Risk of gout flare after medication: prescription symmetry sequence analysis.

OBJECTIVES: The research aimed to study the following questions: (1) five well-known gout-related medications were selected to test the validity of the prescription symmetry sequence analysis in Taiwan; (2) four exploratory medications were selected to test their relation to gout flares. METHODS: We utilized the 2003-2017 dataset of the Taiwan National Health Insurance Program containing all claims data with 2 million beneficiaries as a data source. In order to explore the temporal association, we designed a scenario of medication-induced gout flares. Nine medications were selected as the index agent, including aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol, pyrazinamide, metformin, pioglitazone, fenofibrate, and losartan. The gout flare was defined as subjects with use of the marker agent for treatment of gout flares. The observation-window period between initiation of the index agent and initiation of the marker agent was 1 year. Subjects who used an index agent and a marker agent on the same day were excluded. The prescription symmetry sequence analysis was carried out to compare the observed number of persons who took an index agent prior to starting a marker agent with the observed number of persons who took a marker agent before starting an index agent. The adjusted sequence ratio (adjusted SR) with 95% confidence interval was applied to estimate the relation between an index agent and the marker agent. RESULTS: Among five medications including aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol, and pyrazinamide, the adjusted sequence ratio ranged from 1.15 to 3.35 and all reached statistical significance. Fenofibrate use and losartan use were associated with a lower probability of gout flares, with reaching statistical significance (adjusted SR = 0.60 for fenofibrate and adjusted SR = 0.92 for losartan). Metformin use was associated with a greater probability of gout flares, with reaching statistical significance (adjusted SR = 1.14). Pioglitazone use did not reach statistical significance. CONCLUSION: Based on the confirmatory analysis including five well-known gout-related medications, this study supports that the prescription symmetry sequence analysis can be used to detect an adverse drug event associated with one potential offending agent. The exposure to fenofibrate or losartan might be a protective factor against gout flares. Metformin use could be associated with a greater probability of gout flares, but this finding should be validated by other studies. KEY POINTS: • What is already known about this subject? 1. The prescription symmetry sequence analysis is a useful method for detecting an adverse drug reaction associated with one potential offending drug. 2. Numerous medications are found to induce gout flares. • What does this study add? 1. The prescription symmetry sequence analysis supports the evidence that aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol and pyrazinamide are associated with a greater probability of gout flares. 2. The exposure to fenofibrate or losartan might be a protective factor against gout flares. 3. Metformin use could be associated with a greater probability of gout flares. • How might this impact on clinical practice or future developments? 1. Clinicians should always consider the possibility of medication-induced gout flares. If gout flares develop, discontinuation of risky medications is the first step. Then prescribing cascades can be eliminated.

Role of Fenofibrate Use in Dyslipidemia and Related Comorbidities in the Asian Population: A Narrative Review.

Hypertriglyceridemia and decreased high-density lipoprotein cholesterol (HDL-C) persist despite statin therapy, contributing to residual atherosclerotic cardiovascular disease (ASCVD) risk. Asian subjects are metabolically more susceptible to hypertriglyceridemia than other ethnicities. Fenofibrate regulates hypertriglyceridemia, raises HDL-C levels, and is a recommended treatment for dyslipidemia. However, data on fenofibrate use across different Asian regions are limited. This narrative review summarizes the efficacy and safety data of fenofibrate in Asian subjects with dyslipidemia and related comorbidities (diabetes, metabolic syndrome, diabetic retinopathy, and diabetic nephropathy). Long-term fenofibrate use resulted in fewer cardiovascular (CV) events and reduced the composite of heart failure hospitalizations or CV mortality in type 2 diabetes mellitus. Fenofibrate plays a significant role in improving irisin resistance and microalbuminuria, inhibiting inflammatory responses, and reducing retinopathy incidence. Fenofibrate plus statin combination significantly reduced composite CV events risk in patients with metabolic syndrome and demonstrated decreased triglyceride and increased HDL-C levels with an acceptable safety profile in those with high CV or ASCVD risk. Nevertheless, care is necessary with fenofibrate use due to possible hepatic and renal toxicities in vulnerable individuals. Long-term trials and real-world studies are needed to confirm the clinical benefits of fenofibrate in the heterogeneous Asian population with dyslipidemia.

Associations of omega-3 fatty acids vs. fenofibrate with adverse cardiovascular outcomes in people with metabolic syndrome: propensity matched cohort study.

