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Dyslipidemias in Chronic Kidney Disease: Pathophysiology and Emerging Therapies
Corresponding author: Mohamed Hassanein, Department of Nephrology, Kidney and Urology Center, Portsaid Street, Alexandria, Egypt. E-mail: moh.h.hassanein@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Martin Capon I, Lerma EV, Anandh U, So PNH, Hassanein M. Dyslipidemias in Chronic Kidney Disease: Pathophysiology and Emerging Therapies. Indian J Nephrol. doi: 10.25259/IJN_711_2025
Abstract
Dyslipidemia plays a critical role in the pathogenesis of both cardiovascular (CVD) and chronic kidney diseases (CKD). Although modifiable, dyslipidemia remains undertreated, probably due to the differences in management across clinical guidelines and the lack of evidence supporting treatment benefits in patients with advanced CKD and those on dialysis. High levels of lipids or changes in their structure are involved in kidney damage due to oxidative stress, inflammation, and lipotoxicity. This review explores the pathophysiology of dyslipidemia in kidney injury and the current strategies for lipid management across different CKD populations, including non-dialysis, dialysis, and kidney transplant recipients. Statins remain the first-line therapy; however, their efficacy is reduced in advanced CKD and patients on dialysis. Emerging therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, bempedoic acid, inclisiran, and icosapent ethyl, offer promising options for patients with statin intolerance or persistent dyslipidemia and have been tested in patients with CKD with a glomerular filtration rate (GFR) > 30 mL/min/m2. Newer targets, such as ANGPTL3, APOC3, CETP, and Lp(a), are currently being studied. Effective lipid management in patients with CKD requires a personalized, multidisciplinary approach involving nephrologists, cardiologists, endocrinologists, and primary care physicians to implement evidence-based interventions and improve long-term outcomes.
Keywords
Cholesterol
Chronic kidney disease
Dyslipidemia
Hyperlipidemia
Statins
Introduction
Cardiovascular disease (CVD) remains the leading cause of death worldwide, with dyslipidemia being a major contributing factor, especially higher low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels, and lower high-density lipoprotein cholesterol (HDL-C).1,2 Dyslipidemia enhances chronic kidney disease (CKD) progression, and given that it is a modifiable risk factor, it has become one of the main treatment targets in this patient population by many professional societies, including the American Heart Association (AHA), the American College of Cardiology (ACC), the European Society of Cardiology (ESC), and the Kidney Disease: Improving Global Outcomes (KDIGO).1-4
While cardiology societies suggest aggressive LDL-C lowering strategies,1,3 KDIGO guidelines4 offer a less aggressive approach. Residual cardiovascular risk (CVR) may persist despite treatment, prompting the development of new strategies. This review explores contemporary approaches to lipid management across different CKD stages and discusses the current treatment guidelines and emerging therapies.
Pathophysiology of Dyslipidemia in Kidney Disease
The prevalence of dyslipidemia in CKD ranges between 23-30%, although the exact prevalence has not been established due to several factors.5 In patients with CKD, dyslipidemia does not follow a uniform pattern. It varies significantly depending on the stage, presence of proteinuria, type of kidney replacement therapy (KRT), and the pharmacological treatment received.6 In patients with advanced CKD (estimated glomerular filtration rate [eGFR] < 30 mL/min/m2) and on hemodialysis, total cholesterol and LDL-C levels are usually normal or even low. In contrast, TG and very-low-density lipoprotein cholesterol (VLDL-C) levels are elevated due to reduced clearance of these particles. However, patients with nephrotic syndrome or those on peritoneal dialysis show more marked hyperlipidemia, with elevated LDL-C and total cholesterol. In kidney transplant recipients, immunosuppressants alter lipid metabolism, leading to increases in total cholesterol, LDL-C, and TG [Figure 1, Table 1]. In addition, the characteristics and activity of lipoproteins vary across all CKD stages.6
- Lipid abnormalities in CKD, patients on dialysis, kidney transplant recipients, and nephrotic syndrome. “Created in BioRender. So, P. (2025) https://BioRender.com/wizjph1“. LDL-C: Low-density lipoprotein cholesterol, TG: Triglycerides, VLDL-C: Very low-density lipoprotein cholesterol.
| Condition/Stage CKD | Lipid profile alterations | Comments |
|---|---|---|
| Early CKD (eGFR ≥ 30 mL/min/m2) |
|
Lipoprotein metabolism begins to change, with reduced activity of lipoprotein lipase and hepatic lipase. |
| Advanced CKD (eGFR < 30 mL/min/m2) |
|
Uremia alters lipoprotein clearance; increases VLDL-C production and impairs HDL-C maturation. |
| Hemodialysis |
|
Chronic inflammation and oxidative stress contribute to these changes. |
| Peritoneal dialysis |
|
Glucose absorbed from dialysis fluid promotes lipogenesis. |
| Kidney transplant |
|
Immunosuppressants (e.g., corticosteroids, calcineurin inhibitors) contribute to dyslipidemia. |
| Nephrotic syndrome |
|
Massive proteinuria leads to hepatic overproduction of lipoproteins and decreased catabolism. |
CKD: Chronic kidney disease, eGFR: estimated Glomerular filtration rate, LDL-C: Low-density lipoprotein cholesterol, HDL-C: High-density lipoprotein cholesterol, VLDL-C: Very-low-density lipoprotein cholesterol, TGs: Triglycerides.
