Can fenofibrate be used for hypertriglyceridemia in patients receiving chronic hemodialysis?

Can fenofibrate be used for hypertriglyceridemia in patients receiving chronic hemodialysis? If not, what can be used safely in this population?

Comment by InpharmD Researcher

There is a paucity of literature evaluating whether fenofibrate is safe to use in patients receiving chronic hemodialysis. Several clinical trials report a lack of adverse events and similar tolerability to statins when used in patients with hemodialysis; however, case reports caution elevated serum creatinine levels and potential adverse drug reactions with fenofibrate therapy, and one dated pharmacokinetic study reported a lack of fenofibrate removal with hemodialysis, resulting in greater concentration after repeated administration compared to patients with normal renal function and greater daily doses. Evidence to support the use of alternative lipid-lowering agents in hemodialysis patients is also limited; some studies have investigated the use of statins in hemodialysis and ESRD patients, with inconclusive results.

Background

A dated pharmacokinetic study investigated the influences of hemodialysis on plasma kinetics of fenofibrate in patients with chronic renal failure. A total of 15 patients with chronic renal failure were included, with six receiving hemodialysis and nine not receiving hemodialysis. All 15 patients were given a single oral dose of fenofibrate 300 mg, and plasma samples were collected over 48 hours to analyze fenofibrate kinetics. Additionally, five renal patients on regular hemodialysis received fenofibrate 100 mg daily for two weeks, with plasma levels monitored. The findings revealed a pronounced lengthening of fenofibric acid plasma decay in both hemodialyzed and non-hemodialyzed patients. Notably, hemodialysis did not significantly alter plasma levels, and ultrafiltrates contained very small amounts of fenofibric acid. In the group of five renal patients on regular hemodialysis receiving repeated doses, plasma levels increased progressively, indicating cumulative fenofibric acid. No significant clinical side effects or increases in creatine phosphokinase, glutamic oxaloacetic transaminase, or glutamic pyruvic transaminase were observed. Based on the overall findings, the authors suggested avoiding the use of fenofibrate in patients with chronic renal failure. [1]

Several published case studies have reported use of fenofibrate in patients on hemodialysis with varying tolerability. One case report notes a potential association between fenofibrate and renal impairment in a patient who developed elevated serum creatinine levels during therapy, while another reports severe rhabdomyolysis and acute renal failure potentially caused by concomitant treatment with fenofibrate in two patients who exhibited intense muscle symptoms, hemoglobinuria, oliguria, and elevations in serum creatinine and blood urea nitrogen. Yet another case study reports a sharp rise in triglycerides in an older adult patient with end-stage renal disease on hemodialysis and fenofibrate therapy; however, the adverse drug reaction may have been exacerbated due to venlafaxine initiation. Limited data precludes applicability to a larger patient population. [2], [3], [4]

A 2019 review discussed lipid management in patients with chronic kidney disease, noting that overall lowering of LDL-C in patients with CKD is beneficial for prevention of major atherosclerotic events in patients with CKD but not in patients requiring dialysis. Risk of cardiovascular events for patients with end-stage renal disease (ESRD) is extremely high, yet dysregulation of lipid metabolism in these patients is characterized by increased triglycerides and oxidized lipoproteins, reduced levels of HDL-C, but normal levels of LDL-C. Interestingly, it is hypothesized that patients with ESRD present with a unique cardiovascular phenotype that demonstrates an inverse relationship between LDL-C levels and all-cause mortality, resulting in fewer deaths due to atherosclerosis processes but increased deaths due to heart failure and sudden cardiac death. Based on a 2018 study, which included a substantial sample size of hemodialysis patients, a weak linear relationship was observed between LDL-C levels and risk of major vascular events as well as an inverse relationship with non-atherosclerotic events. Correspondingly some studies have observed no benefit of statin therapy in patients with ESRD, with one study noting a reduction in LDL-C levels in 1,255 diabetic hemodialysis patients after 4 weeks of atorvastatin 20 mg but no subsequent reduction in the incidence of combined outcome of major cardiovascular events compared to placebo over a median follow-up duration of 4 years (hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.77 to 1.10). However, a decrease in rate of all cardiac events was noted with atorvastatin. [5]