AIMS: Omega-3 fatty acids and fenofibrates have shown some beneficial cardiovascular effects; however, their efficacy has not been compared. This study aimed to compare the effectiveness of currently available omega-3 fatty acids and fenofibrate for reducing major adverse cardiovascular events (MACE). METHODS AND RESULTS: From a nationwide population-based cohort in South Korea (2008-2019), individuals with metabolic syndrome (≥30 years) who received statin with omega-3 fatty acids and those receiving statin with fenofibrate were matched by propensity score (n = 39 165 in both groups). The primary outcome was MACE, including ischaemic heart disease (IHD), ischaemic stroke (IS), and death from cardiovascular causes. The risk of MACE was lower [hazard ratio (HR), 0.79; 95% confidence interval (CI), 0.74-0.83] in the fenofibrate group than in the omega-3 fatty acid group. Fenofibrate was associated with a lower incidence of IHD (HR, 0.72; 95% CI, 0.67-0.77) and hospitalization for heart failure (HR, 0.90; 95% CI, 0.82-0.97), but not IS (HR, 0.90; 95% CI, 0.81-1.00) nor death from cardiovascular causes (HR, 1.07; 95% CI, 0.97-1.17). The beneficial effect of fenofibrate compared to omega-3 fatty acids was prominent in patients with preexisting atherosclerotic cardiovascular disease and those receiving lower doses of omega-3 fatty acids (≤2 g per day). CONCLUSION: In a real-world setting, fenofibrate use was associated with a lower risk of MACE compared with low-dose omega-3 fatty acids when added to statins in people with metabolic syndrome.

Efficacy and safety of fenofibrate in combination with phototherapy for the treatment of neonatal hyperbilirubinemia: a systematic review and meta-analyses.

Phototherapy is the standard treatment for neonatal jaundice. We aimed to review the efficacy and safety of fenofibrate as an adjunct therapy. Twelve databases were searched and a systematic review and meta-analysis were conducted. Mean change (MC), mean difference (MD), and risk ratios (RR) with a 95% confidence interval (CI) were calculated using a random effects model. The GRADE approach was used to evaluate the evidence's certainty. Nine randomized trials were included. The MC of total serum bilirubin (mg/dL) was significant at 12, 24, 36, 48, and 72 h with respective MC (95% CI) values of -0.46 (-0.61, -0.310), -1.10 (-1.68, -0.52), -2.06 (-2.20, -1.91), -2.15 (-2.74, -1.56), and -1.13 (-1.71, -0.55). The FEN + PT group had a shorter duration of phototherapy (MD: -14.36 h; 95% CI: -23.67, -5.06) and a shorter hospital stay (MD: -1.40 days; 95% CI: -2.14, -0.66). There was no significant difference in the risk of complications (RR: 0.89; 95% CI: 0.54, 1.46) or the need for exchange transfusion (RR: 0.58; 95% CI: 0.12, 2.81). The certainty of the evidence was very low for all outcomes. In conclusion, fenofibrate might be a safe adjunct to neonatal phototherapy. Larger randomized controlled trials are needed for the confirmation of these results.

Fenofibrate for diabetic retinopathy.