All these changes in the lipid levels and composition contribute to increasing CVD, an effect that may be higher in patients with additional diabetes and hypertension.7 The latter are associated with more albuminuria and CKD progression.8 In patients with advanced CKD, the azotemic environment enhances the oxidation of LDL-C and HDL-C particles, leading to higher oxidative stress and kidney toxicity.7 Lipid overload drives cellular lipid accumulation, where they form small droplets, disrupting normal cellular activity and increasing the expression of cytokines such as TNF-α, IL-6, and monocyte chemoattractant protein (MCP)-1, which recruit immune cells and sustain a chronic inflammatory microenvironment in the kidney parenchyma. Moreover, lipid accumulation triggers the production of profibrotic mediators such as transforming growth factor-beta (TGF-β), which augments extracellular matrix expansion, glomerulosclerosis, and interstitial fibrosis [Figure 2], increasing the risk of CKD progression.9 Alternatively, podocytes are particularly vulnerable to lipid-induced injury. When lipid molecules deposit in podocytes, podocytes lose their cytoskeletal integrity, leading to apoptosis, proteinuria, and a reduction in the GFR.10
- Pathophysiology of Dyslipidemia-Induced Kidney Injury. “Created in BioRender. So, P. (2025) https://BioRender.com/zkr7653 “. CKD: Chronic kidney disease, LDL: Low-density lipoprotein, ROS: Reactive oxygen species.
Vascular calcification is aggravated by elevated oxidized LDL-C, which can increase osteogenic transformation of vascular smooth muscle cells and promote calcium deposition within the vascular wall. Dysregulated mineral metabolism, including hyperphosphatemia and secondary hyperparathyroidism, may exacerbate lipid abnormalities by altering systemic inflammation. Moreover, some phosphate binders, especially calcium-based formulations, may affect lipid absorption in the gut, while others, such as sevelamer, have been shown to reduce LDL-C levels. Therefore, lipid-lowering strategies in CKD should consider the bone-vascular interplay to avoid interventions that might improve lipid profiles but worsen vascular calcification or bone fragility.11
Management of Dyslipidemia in Chronic Kidney Disease
Given the significant impact of dyslipidemia on both kidney and cardiovascular outcomes in patients with CKD, it is important to treat lipid abnormalities proactively and effectively.1,3,4 [Figure 3].
- Proposed algorithm for the monitoring and management of dyslipidemia in patients with CKD according to KDIGO guidelines. “Created in BioRender. So, P. (2026) https://BioRender.com/tq4fkqx“. CKD: Chronic kidney disease, eGFR: Estimated glomerular filtration rate, HD: Hemodialysis, CV: Cardiovascular. * Avoid initiating statins if the patient is frail or has limited life expectancy. ** Watch for drug interactions (e.g., cyclosporine + statins ↑ risk of myopathy)
Lifestyle interventions
Lifestyle interventions are the universally recommended, first-line treatment, although evidence in patients with CKD is limited.1-4 Some recommendations include: following a healthy diet, regular exercise, smoking cessation, and weight loss.12 Importantly, dietary interventions must be tailored to the special needs of patients with CKD, particularly concerning potassium and protein intake.