Similar results were obtained in another study comprising 2,776 hemodialysis patients (74% with diabetes), finding a 43% reduction in LDL-C levels when treated with rosuvastatin but no significant reduction of incidence of major cardiac events compared to placebo at 3.8 years (HR 0.96, 95% CI 0.84 to 1.11). Similar outcomes were found in yet another study, suggesting lack of efficacy of statins for prevention of cardiovascular events in patients on dialysis. Extrapolation of these data directly are limited however, as patients enrolled in these trials were not selected due to baseline hypercholesterolemia. A subanalysis of one study investigated the effect of atorvastatin on risk of fatal and nonfatal cardiac events in patients with type 2 diabetes on hemodialysis with pretreatment LDL-C levels > 3.76 mmol/L, finding significantly lower risk. Studies of fibrate used to lower triglyceride levels found increases in serum creatinine; the mechanism behind this is unknown. Data regarding the use of lipid-lowering treatments in CKD and ESRD, including fibrates, bile acid sequestrants, and omega-3 fatty acids, is further limited. Overall, evidence to support use of lipid-lowering agents in ESRD/dialysis patients is lacking. [5]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Can fenofibrate be used for hypertriglyceridemia in patients receiving chronic hemodialysis? If not, what can be used safely in this population?

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-4 for your response.

Treatment of chronic hemodialysis patients with low-dose fenofibrate effectively reduces plasma lipids and affects plasma redox status
Design	Prospective, double-blind crossover, placebo-controlled study N= 27
Objective	To assess the safety and lipid lowering efficacy of fenofibrate in chronic dialysis patients
Study Groups	Study cohort (N= 27)
Inclusion Criteria	Adult patients; at least 12 months on chronic hemodialysis therapy with three dialysis sessions per week; total cholesterol concentration ≥200 mg/dL or LDL-cholesterol ≥120 mg/dL and serum triglycerides ≥150 mg/dL; residual diuresis <500 ml/day
Exclusion Criteria	Fibrate or statin within 6 months prior to the study; previous intolerance of fibrates or statins; chronic immunosuppressive and/or steroid therapy; diabetes mellitus requiring insulin therapy; arterial hypertension resistant to treatment; cancer; acute or chronic inflammatory diseases; psychiatric disorders
Methods	Baseline parameters were measured in fasting patients ont he morning of a scheduled mid-week dialysis session. Hemodialysis occurred for 240 minutes three times weekly in a morning dialysis shift, blood flow of 200–250 mL/min and dialysate flow of 500 mL/min. Dialyzers were not reprocessed. Measurements were conducted at baseline, after 28 days of treatment with fenofibrate or placebo, and after 63 days when the patients completed the second treatment period. Patients were randomly assigned to placebo followed by fenofibrate or fenofibrate followed by placebo; fenofibrate 100 mg was given on the morning of a dialysis session shortly after arrival to the center. Treatments were separated by a wash out of 1 week.
Duration	63 days
Outcome Measures	Laboratory parameters
Baseline Characteristics		Study cohort (N= 27)
	Age, years	58.5 ± 13
	Female	9 (33.3%)
	White	100%
	Time on dialysis, years	3.9 ± 4.0
	Blood pressure Systolic, mmHg Diastolic, mmHg	138 ± 17 91 ± 22
Results	Endpoint	After placebo	After fenofibrate
	Blood pressure Systolic, mmHg Diastolic, mmHg	137 ± 12 92 ± 18	134 ± 11 93 ± 23
	Total aminothiols Glutathione, nmol/mL Homocysteine, nmol/mL Cysteine, nmol/mL Cysteinylglycine, nmol/mL	5.6 ± 1.6 26.9 ± 13.1 552 ± 107 56 ± 10	6.5 ± 1.7 29.4 ± 20.2 542 ± 106 56 ± 14
	Total free aminothiols Glutathione, nmol/mL Homocysteine, nmol/mL Cysteine, nmol/mL Cysteinylglycine, nmol/mL	3.4 ± 1.1 7.8 ± 5.0 163 ± 47 23 ± 4	4.2 ± 1.4 9.0 ± 7.4 167 ± 51 25 ± 7
	Mean baseline CRP was increased, but no changes in its concentration were observed throughout the study. Data for changes in lipid fractions depicted via figure. From baseline, fenofibrate caused a significant decrease of total serum cholesterol (18.9%), LDL cholesterol (26%) and triglycerides (36.7%) and an increase of HDL cholesterol (12.1%). However, placebo did not cause significant changes of serum lipid concentration.
	By day 28, fenofibrate caused a significant increase of total plasma glutathione (p= 0.02) and homocysteine (p= 0.04). Additionally, fenofibrate caused a significant increase of plasma free glutathione fraction (p= 0.01) and decrease in free homocysteine (p= 0.04). No significant effect of placebo was reported on any aminothiols.
Adverse Events	None observed
Study Author Conclusions	The study shows that a treatment with reduced fenofibrate dose is safe and effective in reducing serum triglycerides and cholesterol in chronic dialysis patients and may shift plasma aminothiol balance towards a more antioxidative pattern.
InpharmD Researcher Critique	Limitations include use of a small study sample, an ethnically homogenous patient population, lack of a comparator group, and short follow-up duration. Additionally, changes in biochemical markers do not inherently translate to clinically meaningful outcomes.

