on dialysis. The inverse association between low LDL-Ｃ and survival may reflect underlying malnutrition-inflammation-atherosclerosis (MIA) syndrome rather than a direct protective effect of higher LDL-Ｃlevels [20-22].
STATIN AS A SAVIOR
Given the high CV risk in patients with CKD and ESKD, it is evident that incorporating current guideline-based recommendations into clinical practice is essential for these populations. Statins have pleiotropic benefits, including renoprotective effects and CVD prevention. Statin therapy slows eGFR decline in CKD 3b to 5 patients with eGFR less than 45 mL/min/1.73 m2 [23]. Statins may have beneficial effects in reducing albuminuria [24,25]. Vogt et al. [26] reported that atorvastatin preserved kidney function. They analyzed six randomized clinical trials (RCTs) comparing atorvastatin 10 mg, 80 mg, and placebo, conducting a post hoc analysis. The serum creatinine slope estimates indicated greater improvement with atorvastatin 80 mg compared with atorvastatin 10 mg or placebo.
A significant negative association was observed between kidney function decline and CV outcomes, indicating that better kidney function is associated with lower CV risk. Although Kidney Disease: Improving Global Outcomes (KDIGO) guidelines do not actively recommend statin use in these patients, statins are often continued in patients already on statins or initiated in patients with severe CVD with elevated LDL-Ｃ levels. Analyses of real-world data consistently reported that statin therapy remains beneficial, even in patients with CKD and patients on dialysis. A retrospective cohort study of United States veterans transitioning to dialysis showed that statin continuation was associated with lower all-cause mortality (21.9 deaths per 100 person-years vs. 30.3 deaths per 100 person-years) and CV mortality (8.1 deaths per 100 person-years vs. 9.8 deaths per 100 person-years) compared to statin discontinuation [27]. Adjusted analyses confirmed these benefits, with hazard ratios (HR) of 0.72 for all-cause mortality and 0.82 for CV mortality, favoring statin continuation. These associations were consistent across subgroups, including age, race, and diabetes status. Using the Korean Health Insurance Review and Assessment Service (HIRA) database, statin use in patients on dialysis, particularly in combination with ezetimibe, was associated with a lower risk of all-cause mortality. Moreover, the study found that discontinuation of statin therapy was associated with an increased risk of mortality [28]. Similar effects were observed in a Taiwanese cohort [29]. In the Observational Medical Outcomes Partnership Common Data Model (OMOP-CDM) from the two hospitals, statin users had significantly lower all-cause and CV mortality rates compared to non-users. The Korean National Health Insurance dataset also validated that the mortality benefit of statins was consistent across all subgroups, regardless of dialysis status or other conditions [30]. Ghayda et al. [31] reviewed 14 meta-analyses and found that statins improved all-cause and CV mortality in non-dialysis patients with CKD.
Since lovastatin introductions, the first statin, statins have been established as highly successful drugs, with extensive large-scale clinical trials. Numerous studies have demonstrated the protective effects of CVD and their association with reduced overall mortality. Subsequently, intensive research has focused on specific patient populations. Although studies targeting patients with kidney disease have not yielded promising results, follow-up studies are ongoing (Fig. 1). The Die Deutsche Diabetes Dialyse study (4D) study, A study to evaluate the Use of Rosuvastatin in subjects On Regular haemodialysis (AURORA), and Study of Heart and Renal Protection (SHARP) trials did not achieve primary outcome [32-34]. However, post hoc analysis identified clues regarding subpopulation in which treatment could be effective. The post hoc analysis of the 4D trial identified that patients with an initial LDL-C level > 145 mg/dL had fatal and non-fatal CV risks and allcause death [32]. Another 4D post hoc analysis reported that ESKD patients encountered more sudden cardiac deaths and infection/sepsis [35]. During the median 4-year follow-up, 49% of the patients died, indicating that atorvastatin might require 1 to 2 years to stabilize CV risk in this high-risk population, This implies that statins may not provide immediate or short-term protective effects but could reduce CV risk with long-term treatment. These findings indicate that in patients with diabetes on hemodialysis, the benefits of statin therapy may not be immediate, and long-term follow-up is necessary to assess its full impact.
STATIN CANNOT SAVE EVERYONE
Statin inefficient in CKD because of pathophysiologic alteration: pre-clinical
Regardless of the presence of diabetic kidney disease or non-diabetic CKD, abnormal lipid regulation, in addition to LDL-C, was notable. TRL-apoC3 (inhibitors of lipolysis) levels are elevated, and peroxisome proliferator-activated receptor (PPAR)-alpha gene expression is reduced in an animal model with CKD [36,37]. Hepatic TG lipase levels are decreased in advanced CKD [38]. Apolipoprotein A5, a modulator of plasma TG levels, is also decreased in CKD [39]. Statin-induced insulin resistance may be linked to decreased mitochondrial oxidation and lipid synthesis capacity, which may lead to lipotoxic intermediates accumulation, and impaired glucose tolerance. Recently, Huang et al. [40] demonstrated that longterm statin administration might increase insulin resistance, interfere with lipid metabolism, cause inflammation and fibrosis, and aggravate diabetic nephropathy in diabetic mice. They concluded that statin administration increased lipid uptake, inhibited fatty acid oxidation, and resulted in lipid deposition. Long-term statin administration may have adverse effects, particularly in patients with diabetic nephropathy and long-standing diabetes.