Pharmacological management
Statins
Statin therapy has been well-established for reducing cardiovascular events (CVE) in the general population and is the cornerstone of pharmacological management of dyslipidemias. In patients with CKD, the strongest evidence came from the SHARP trial, which compared major CVE rates in 4,650 patients with CKD stages III-V who received the combination of simvastatin (20 mg) and ezetimibe (10 mg) with those of 4,620 patients who received placebo. A 17% relative reduction in atherosclerotic events with simvastatin plus ezetimibe was demonstrated >5 years. However, the study did not detect a significant reduction in overall or cardiovascular mortality.13 These results are supported by several meta-analyses that evaluated subgroups with CKD.13-15 The largest meta-analysis is the one conducted by Tunnicliffe et al.,[16] including 63 studies with 50,725 randomized patients. It concluded that compared to placebo or standard care, statins prevent major CVE, cardiovascular death, myocardial infarction, and overall mortality.16 A meta-analysis by Liao et al.[17] evaluated different antilipidemic therapies in patients with CKD (eGFR ≤ 60 mL/min/1.73 m2), including high and low-intensity statins, and several combination therapies, including statins and ezetimibe, statins and PCSK9 inhibitors, and statins and fibrates. PCSK9 inhibitor therapy was the most effective treatment (OR 0.62), and high and low-intensity statins also reduced mortality (OR 0.76 and 0.89, respectively).17 Regarding side effects, statins had little effect on liver enzymes, and very few studies reported rhabdomyolysis or elevated creatinine.16 Although proteinuria has been associated with certain statins, such as rosuvastatin, the association of this side effect has not been well established in clinical trials.18
The KDIGO guidelines recommend that patients aged ≥50 years with an eGFR <60 mL/min/1.73 m2 be treated with a statin or a statin/ezetimibe combination, regardless of baseline LDL levels,4 although clinical guidelines do not specify the exact statin to initiate.1,3,4 Younger patients with diabetes, established CVD, or high calculated CVR also benefit from lipid-lowering therapy.4 Although the KDIGO guidelines have not updated the lipid guidelines in CKD since 2013, the 2024 CKD guidelines highlight a section dedicated to lipid management, maintaining the same recommendations and emphasizing that statin-based regimens should be selected to achieve the greatest possible absolute reduction in LDL-C.19 Some authors have referred to this treatment strategy as “fire and forget”, because treatment is initiated without aiming for specific LDL-C targets and without recommending routine follow-up of lipid levels.20 On the other hand, the AHA/ACC 2018 guidelines recommend initiating moderate-intensity statins, alone or in combination with ezetimibe, for adults aged 40-75 years with LDL-C concentrations between 70 and 189 mg/dL who have a 10-year atherosclerotic CVD risk of 7.5% or higher.1 [Table 2]. In contrast, the ESC/EAS categorizes patients as high risk (G3a-3b CKD category) and very high risk (G4-5 not on dialysis). For both groups, the recommended LDL-C reduction is at least 50% from baseline, with targets of <70 mg/dL for high-risk patients and <55 mg/dL for those at very high risk.3 Similarly, the UK Renal Association outlines specific treatment thresholds: total cholesterol ≤4 mmol/L, LDL-C ≤2 mmol/L, and non-HDL-C ≤2.5 mmol/L, further emphasizing a quantitative approach to dyslipidemia management in CKD.21
| Society/Guideline | CKD (non-dialysis) | Dialysis | Kidney transplant recipients |
|---|---|---|---|
| ACC 20102 | No specific recommendations, provides data from TNT study: patients with diabetes and mild to moderate CKD demonstrated a marked reduction in cardiovascular events with intensive lipid-lowering | No specific recommendations. | No specific recommendations. |
| KDIGO 20244 |
|
|
Suggest statins for all adult recipients (2B). |
| AHA/ACC 20181 |
|
|
|
| ESC/EAS 20193 |
|
|
|
CKD: Chronic kidney disease, ACC: American college of cardiology, AHA/ACC: American heart association/American college of cardiology, ESC/EAS: European society of cardiology/atherosclerosis society, LDL-C: Low-density lipoprotein cholesterol, eGFR: Estimated glomerular filtration rate, CV: Cardiovascular
However, evidence for initiating statins in patients on dialysis is limited. The 4D and AURORA trials did not demonstrate a significant CVE reduction with statin use in this population, but showed an increase in hemorrhagic stroke in the intervention group.22,23 On the other hand, although the SHARP trial observed a reduction in CVR in the overall treatment group receiving statins, this effect was not replicated in the subgroup on dialysis.13 Furthermore, observational data suggest a U-shaped relationship between cholesterol levels and mortality in dialysis populations, a phenomenon known as reverse epidemiology.24 This phenomenon could be explained by the fact that in patients with CKD, low cholesterol levels are often associated with malnutrition or a syndrome known as malnutrition-inflammation complex syndrome (MICS), which is associated with higher mortality.12 Although patients on peritoneal dialysis may benefit from more aggressive lipid management due to their higher LDL-C levels from glucose absorption from the dialysate, current KDIGO guidelines recommend against initiating statin therapy in patients on dialysis, though patients who were already receiving treatment before dialysis initiation can continue therapy.4
In kidney transplant recipients, statins are considered safe and are recommended by KDIGO for all patients to reduce CVR.4 The largest meta-analysis in transplant recipients did not show an overall reduction in major CVE in patients treated with statins.25 Nevertheless, given the high CVR in this group, statin therapy remains an important treatment for long-term management of dyslipidemia in this patient population.4 It is important to consider various potential drug interactions in transplant recipients, especially with cyclosporine, which is metabolized by the CYP3A4 enzyme system and can increase blood concentrations of statins, potentially elevating the risk of myopathy.3 Fluvastatin, pravastatin, pitavastatin, and rosuvastatin are metabolized by enzymes other than CYP3A4, which reduces their potential for interaction with cyclosporine.26 On the other hand, tacrolimus appears to have a lower risk of interaction with statins compared to cyclosporine.