References:

Makówka A, Dryja P, Chwatko G, Bald E, Nowicki M. Treatment of chronic hemodialysis patients with low-dose fenofibrate effectively reduces plasma lipids and affects plasma redox status. Lipids Health Dis. 2012;11:47. Published 2012 Jul 6. doi:10.1186/1476-511X-11-47

Randomized comparative efficacy and safety study of intermittent simvastatin versus fenofibrate in hemodialysis
Design	Multicenter, prospective, randomized, parallel study N= 60
Objective	To compare the safety and efficacy of intermittent fenofibrate versus simvastatin in chronic hemodialysis (HD) patients
Study Groups	Fenofibrate (n= 30) Simvastatin (n= 30)
Inclusion Criteria	Aged >18 years; at least 12 months on chronic HD therapy with three sessions weekly; diagnosed with hyperlipidemia (total cholesterol [TC] >200 mg/dL or low density lipoprotein cholesterol [LDL-C] >130 mg/dL and triglycerides [TGs] >150 mg/dL); newly diagnosed hyperlipidemic patients or those who did not use any fibrates or statins 6 months prior
Exclusion Criteria	Treated with immunosuppressants or steroids; intolerant to fibrates or statins previously; had any of the following conditions: hypothyroidism, uncontrolled hypertension, gall bladder disease, active liver disease, muscle toxicity, history of myocardial infarction or coronary bypass surgery in last 3 months
Methods	Patients were randomized in a 1:1 ratio to receive either fenofibrate 100 mg or simvastatin 20 mg three times weekly after their dialysis sessions. Blood samples were collected after a 12-hour fast and immediately before dialysis following vascular access cannulation. Hemodialysis was scheduled as a 4-hour session thrice weekly for all patients, with a blood flow of 250-300 mL/min and bicarbonate dialysate flow of 500-800 mL/min.
Duration	Trial Duration: October 2013 to January 2016 Intervention Duration: 16 weeks
Outcome Measures	Laboratory parameters
Baseline Characteristics		Fenofibrate group (n= 30)	Simvastatin (n= 30)
	Age, years	48.8 ± 11.55	51.83 ± 11.01
	Males	12 (40%)	15 (50%)
	Weight, kg	72.9 ± 13.89	72.2 ± 16.71
	Duration on HD, years (IQR)	3 (2 to 10)	3 (2 to 6.5)
	Laboratory parameters SBP, mmHg DBP, mmHg Urea, mg/dL (IQR) Creatinine, mg/dL (IQR) ALT, U/L (IQR) AST, U/L (IQR) Albumin, g/dL (IQR) CK, U/L (IQR) Hb, g/dL (IQR)	132 ± 17.89 81 ± 11.25 142.5 (75.25 to 172) 9.65 (8.25 to 11.8) 25.5 (20.25 to 32.25) 25.5 (21.75 to 34.75) 3.91 (3.58 to 4.08) 105.5 (70 to 138) 9.7 (8.8 to 11.9)	130.67 ± 23.03 82.67 ± 10.48 113 (36 to 156) 10 (7.6 to 12) 30.88 (27.89 to 35.34) 27.63 (23.95 to 35.88) 3.77 (3.35 to 4.21) 118 (81.5 to 145.5) 10.05 (7.87 to 10.57)
	Abbreviations: AST= aspartate aminotransferase; ALT= alanine aminotransferase; CK= creatinine kinase; DBP= diastolic blood pressure; Hb= hemoglobin; IQR= interquartile range; SD= standard deviation; SBP= systolic blood pressure
Results	Endpoint	Fenofibrate group (n= 29)*	Simvastatin (n= 28)*