Statin inefficient in CKD because of pathophysiologic alteration: clinical
Statins reduce serum LDL-C levels; however, their effects vary across LDL subtypes. One study reported that statins may increase small, dense LDL levels [41]. The effect of CKD-related lipid profile abnormalities on atherosclerotic cardiovascular disease (ASCVD) cannot be explained when lipid levels are controlled in ESKD patients on dialysis. In patients with ESKD on dialysis, various pathophysiological mechanisms other than traditional CV risk factors contribute to CVD development. These include hyperphosphatemia-induced vascular calcification, chronic systemic inflammation, and dialysis adequacy [42-44]. Additionally, among CV-related conditions, dialysis patients have a higher incidence of sudden cardiac death. This is more frequently attributed to long-term structural changes in the heart, arrhythmias, and electrolyte imbalances rather than atherosclerotic plaque rupture. There fore, the prevalence of conditions preventable by lipid-lowering therapy may be lower in patients on dialysis compared to the general population.
Statins can reduce kidney events; however, this remains uncertain. Su et al. [45] conducted a meta-analysis showing that statins could not prevent kidney failure or progression to kidney replacement therapy. Additionally, a nationwide population-based case-control study in Taiwan showed that statin use was associated with a 1.59-fold increased risk of ESKD compared to non-users [46]. The risk remained elevated across statin types, with atorvastatin, fluvastatin, and rosuvastatin showing the strongest associations. A dose-dependent relationship was observed, where cumulative statin exposure correlated with an increased ESKD risk. Patients using ≥ 600 cumulative defined daily doses of statins had nearly double the ESKD risk compared to non-users. Since statin may not be highly effective in significantly slowing the progression to ESKD, it is challenging to conclude that they play a key role in determining ESKD progression. It is also important to recognize the limitations of retrospective observational cohort studies, as statin users often have a greater burden of CV risk factors than non-users. Many of these factors may not be fully captured or properly adjusted for in nationwide cohort studies, potentially leading to confounding in the observed associations. Similarly, in patients with diabetic CKD, statins could improve albuminuria but not overt proteinuria or eGFR slope, which is the same as that reported by Zhao et al. [25]. One study reported that statins significantly reduced urinary albumin and protein excretion while increasing creatinine clearance, suggesting potential renoprotective effect. However, no significant changes in eGFR or serum creatinine levels were observed compared to the control group. These findings indicated that although statins may slow CKD progression by reducing proteinuria, their impact on overall kidney function remains unclear. The renoprotective effects of statins may result from their anti-inflammatory and endothelial-stabilizing properties [25]. However, long-term clinical benefits, particularly in preventing dialysis, have not yet been achieved.
Large RCTs of statin therapy in patients with CKD have yielded mixed results. Although statins reduced CV events in patients with mild to moderate CKD, their benefits in patients with ESKD remain uncertain. Studies have reported a lack of significant CV benefits in these patients [32-34,47], resulting in ongoing debates with statin use in this population. The KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) cohort study revealed that the linear protective effect associated with LDL reduction shifted to a U-shaped relationship, with statins use showing higher coronary arterial calcification (CAC) scores, suggesting that the pathophysiology in CKD patients differs from that in the general population [48,49]. Yang et al. [48] have reported an association between statin use and coronary calcification progression. Participants in this prospective observational cohort underwent coronary computed tomography scans at the start of the study and again after 4 years. Statin users (38% of the participants) showed significantly higher rate of CAC progression than non-users with an adjusted OR of 1.78, suggesting that statins independently contribute to calcification. These findings highlight the complexity of statins effects on CKD. While statins reduce CV risk, they may accelerate CAC, potentially stabilizing plaques rather than preventing new calcifications. This aligns with previous research showing that high-intensity statins increase CAC but reduce CV events, suggesting a paradoxical but protective role. Findings from intracoronary imaging studies (optical coherence tomography, intravascular ultrasoud, intravascular ultrasound with near-infrared spectroscopy) suggest that lipid-lowering therapies, including statins, ezetimibe, and PCSK9 inhibitors, tend to result in plaque volume regression with lower achieved LDL-C levels [50-53]. During this regression process, lipid content—rather than irreversible calcification components—has a higher propensity for regression, which may lead to a higher density of calcification in the remaining plaque area. Jhee et al. [49] reported no significant relationship between statin intensity and CKD progression. HR for CKD progression were 0.97 for the moderate-intensity group and 1.15 for the high-intensity group, compared to the low-intensity group, indicating no protective or harmful effects. The high-intensity statin group had slightly higher proteinuria levels and lower serum albumin levels. However, there was no significant difference observed in CKD progression. Although statins are cornerstones of CV risk management, their role in slowing CKD progression appears negligible (Fig. 2).