Fibrates
Fibrates (fenofibrate, bezafibrate, and gemfibrozil) may have cardiovascular benefit in patients with GFR between 30–60 mL/min/1.73 m2.27 The meta-analysis conducted by Liao et al.[17] did not show a clear mortality benefit in patients with CKD (eGFR ≤ 60 mL/min/1.73 m2) treated with a combination of statins and fibrates, and a slight worsening of kidney function was observed when a combination of rosuvastatin and fenofibrate was administered, though this effect was reversible upon discontinuation of treatment.17 Furthermore, several studies have associated an increased risk of rhabdomyolysis with the combination of statins and fibrates.28 Thus, the KDIGO guidelines recommend against the combined use of statins and fibrates in patients with CKD.
Bile acid sequestrants
Bile acid sequestrants (cholestyramine, colestipol, colesevelam) are resins that bind to bile acids, preventing their absorption from the intestinal lumen. This forces the liver to produce more bile acids from hepatic cholesterol, thereby increasing LDL-C receptor expression and reducing circulating LDL-C. These drugs are currently used as second-line therapy in patients with CVD who do not have kidney disease,3 and have been associated with a 25% LDL-C reduction, with a decrease in CVR proportional to LDL-C.29 However, the evidence in patients with CKD, on dialysis, or kidney transplant recipients is limited. There are no specific recommendations in any guideline regarding the use of bile acid sequestrants in patients with CKD.1,3,4
Orlistat
Orlistat is a gastric and pancreatic lipase inhibitor indicated for treating obesity that decreases the absorption of dietary fats in the gastrointestinal tract. There is limited data on Orlistat use in kidney disease. MacLaughlin et al. conducted a prospective, non-randomized study evaluating weight loss in 44 patients with CKD (eGFR 15–60 mL/min/1.73 m2) following a program that included a low-calorie diet, exercise, nutritional education, and orlistat. A significant decrease in total cholesterol, LDL-C, and TG levels, and weight loss was observed at 24 months. Side effects were mild and primarily gastrointestinal.30
Niacin
Niacin is a lipid-modulating agent that decreases the release of free fatty acids from adipose tissue by blocking lipase. This reduces hepatic TG synthesis and the production of LDL-C and VLDL-C. Furthermore, by inhibiting hepatic uptake of apoA-I, it increases the half-life of HDL-C. Despite some data supporting the use of niacin for CVR prevention, a meta-analysis of 11 clinical trials with 35,031 patients showed no statistically significant reduction in all-cause mortality or mortality from coronary artery disease.31 Adverse effects included flushing, increased risk of diabetes, and major bleeding.31,32 Data in patients with CKD is limited, with no current specific clinical guidelines guiding their use in patients with kidney disease.1,3,4
Protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors
PSCK9 inhibitors (evolocumab and alirocumab) are monoclonal antibodies against PCSK9, both approved by the Food and Drug Administration (FDA) in 2015 for the treatment of heterozygous familial hypercholesterolemia and atherosclerotic CVD. They inhibit the degradation of LDL-C receptors and increase the clearance of LDL-C molecules. The FOURIER trial33 assessed the safety and efficacy of evolocumab compared with placebo in patients with atherosclerotic disease on statin therapy. A significant reduction in the primary composite outcome (cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina or coronary revascularization) was observed with evolocumab compared to placebo. In a sub-analysis of patients with CKD (GFR > 30 mL/min/m2), evolocumab maintained a relative risk reduction of the primary outcome and reductions in LDL-C. Similarly, the ODYSSEY OUTCOMES trial evaluated the efficacy of alirocumab compared with ezetimibe in patients with high CVR and elevated LDL-C despite maximal statin doses.34 This trial showed a greater reduction in LDL-C in patients who were treated with alirocumab, with a similar rate of CVE in both groups. This effect was maintained even in patients with CKD, although it diminished as GFR decreased.34 As monoclonal antibodies are not cleared through the kidneys, no dose adjustments are necessary, making them safe for use even in CKD. However, clinical trials in patients on dialysis are still limited.
Emerging Therapies
While statins remain the cornerstone of lipid management, residual CVR may persist, especially in advanced CKD, where conventional therapies may show less efficacy.13 In recent years, new agents have been developed to target lipid metabolism through alternative pathways, to increase the efficacy of currently available drugs [Table 3].