	Laboratory parameters by month 4; p-value (IQR) Urea, mg/dL Creatinine, mg/dL ALT, U/L AST, U/L Albumin, g/dL CK, U/L Hb, g/dL SBP, mmHg DBP, mmHg TC, mg/dL LDL-C, mg/dL HDL-C, mg/dL TG, mg/dL	104 (59 to 179.5); 0.599 8.8 (8.35 to 9.8); 0.593 37 (28 to 44); 0.004† 33 (25 to 37); 0.219 3.81 (3.5 to 4.25); 0.324 112 (100 to 136.5); 0.047† 10 (9.15 to 11.4); 0.084 130 (110 to 140); 0.453 80‡ (70 to 90); 0.330 184 (164.5 to 194); 0.000† 105.64 (80.73 to 124.63); 0.000† 43.89 (33.13 to 64.12); 0.027† 139 (114 to 180); 0.000†	122 (68 to 161); 0.790 9.8 (7.9 to 12.3); 0.556 29 (24.5 to 40); 0.862 31 (26.5 to 40); 0.475 4 (3.68 to 4.23); 0.541 110 (88.75 to 136.75); 0.323 10.15 (9 to 11.47); 0.361 130 (130 to 140); 0.472 90 (80 to 90); 0.104 183 (164 to 203.5); 0.000† 113.25 (85.93 to 127.71); 0.000† 46.36 (36.56 to 52.72); 0.206 139 (108 to 183); 0.000†
	Abbreviations: HDL-C= high-density lipoprotein cholesterol; LDL-C= low-density lipoprotein cholesterol; TC= total cholesterol; TG= triglycerides * By month 4, group 1 had follow-up data for 29 patients only, while group 2 had follow-up data for 28 patients. ^†p< 0.05: Significant within the groups ^‡p< 0.05: Significant between the two groups After 16 weeks, the median reduction in TC, TG, LDL-C and oxidized LDL-C was 25.79%, 44.86%, 32.8%, and 17%, respectively, in group 1 versus 30.34%, 26.8%, 38.52%, and 13%, respectively, in group 2. Glutathione peroxidase increased significantly by 32.01% and 35.4% in groups 1 and 2, respectively. There was no significant difference in C-reactive protein in either group. Notably, changes in the efficacy outcomes between the two treatment groups were not significantly different (all p> 0.05).
Adverse Events	Both drugs were well tolerated during the study with no serious side effects reported.
Study Author Conclusions	In summary, we found out that both the drugs had comparable efficacy and safety when used as intermittent low dose regimen in HD patients. Satisfactory safety profile and improved lipid profile and oxidative stress status are the main outcomes for both simvastatin and fenofibrate in HD in this study. Moreover, patients might have benefited from the use of intermittent low dose regimen in minimizing the drug related adverse events. However, these results need to be confirmed by larger studies with longer follow-up periods to ensure that the effects of both drugs will be sustained with favorable effects on cardiovascular disease development and mortality rates.
InpharmD Researcher Critique	The study's main limitation was its small sample size, as only 60 out of 402 eligible patients could be recruited due to recruitment challenges and limited resources. This may have obscured potential differences between the two treatments and reduced statistical power. Notably, the lack of adverse events may be due to patients benefitting from use of an intermittent low dose regimen.