In contrast to the general population, in which elevated levels of LDL-C are a known CV risk factor, in patients on hemodialysis, low LDL-C might indicate malnutrition, inflammation, or other metabolic imbalances, leading to worse outcomes. Among incident hemodialysis older adult patients aged > 70 years and statin-naïve (who had not previously received statins), lower LDL-C levels have been associated with an increased risk of mortality in older patients on hemodialysis [54]. Compared to the lowest quartile (mean LDL-C, 47.5 mg/dL), those in higher LDL-C quartiles had progressively lower mortality risks, with the highest quartile (mean LDL-C, 143 mg/dL) showing the most significant survival benefit. Kaplan-Meier survival analysis confirmed these results, and multivariate Cox regression models adjusted for confounders consistently demonstrated lower mortality (HR, 0.654; 95% CI, 0.519 to 0.824). The findings suggested that statin therapy should primarily be prescribed for CV benefits rather than for kidney protection in patients with CKD. Current guidelines recommended statin therapy primarily for non-dialysis patients with CKD at high CV risk. Although there is no compelling need to discontinue statin therapy in patients on hemodialysis, evidence supporting statin initiation in this population remains insufficient. Therefore, it may be more reasonable to cautiously consider discontinuing statins or statin/ezetimibe combination therapy rather than continuing the therapy, with the expectation of reducing CV events. In patients receiving renal replacement therapy, the risks associated with polypharmacy, drug-drug interactions, and drug toxicity may outweigh medication potential benefits, highlighting the need for careful assessment [10].
We recommend statins for CV protection and reduced mortality; however, their potential side effects cannot be overlooked. Common adverse effects include elevated muscle enzyme levels, drug intolerance, liver enzyme abnormalities, and renal dysfunction. A recent meta-analysis reported that the incidence of adverse effects is approximately 10% [55]. Lin et al. [46] reported that the risk of ESKD progression increased with serious complications. Population-based case-control studies have shown a potential association between statin use and an increased risk of ESKD. The risk of ESKD increased with all statins except lovastatin. As demonstrated in the ‘Living with statins’ (LIFESTAT) study, metabolic alterations may contribute to this adverse effect. We should emphasize the importance of informing outpatients about these potential risks and carefully weighing the risk-benefit balance before initiating statin therapy. For patients with CKD who may have concerns about the potential adverse effects of high-intensity statin therapy, an alternative option is a combination of moderate-intensity statin and ezetimibe. This combination has been repeatedly shown to be non-inferior to high-intensity statin therapy in ASCVD patients, providing a viable and potentially safer approach for lipid management in this population [56,57].
Considerations for dyslipidemia management in routine clinical practice for CKD/ESKD patients
Imagine the patients encountered daily in the clinic (Table 1). A 60-year-old woman with a 20-year history of diabetes, and dialysis was initiated. At the age of 55, she experienced a MI, underwent stent placement, and has been taking statins since then. She also had diabetic foot disease and carotid ultrasonography revealed a thickened intima. In this case, there was no reason to discontinue the statin therapy. Now, consider a 75-year-old man who has hypertension medication, but started dialysis after a traumatic brain hemorrhage and AKI. It is his second month of dialysis, and as the urine output gradually improves, doctors are waiting to see if he can discontinue dialysis. Should statin therapy be initiated in this patient? Before making this decision, the patient’s overall condition, including adaptation to dialysis and dietary intake, should be assessed. Finally, considered a frail 91-year-old woman weighing 40 kg. She has experienced multiple CV complications and did not want futile, life-prolonging treatment. She had difficulty eating due of the large number of medications she was taking. Both the patient and her family wished for her remaining time to be as comfortable as possible. In this situation, would continuing statin therapy be the right choice?
CONCLUSION
In conclusion, managing dyslipidemia in patients with CKD is a complex and challenging task that requires a multifaceted approach. While statins play a crucial role in reducing CV risk in patients with CKD, their use should be tailored to individual patient factors, including lipid profile, renal function, comorbid conditions, life expectancy, and new-onset complications. Further research is needed to optimize lipid-lowering strategies in patients with CKD and explore alternative therapeutic options beyond statins.
PDF Links
PubReader
ePub Link
XML Download
Full text via DOI
Download Citation
Print