| Therapy | Mechanism of action | Primary metabolism | Administration | Main adverse effects | Studies in CKD |
|---|---|---|---|---|---|
| Statins14,15,17 | Inhibit HMG-CoA reductase, reducing hepatic cholesterol synthesis | Liver(CYP450) | Oral, daily | Muscle pain, elevated liver enzymes |
SHARP, metanalysis eGFR ≥ 30 mL/min/m2 |
| Ezetimibe13 | Inhibits intestinal absorption of cholesterol | Liver and Intestine | Oral, daily | GI upset, rare liver enzyme elevations |
SHARP eGFR ≥ 30 mL/min/m2 |
| Fibrates17,27 | Activate PPARα, reducing TG and increasing HDL | Kidney and Liver | Oral, daily | Increased creatinine, possible nephrotoxicity | 30-60 mL/min in limited studies, avoid in ESKD |
| PSCK9 inhibitors (evolocumab)33,34 | Block PCSK9 to increase LDL receptor recycling and LDL clearance | Liver | Subcutaneous, every 2-4 weeks | Injection site reactions, nasopharyngitis |
FOURIER/ODYSSEY eGFR ≥ 30 mL/min/m2 |
| Bempedoic acid35 | Inhibits ATP citrate lyase upstream of HMG-CoA reductase | Liver (minimal kidney excretion | Oral, daily | Elevated uric acid and creatinine |
CLEAR eGFR ≥ 30 mL/min/m2 |
| Inclisiran37 | siRNA that inhibits PCSK9 synthesis in hepatocytes | Liver | Subcutaneous, every 6 months | Injection site reactions, mild flu-like symptoms |
ORION eGFR ≥ 30 mL/min/m2 Not studied in dialysis |
| Icosapent ethyl39 | Purified EPA with anti-inflammatory and lipid-lowering effects | Liver | Oral, daily | Arthralgia, bleeding risk |
REDUCE-IT RENAL eGFR ≥ 30 mL/min/m2 Not in ESKD |
| CETP inhibitors (Anacetrapib, obicetrapib)43 | Inhibit CETP, raising HDL and lowering LDL | Under investigation | Oral | Hypertension, no proven benefit | No CKD-specific data |
| ANGPTL3 inhibitors (Evinacumab)44,46 | Inhibit ANGPTL3 to reduce LDL and TG levels | Liver | Intravenous | Possible liver enzyme elevation | No CKD-specific data |
| APOC3 inhibitors (volanesorsen, olezarsen)47,48 | Inhibit APOC3 to reduce plasma triglycerides | Liver | Subcutaneous | Injection site reactions, thrombocytopenia | No CKD-specific data |
| Lipoprotein A inhibitors (Pelacarsen)49 | Antisense oligonucleotide targeting Lp(a) mRNA to lower Lp(a) | Liver | Subcutaneous | Uncertain; studies ongoing | No CKD-specific data |
LDL-C: Low-density lipoprotein cholesterol, HDL-C: High-density lipoprotein cholesterol, TG: Triglycerides, PCSK9: Proprotein convertase subtilisin/kexin type 9, HMG-CoA: 3-hydroxy-3-methylglutaryl-coenzyme A, ATP: Adenosine triphosphate, EPA: Eicosapentaenoic acid, PPARα: Peroxisome proliferator-activated receptor alpha, CETP: Cholesteryl ester transfer protein, ANGPTL3: Angiopoietin-like protein 3, APOC3: Apolipoprotein C-III, Lp(a): Lipoprotein(a), siRNA: Small interfering RNA, CKD: Chronic kidney disease, ESKD: End-stage kidney disease, eGFR: Estimated glomerular filtration rate, GI: Gastrointestinal, IV: Intravenous, mRNA: Messenger RNA.
Bempedoic acid
Bempedoic acids (nexletol and nexlizet) are FDA-approved prodrugs that inhibit adenosine triphosphate citrate lyase (ACLY), a key enzyme upstream of HMG-CoA reductase in the cholesterol synthesis pathway. Activated only in the liver, it avoids muscle tissue, making it potentially beneficial for statin-intolerant patients. The CLEAR Outcomes trial showed that bempedoic acid reduced LDL-C by 21.1% and the risk of major CVE by 13% (HR 0.87; 95% CI, 0.79-0.96). Among patients with CKD, the drug also showed a significant reduction in CVR with a hazard ratio of 0.77 (95% CI, 0.66–0.91).35 Bempedoic acid has been associated with higher levels of creatinine and uric acid, probably due to tubular secretion inhibition.36 As there are no data in patients with eGFR < 30 mL/min /1.73 m2, it is currently not recommended for use in these patients.
Inclisiran
Inclisiran is a small interfering RNA molecule that inhibits hepatic PCSK9 synthesis. It was approved by the FDA in 2021 for the treatment of heterozygous familial hypercholesterolemia and atherosclerotic CVD. In the ORION trial, patients who received the treatment reduced LDL-C levels up to 50%.37 This trial included patients with GFR > 30 mL/min/1.73 m2, and did not show less efficacy or an increase in secondary effects in this group of patients. However, it has not been tested in patients with eGFR < 30 mL/min/m2 or patients on dialysis.37 Its administration is a biannual dose, and the liver metabolizes it; hence, there is no need for dose adjustment in patients with CKD. Future studies will provide more data about Inclisiran use in CKD populations [ClinicalTrials.gov Identifier: NCT03705234].