References:

Abdel Magid AM, Abbassi MM, Iskander EEM, Mohamady O, Farid SF. Randomized comparative efficacy and safety study of intermittent simvastatin versus fenofibrate in hemodialysis. J Comp Eff Res. 2017;6(5):413-424. doi:10.2217/cer-2016-0076

Long-term use of fenofibrate is associated with increased prevalence of gallstone disease among patients undergoing maintenance hemodialysis
Design	Observational, cross-sectional study N= 108
Objective	To assess the influence of long-term use of lipid-lowering drugs (LLDs) on the prevalence of gallstone disease (GSD) among patients undergoing hemodialysis (HD)
Study Groups	Lovastatin (n= 35) Fenofibrate (n= 34) No LLD (n= 39)
Inclusion Criteria	HD patients; received LLDs for a total period of more than 1 year
Exclusion Criteria	Undergone peritoneal dialysis or transplantation; received other types of LLDs (except lovastatin and fenofibrate); used oral conceptive agents; history of GSD prior to receiving LLDs
Methods	Data were collected from patients at two dialysis centers who received either 20 mg lovastatin tablets or 200 mcg fenofibrate micronized capsules after HD initiation. Age- and sex-matched patients were chosen to serve as a control group. Biochemical daata and parameters of dialysis adequacy were collected, in addition to ultrasonography to determine gallstone presence. Subjects were asked to fast for at least 8 h before sonography studies.
Duration	December 2009 (duration not provided)
Outcome Measures	GSD prevalence
Baseline Characteristics		No LLD (n= 39)	Lovastatin (n= 35)	Fenofibrate (n= 34)
	Age, years	59.0 ± 14.1	62.8 ± 14.9	58.4 ± 10.1
	Female	51.3%	40.0%	52.9%
	Duration, years HD LLD treatment	6.2 ± 1.6 -	5.2 ± 2.0 3.2 ± 2.3	5.4 ± 2.1 3.1 ± 1.9
	Body mass index, kg/m2	23.9 ± 3.3	24.1 ± 3.6	24.4 ± 3.4
	Laboratory parameters Corrected calcium, mg/dL Phosphate, mg/dL Total cholesterol, mg/dL Triglyceride, mg/dL	9.7 ± 1.0 4.8 ± 1.5 156 ± 23 131 ± 26^a	9.5 ± 0.7 4.1 ± 1.7 198 ± 48 148 ± 31^b	9.8 ± 0.4 4.6 ± 1.4 177 ± 26 199 ± 43^a,b
	Comorbidities Diabetes mellitus Cholelithiasis	33.3% 10.3%^c	45.7% 11.4%^d	52.9% 35.3%^c,d
	^a Control versus fenofibrate (p< 0.01). ^b Lovastatin versus fenofibrate (p< 0.05). ^c Control versus fenofibrate (p< 0.05). ^d Lovastatin versus fenofibrate (p< 0.05).
Results	Endpoint	No LLD (n= 39)	Lovastatin (n= 35)	Fenofibrate (n= 34)
	GSD development	4 (10.3%)	4 (11.4%)	12 (35.3%)
	Cholecystectomy	1 (2.6%)	1 (2.9%)	9 (26.5%)
	Patients receiving fenofibrate had a significantly higher prevalence of GSD versus lovastatin or control groups (p< 0.05), as well as the highest cholecystectomy rate among the three groups (p= 0.001). In a subgroup analysis, increased age (p= 0.020), female gender (p= 0.013), higher daily dose of fenofibrate (p= 0.006), and longer duration of treatment (p= 0.048) were associated with increased risks for GSD.
Adverse Events	Not disclosed
Study Author Conclusions	In conclusion, our study demonstrated that HD patients receiving fibrates had a higher prevalence of GSD. Among HD patients on fibrates, those on a higher daily dose, the elderly, women, and patients with a longer duration of treatment, were more likely to develop GSD. Our findings highlight the fact that the use of fenofibrates should be avoided in patients undergoing long-term HD.
InpharmD Researcher Critique	Due to variance in clinical practice, findings in the Taiwanese patient population may not be wholly applicable to a domestic patient population. Additionally, although GSD prevalence was reported among the patient groups, it is uncertain whether GSD development is due to fenofibrate administration, or if development had begun prior to formuation.

References:

Liang CC, Wang IK, Kuo HL, et al. Long-term use of fenofibrate is associated with increased prevalence of gallstone disease among patients undergoing maintenance hemodialysis. Ren Fail. 2011;33(5):489-493. doi:10.3109/0886022X.2011.577545

Fenofibrate Delays the Need for Dialysis and Reduces Cardiovascular Risk Among Patients With Advanced CKD
Design	Retrospective, observational cohort study N= 52,890
Objective	To compare outcomes among advanced chronic kidney disease (CKD) patients treated with fenofibrate, statins, a combination of both, or none of the above
Study Groups	Nonuser (n= 27,996) Fenofibrate (n= 1,774) Statins (n= 22,338) Fenofibrate + statin (F+S) combination (n= 782)
Inclusion Criteria	Aged ≥20 years with advanced CKD (erythropoiesis-stimulating agent first prescribed after outpatient CKD diagnosis between the index date), diagnosed hyperlipidemia
Exclusion Criteria	Never diagnosed with hyperlipidemia, received kidney transplantation, received any dialysis before the index date, or taken another type of fibrate or gemfibrozil within three months before the index date
Methods	Patient data was collected from Taiwan’s National Health Insurance Research Database and randomized into four cohorts based on whether they received no fenofibrate or statin therapy, fenofibrate monotherapy, statin monotherapy, or a combination of fenofibrate and a statin.
Duration	Index date: January 1, 2001 to December 31, 2013
Outcome Measures	All-cause mortality, cardiovascular death, major adverse cardiac and cerebrovascular events (MACCEs), and incidence of permanent dialysis
Baseline Characteristics		Nonuser (n= 27,996)	Fenofibrate (n= 1,774)	Statins (n= 22,338)	F+S combination (n= 782)
	Age, years 20-64 65-74 ≥ 75	66.8 ± 12.6 11,541 (41.2%) 8,322 (29.7%) 8,133 (29.1%)	63.7 ± 12.5 921 (51.9%) 488 (27.5%) 365 (20.6%)	63.4 ± 12.4 11,985 (53.7%) 6,145 (27.5%) 4,208 (18.8%)	60.9 ± 11.1 499 (63.8%) 205 (26.2%) 78 (10.0%)
	Female	49.6%	49.9%	51.7%	49.7%
	CKD duration, years	5.5 ± 3.8	5.5 ± 3.7	5.3 ± 3.9	5.7 ± 3.7
	Outpatient visits in previous year At nephrology In general	13.0 ± 10.0 42.0 ± 24.0	13.0 ± 11.0 45.0 ± 23.0	14.0 ± 10.0 43.0 ± 22.0	13.0 ± 11.0 47.0 ± 24.0
	Comorbid conditions HTN Diabetes mellitus Atrial fibrillation Liver cirrhosis PAD Dementia SLE	24,854 (88.8%) 19,219 (68.7%) 928 (3.3%) 900 (3.2%) 1,170 (4.2%) 1,060 (3.8%) 228 (0.81%)	1,596 (90.0%) 1,438 (81.1%) 44 (2.5%) 29 (1.6%) 74 (4.2%) 44 (2.5%) 12 (0.68%)	20,039 (89.7%) 17,556 (78.6%) 482 (2.2%) 395 (1.8%) 958 (4.3%) 495 (2.2%) 192 (0.86%)	714 (91.3%) 683 (87.3%) 14 (1.8%) 9 (1.2%) 32 (4.1%) 11 (1.4%) 0