Icosapent ethyl
Icosapent ethyl is an omega-3 fatty acid that inhibits hepatic production of TG and VLDL and has an anti-inflammatory effect that stabilizes atheroma plaques. In the REDUCE-IT trial,38 it was associated with a 25% reduction in major CVE in statin-treated (HR 0.75; 95% CI, 0.68–0.83). In a sub-analysis (REDUCE-IT RENAL trial), patients with CKD > 30 mL/min1.73 m2 maintained their kidney function during the treatment.39 Icosapent ethyl has a hepatic metabolism, therefore it may have a favorable safety profile in the CKD population. It was initially approved by the FDA in 2012 as a treatment for hypercholesterolemia, although in 2019 the FDA expanded the indication to reduce the risk of major CVE (heart attack, stroke, revascularization, CV death) in patients with established CVD or diabetes and other risk factors, and elevated TG levels (≥150 mg/dL) despite statin treatment.
Cholesterol ester transfer protein (CETP) inhibitors
CETP inhibitors aim to raise HDL-C and lower LDL-C by modifying lipid exchange between lipoproteins. Despite promising lipid effects, most CETP inhibitors have failed to demonstrate clinical benefits or have been associated with adverse outcomes. Torcetrapib was associated with increased mortality and higher hypertension, and was withdrawn from clinical development before reaching the market.40 Dalcetrapib and evacetrapib were discontinued after showing no cardiovascular benefit.41,42 On the other hand, Anacetrapib, studied in the REVEAL trial, showed modest efficacy in major coronary events (HR 0.91; 95% CI 0.85-0.97; p = 0.004), although it was not evaluated in patients with advanced CKD or macroalbuminuria.43 The latest CETP inhibitor, obicetrapib, is still under investigation. Therefore, none of these treatments has been approved by the FDA.
Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (APOC3) inhibitors
ANGPTL3 and APOC3 were first described in patients with loss-of-function mutations of genes ANGPTL3 and APOC3, who had less CVR.44,45 Evinacumab, an ANGPTL3 monoclonal antibody, was tested in patients with familial hypercholesterolemia and mixed dyslipidemia showing significant reduction in LDL-C and TG levels, and was approved by FDA in 2021.46 Although it has not been studied in the CKD population, its hepatic metabolism may make it a safe option for patients with CKD.46 Similarly, volanesorsen and olezarsen, antisense oligonucleotides targeting APOC3, have been associated with a reduction in TG levels in patients with familial chylomicronemia syndrome.47,48 In the same way, their impact on patients with CKD remains unknown. Of these, olezarsen was approved by the FDA in December 2024. ANGPTL3 is administered intravenously and APOC3 subcutaneously.44,45
Lipoprotein(a) targeted therapies
Elevated lipoprotein(a) [Lp(a)] is a strong independent risk factor for cardiovascular and CKD progression. Pelacarsen is an antisense oligonucleotide designed to lower Lp(a) by targeting its mRNA.49 It has been studied in the HORIZON trial and was associated with up to 80% reduction in Lp(a) levels50 (NCT04023552), although its cardiovascular profile is still under investigation. Given the high prevalence of elevated levels of Lp(a) in patients with CKD, especially when it is associated with nephrotic syndrome, targeting Lp(a) may be a promising strategy for the management of dyslipidemia in these patients.
Limitations Of Emerging Therapies
Despite promising lipid-lowering efficacy, emerging therapies such as PSCK9 inhibitors, bempedoic acid, inclisiran, and ANGPTL3 or APOC3 inhibitors face important barriers to widespread implementation in CKD. Most clinical trials have limited representation of patients with advanced CKD, particularly kidney transplant recipients or patients on dialysis, which limits the generalizability of results. Additionally, the high cost and limited availability in low-resource settings limit access to treatment. The safety of these drugs in patients with CKD has not been fully established yet, limiting their current use in patients with kidney disease.
Lipid Management in Resource-Limited Settings
In low-resource areas, implementing lipid-lowering strategies in CKD faces multiple challenges, including limited access to medications, laboratory services, lack of health insurance, and increased cost burden of lab tests and medications. In such settings, the KDIGO guidelines offer specific recommendations, prioritizing statin prescription based on clinical risk factors rather than biochemical parameters, adopting a “fire-and-forget” strategy to avoid unnecessary follow-up testing.4 Additionally, the high cost of medications, particularly the latest therapies, complicate access to medications. Generic statins, which are inexpensive and widely available, remain the most practical option and are supported by strong evidence even in CKD population. Governmental insurance programs are required to cover generic therapies and improve access of patients with CKD to lipid-lowering therapy.
Summary and Future Directions
Dyslipidemia is a key contributor to both cardiovascular morbidity and kidney disease progression in patients with CKD. Although KDIGO guidelines recommend statin or statin-ezetimibe therapy without defined LDL-C targets, this conservative approach contrasts with cardiology guidelines, which support more aggressive, goal-directed lipid-lowering strategies tailored to CVR levels. Given the heterogeneity in CKD presentation, lipid management should be individualized, taking into account kidney function, CVR, and therapy’s tolerability. Novel agents, including PCSK9 inhibitors, inclisiran, bempedoic acid, and icosapent ethyl, are promising alternatives, although cost-minimization strategies and specific clinical trials in the CKD population are necessary. Multidisciplinary approaches involving nephrologists, cardiologists, endocrinologists, and primary care providers are key to optimizing dyslipidemia management. In the future, health systems should prioritize developing cost-effective models, generating real-world evidence, and implementing quality improvement initiatives to bridge the gap between innovation and access. While emerging therapies offer potential to reduce residual CV risk, their impact will ultimately depend on affordability, accessibility, and thoughtful integration into current care pathways.
Conflicts of interest
Edgar V. Lerma: - Speaker/Advisory Board: Amgen, AstraZeneca, Bayer, Calliditas, Novartis, Novo Nordisk, Otsuka, scPharmaceuticals, Travere, Vera, Vertex, Vifor - Royalty: Elsevier, McGraw-Hill, Springer, Wolters Kluwer. All other authors report no conflicts of interest.
References
- 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: Executive summary: A report of the american college of cardiology/american heart association task force on clinical practice guidelines. J Am Coll Cardiol. 2019;73:3168-209.
- [CrossRef] [PubMed] [Google Scholar]
- 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: Executive summary: A report of the American College of cardiology foundation/American heart association task force on practice guidelines. Circulation. 2010;122:2748-64.
- [CrossRef] [PubMed] [Google Scholar]
- 2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41:111-88.
- [CrossRef] [PubMed] [Google Scholar]
- Eknoyan G, Lameire N, Founding KDIGO Co-Chairs. KDIGO clinical practice guideline for lipid management in chronic kidney disease. 2013;3. Available from: http://www.kidney-international.org
- Prevalence and factors associated to chronic kidney disease in older adults. Rev Saude Publica. 2019;53:44.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Lipid abnormalities and oxidized LDL in chronic kidney disease patients on hemodialysis and peritoneal dialysis. Ren Fail. 2012;34:160-4.
- [CrossRef] [PubMed] [Google Scholar]
- Predictors of new-onset kidney disease in a community-based population. JAMA. 2004;291:844-50.
- [CrossRef] [PubMed] [Google Scholar]
- Serum triglycerides are a predictive factor for the development and the progression of renal and retinal complications in patients with type 1 diabetes. Diabetes Metab. 2004;30:43-51.
- [CrossRef] [PubMed] [Google Scholar]
- Oxidative stress in the pathogenesis and evolution of chronic kidney disease: Untangling Ariadne’s thread. IJMS. 2019;20:3711.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Metabolic syndrome, and not obesity, is associated with chronic kidney disease. Am J Nephrol. 2021;52:666-72.
- [CrossRef] [PubMed] [Google Scholar]
- Hyperphosphatemia and hs-CRP initiate the coronary artery calcification in peritoneal dialysis patients. Biomed Res Int. 2017;2017:2520510.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- The effects of a low-to-moderate intensity pre-conditioning exercise programme linked with exercise counselling for sedentary haemodialysis patients in The Netherlands: Results of a randomized clinical trial. Nephrol Dial Transplant. 2005;20:141-6.
- [CrossRef] [PubMed] [Google Scholar]
- The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of heart and renal protection): A randomised placebo-controlled trial. Lancet. 2011;377:2181-92.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Efficacy and safety of cholesterol-lowering treatment: Prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267-78.
- [CrossRef] [PubMed] [Google Scholar]
- Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidney disease: A systematic review and meta-analysis. Eur Heart J. 2013;34:1807-17.
- [CrossRef] [PubMed] [Google Scholar]
- HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev. 2023;11:CD007784.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Antidyslipidemia pharmacotherapy in chronic kidney disease: A systematic review and bayesian network meta-analysis. Pharmaceutics. 2022;15:6.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Association of rosuvastatin use with risk of hematuria and proteinuria. J Am Soc Nephrol. 2022;33:1767-7.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- KDIGO 2024 Clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. 2024;105:S117-34.
- [CrossRef] [PubMed] [Google Scholar]
- Management of dyslipidaemia in patients with comorbidities: Facing the challenge. Eur Heart J Cardiovasc Pharmacother. 2024;10:608-13.
- [CrossRef] [PubMed] [Google Scholar]
- Mark PB, Winocou P. Clinical practice guidelines for management of lipids in adults with diabetes mellitus and nephropathy and/or chronic kidney disease. Association of British clinical diabetologists - Renal association (ABCD-RA); 2017. Available from: chrome-extension://efaidnbmnnnibpcajpcglclefindmkaj/https://www.ukkidney.org/sites/default/files/management-of-lipids-in-adults-with-diabetes-mellitus-and-nephropathy-and-or-chronic-kidney-disease.pdf
- Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353:238-48.