	History of event Heart failure Stroke Myocardial infarction	6,518 (23.3%) 6,357 (22.7%) 1,998 (7.1%)	352 (19.8%) 374 (21.1%) 115 (6.5%)	4,784 (21.4%) 4,630 (20.7%) 1,997 (8.9%)	168 (21.5%) 185 (23.7%) 78 (10.0%)
	Medications ACEi/ARB Other anti-HTN Aspirin/clopidogrel NSAIDs Steroid Proton pump inhibitor Insulin Sulfonylurea DPP-4 inhibitors Acarbose Loops diuretics Ketosteril^a Pentoxyfillin Sodium bicarbonate	12,852 (45.9%) 21,671 (77.4%) 7,220 (25.8%) 2,507 (9.0%) 1,404 (5.0%) 2,089 (7.5%) 5,730 (20.5%) 5,828 (20.8%) 1,390 (5.0%) 2,062 (7.4%) 14,218 (50.8%) 326 (1.2%) 4,632 (16.6%) 1,899 (6.8%)	1,025 (57.8%) 1,511 (85.2%) 642 (36.2%) 188 (10.6%) 71 (4.0%) 143 (8.1%) 699 (39.4%) 435 (24.5%) 142 (8.0%) 205 (11.6%) 959 (54.1%) 17 (0.96%) 360 (20.3%) 105 (5.9%)	12,996 (58.2%) 19,357 (86.7%) 8,496 (38.0%) 1,603 (7.2%) 1,228 (5.5%) 1,485 (6.7%) 7,187 (32.2%) 6,180 (27.7%) 2,077 (9.3%) 2,534 (11.3%) 13,793 (61.8%) 354 (1.6%) 4,974 (22.3%) 1,630 (7.3%)	524 (67.0%) 697 (89.1%) 345 (44.1%) 78 (10.0%) 28 (3.6%) 48 (6.1%) 369 (47.2%) 241 (30.8%) 115 (14.7%) 128 (16.4%) 489 (62.5%) 14 (1.8%) 201 (25.7%) 54 (6.9%)
	Follow-up, years	3.2 ± 2.8	3.3 ± 2.6	3.3 ± 2.7	3.2 ± 2.5
	Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; DPP-4, dipeptidyl peptidase-4; HTN, hypertension; NSAIDs, nonsteroidal anti-inflammatory drugs; PAD, peripheral artery disease; SLE, systemic lupus erythematosus ^aKetosteril, Fresenius Kabi, Bad Homburg, Germany; alpha-Ketoanalogues supplementation The number of male patients (p= 0.041) and patients with PAD (p= 0.010) differed among groups.
Results	Endpoint		HR or SHR (95% CI) (column vs row)
	Endpoint	Incidence^a(95% CI)	Fenofibrate (n= 1,774)	Statins (n= 22,338)	F+S combination (n= 782)
	All-cause mortality Nonuser Fenofibrate Statin Combination	15.4 (15.2 to 15.6) 13.5 (13.3 to 13.7) 13.9 (13.7 to 14.1) 13.2 (13.0 to 13.5)	0.88 (0.81 to 0.96)^c -- -- --	0.91 (0.88 to 0.93)^c 1.03 (0.94 to 1.12) -- --	0.88 (0.76 to 1.01) 0.99 (0.84 to 1.17) 0.97 (0.84 to 1.12) --
	Cardiovascular death Nonuser Fenofibrate Statin Combination	7.9 (7.8 to 8.1) 6.7 (6.5 to 6.8) 7.4 (7.3 to 7.6) 8.0 (7.8 to 8.1)	0.84 (0.75 to 0.94)^c -- -- --	0.94 (0.90 to 0.97)^c 1.12 (0.995 to 1.25) -- --	1.01 (0.82 to 1.24) 1.20 (0.95 to 1.51) 1.08 (0.88 to 1.32) --
	MACCEs^b Nonuser Fenofibrate Statin Combination	11.6 (11.4 to 11.8) 11.3 (11.1 to 11.5) 11.2 (11.0 to 11.3) 11.8 (11.6 to 12.0)	0.97 (0.88 to 1.07) -- -- --	0.96 (0.93 to 0.995)^c 0.99 (0.90 to 1.09) -- --	1.02 (0.86 to 1.21) 1.05 (0.86 to 1.27) 1.06 (0.89 to 1.26) --