- [CrossRef] [PubMed] [Google Scholar]
- Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360:1395-407.
- [CrossRef] [PubMed] [Google Scholar]
- Dyslipidemia in patients with chronic kidney disease: An updated overview. Diabetes Metab J. 2023;47:612-29.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Use of statins in kidney transplant recipients in Norway. Int J Environ Res Public Health. 2022;19:1370.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Drug therapy in the heart transplant recipient: Part IV: Drug-drug interactions. Circulation. 2005;111:230-9.
- [CrossRef] [PubMed] [Google Scholar]
- Effect of gemfibrozil on change in renal function in men with moderate chronic renal insufficiency and coronary disease. Am J Kidney Dis. 2004;44:832-9.
- [CrossRef] [PubMed] [Google Scholar]
- Efficacy and safety of fenofibric acid co-administered with low- or moderate-dose statin in patients with mixed dyslipidemia and type 2 diabetes mellitus: Results of a pooled subgroup analysis from three randomized, controlled, double-blind trials. Am J Cardiovasc Drugs. 2010;10:73-84.
- [CrossRef] [PubMed] [Google Scholar]
- The effects of bile acid sequestrants on lipid profile and blood glucose concentrations: A systematic review and meta-analysis of randomized controlled trials. Int J Cardiol. 2017;227:850-7.
- [CrossRef] [PubMed] [Google Scholar]
- Nonrandomized trial of weight loss with orlistat, nutrition education, diet, and exercise in obese patients with CKD: 2-year follow-up. Am J Kidney Dis. 2010;55:69-76.
- [CrossRef] [PubMed] [Google Scholar]
- Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: Meta-analysis of randomised controlled trials including 117,411 patients. BMJ. 2014;349:g4379.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Serious adverse effects of extended-release niacin/laropiprant: results from the heart protection study 2-treatment of HDL to reduce the incidence of vascular events (HPS2-THRIVE) trial. Clin Ther. 2019;41:1767-7.
- [CrossRef] [PubMed] [Google Scholar]
- Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: Insights from the FOURIER trial (Further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk) Circulation. 2018;137:338-50.
- [CrossRef] [PubMed] [Google Scholar]
- Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: The ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015;36:1186-94.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388:1353-64.
- [CrossRef] [PubMed] [Google Scholar]
- Mechanism of action and therapeutic use of bempedoic acid in atherosclerosis and metabolic syndrome. Front Cardiovasc Med. 2022;9:1028355.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Effects of renal impairment on the pharmacokinetics, efficacy, and safety of inclisiran: An analysis of the ORION-7 and ORION-1 studies. Mayo Clin Proc. 2020;95:77-89.
- [CrossRef] [PubMed] [Google Scholar]
- Rationale and design of REDUCE-IT: Reduction of cardiovascular events with icosapent ethyl-intervention trial. Clin Cardiol. 2017;40:138-4.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Benefits of Icosapent ethyl across the range of kidney function in patients with established cardiovascular disease or diabetes: REDUCE-IT RENAL. Circulation. 2021;144:1750-9.
- [CrossRef] [PubMed] [PubMed Central] [Google Scholar]
- Torcetrapib impairs endothelial function in hypertension. Eur Heart J. 2012;33:1615-24.
- [CrossRef] [PubMed] [Google Scholar]
- Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367:2089-99.
- [CrossRef] [PubMed] [Google Scholar]
- Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N Engl J Med. 2017;376:1933-42.
- [CrossRef] [PubMed] [Google Scholar]
- Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med. 2017;377:1217-2.
- [CrossRef] [PubMed] [Google Scholar]
- Angiopoietin-like 3 regulates hepatocyte proliferation and lipid metabolism in zebrafish. Biochem Biophys Res Commun. 2014;446:1237-42.
- [CrossRef] [PubMed] [Google Scholar]
- Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014;371:32-41.
- [CrossRef] [PubMed] [Google Scholar]
- ANGPTL3 inhibition in homozygous familial hypercholesterolemia. N Engl J Med. 2017;377:296-7.
- [CrossRef] [PubMed] [Google Scholar]
- Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N Engl J Med. 2019;381:531-42.
- [CrossRef] [PubMed] [Google Scholar]
- Olezarsen, a liver-directed APOC3 ASO therapy for hypertriglyceridemia. Expert Opin Pharmacother. 2024;25:1861-6.
- [CrossRef] [PubMed] [Google Scholar]
- Effect of pelacarsen on lipoprotein(a) cholesterol and corrected low-density lipoprotein cholesterol. J Am Coll Cardiol. 2022;79:1035-46.
- [CrossRef] [PubMed] [Google Scholar]
- Design and rationale of Lp(a)HORIZON trial: Assessing the effect of lipoprotein(a) lowering with pelacarsen on major cardiovascular events in patients with CVD and elevated Lp(a) Am Heart J. 2025;87:1-9.
- [CrossRef] [Google Scholar]