	Permanent dialysis Nonuser Fenofibrate Statin Combination	131.6 (130.4 to 132.8) 87.4 (86.5 to 88.3) 126.5 (125.3 to 127.6) 92.9 (91.8 to 94.1)	0.78 (0.77 to 0.80)^c -- -- --	1.00 (0.99 to 1.01) 1.27 (1.26 to 1.29)^c -- --	0.90 (0.89 to 0.91)^c 1.15 (1.13 to 1.17)^c 0.90 (0.89 to 0.92)^c --
	Abbreviations: CI, confidence interval; HR, hazard ratio; SHR, subdistribution hazard ratio; MACCEs, major adverse cardiac and cerebrovascular events; SHR, subdistribution hazard ratio ^aIncidence density is presented as event numbers per 100 person-years (PY). ^bComposite of cardiovascular death, ischemic stroke, or acute myocardial infarction. ^cp< 0.05
	Mean duration between index date and initiation of permanent dialysis for the fenofibrate group was 9.7 months, which was significantly longer than the combination group (8.3 months), statin group (6.9 months), and the nonuser group (6.9 months).
	The fenofibrate + high-intensity statin combination (atorvastatin 40 mg or rosuvastatin 20 mg) and fenofibrate monotherapy showed an equal effect in reducing the probability of permanent dialysis (83.7 vs. 87.4 events/100 PYs; SHR 0.99; 95% CI 0.95 to 1.02). Fenofibrate + high-intensity statin had a significantly lower risk of MACCEs compared to all other cohorts (combination vs. nonuser: HR 0.48; 95% CI 0.26 to 0.88; combination vs. fenofibrate: HR 0.49; 95% CI 0.27 to 0.91; and combination vs. high-intensity statin: HR 0.50; 95% CI 0.27 to 0.92). Fenofibrate with low- to moderate-intensity statins did not exhibit any additional beneficial effect compared to fenofibrate alone.
Adverse Events	See Results
Study Author Conclusions	For patients with advanced CKD, continuing fenofibrate may provide a protective effect on CV outcomes equal to that of statins, and it may further delay the need for permanent dialysis. The combination of fenofibrate and high-intensity statins may have additional benefits.
InpharmD Researcher Critique	Due to the study design, adverse events other than major adverse cardiac and cerebrovascular events were not addressed, which limits the safety data collected from this trial with respect to patients with advanced CKD. Data derived from a Taiwanese database may not be applicable to a domestic patient population.

References:

Yen CL, Fan PC, Lin MS, et al. Fenofibrate Delays the Need for Dialysis and Reduces Cardiovascular Risk Among Patients With Advanced CKD. J Clin Endocrinol Metab. 2021;106(6):1594-1605. doi:10.1210/clinem/dgab137