BACKGROUND: Diabetic retinopathy (DR) remains a major cause of sight loss worldwide, despite new therapies and improvements in the metabolic control of people living with diabetes. Therefore, DR creates a physical and psychological burden for people, and an economic burden for society. Preventing the development and progression of DR, or avoiding the occurrence of its sight-threatening complications is essential, and must be pursued to save sight. Fenofibrate may be a useful strategy to achieve this goal, by reversing diabetes' effects and reducing inflammation in the retina, as well as improving dyslipidaemia and hypertriglyceridaemia.  OBJECTIVES: To investigate the benefits and harms of fenofibrate for preventing the development and progression of diabetic retinopathy in people with type 1 (T1D) or type 2 diabetes (T2D), compared with placebo or observation. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and three trials registers (February 2022). SELECTION CRITERIA: We included randomised controlled trials (RCTs) that included people with T1D or T2D, when these compared fenofibrate with placebo or with observation, and assessed the effect of fenofibrate on the development or progression of DR (or both). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for data extraction and analysis. Our primary outcome was progression of DR, a composite outcome of 1) incidence of overt retinopathy for participants who did not have DR at baseline, or 2) advancing two or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale for participants who had any DR at baseline (or both), based on the evaluation of stereoscopic or non-stereoscopic fundus photographs, during the follow-up period. Overt retinopathy was defined as the presence of any DR observed on stereoscopic or non-stereoscopic colour fundus photographs. Secondary outcomes included the incidence of overt retinopathy, reduction in visual acuity of participants with a reduction in visual acuity of 10 ETDRS letters or more, proliferative diabetic retinopathy, and diabetic macular oedema; mean vision-related quality of life, and serious adverse events of fenofibrate. We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included two studies and their eye sub-studies (15,313 participants) in people with T2D. The studies were conducted in the US, Canada, Australia, Finland, and New Zealand; follow-up period was four to five years. One was funded by the government, the other by industry. Compared to placebo or observation, fenofibrate likely results in little to no difference in progression of DR (risk ratio (RR) 0.86; 95% confidence interval (CI) 0.60 to 1.25; 1 study, 1012 participants; moderate-certainty evidence) in a population with and without overt retinopathy at baseline. Those without overt retinopathy at baseline showed little or no progression (RR 1.00, 95% CI 0.68 to 1.47; 1 study, 804 participants); those with overt retinopathy at baseline found that their DR progressed slowly (RR 0.21, 95% CI 0.06 to 0.71; 1 study, 208 people; test for interaction P = 0.02). Compared to placebo or observation, fenofibrate likely resulted in little to no difference in either the incidence of overt retinopathy (RR 0.91; 95% CI 0.76 to 1.09; 2 studies, 1631 participants; moderate-certainty evidence); or the incidence of diabetic macular oedema (RR 0.39; 95% CI 0.12 to 1.24; 1 study, 1012 participants; moderate-certainty evidence). The use of fenofibrate increased severe adverse effects (RR 1.55; 95% CI 1.05 to 2.27; 2 studies, 15,313 participants; high-certainty evidence). The studies did not report on incidence of a reduction in visual acuity of 10 ETDRS letters or more, incidence of proliferative diabetic retinopathy, or mean vision-related quality of life. AUTHORS' CONCLUSIONS: Current, moderate-certainty evidence suggests that in a mixed group of people with and without overt retinopathy, who live with T2D, fenofibrate likely results in little to no difference in progression of diabetic retinopathy. However, in people with overt retinopathy who live with T2D, fenofibrate likely reduces the progression. Serious adverse events were rare, but the risk of their occurrence was increased by the use of fenofibrate. There is no evidence on the effect of fenofibrate in people with T1D. More studies, with larger sample sizes, and participants with T1D are needed. They should measure outcomes that are important to people with diabetes, e.g. change in vision, reduction in visual acuity of 10 ETDRS letters or more, developing proliferative diabetic retinopathy; and evaluating the requirement of other treatments, e.g. injections of anti-vascular endothelial growth factor therapies, steroids.

Dermatitis asteatósica o de craquelé. A propósito de un caso / Asteatotic or Craquelé Dermatitis. A Case Study

La dermatitis de craquelé o dermatitis asteatósica es una enfermedad cutánea caracterizada por piel eritematosa, pruriginosa, seca y agrietada, que afecta preferentemente a personas de edad avanzada, siendo el tipo de eccema más común en pacientes ancianos. Entre los factores que contribuyen a su aparición, destacan la edad, el clima estacional y los hábitos del baño, que pueden favorecer la alteración del estrato córneo y la aparición de fisuras.(AU)

Craquelé dermatitis or asteatotic dermatitis is a skin disease characterized by erythematous, itchy, dry and cracked skin, which preferentially affects the elderly and is the most common type of eczema in elderly patients. Among the factors that contribute to its appearance are age, seasonal climate and bathing habits, which can favour the alteration of the stratum corneum and the onset of fissures.(AU)

Saroglitazar is noninferior to fenofibrate in reducing triglyceride levels in hypertriglyceridemic patients in a randomized clinical trial.

Saroglitazar, being a dual PPAR-α/γ agonist, has shown beneficial effect in diabetic dyslipidemia and hypertriglyceridemia. Fibrates are commonly used to treat severe hypertriglyceridemia. However, the effect of saroglitazar in patients with moderate to severe hypertriglyceridemia was not evaluated. We conducted a study to compare the efficacy and safety of saroglitazar (4 mg) with fenofibrate (160 mg) in patients with moderate to severe hypertriglyceridemia. This was a multicenter, randomized, double-blinded, double-dummy, active-control, and noninferiority trial in adult patients with fasting triglyceride (TG) levels of 500-1,500 mg/dl. The patients were randomized in a 1:1 ratio to receive daily dose of saroglitazar or fenofibrate for 12 weeks. The primary efficacy end point was the percent change in TG levels at week 12 relative to baseline. The study comprised of 41 patients in the saroglitazar group and 41 patients in the fenofibrate group. We found that the percent reduction from baseline in TG levels at week 12 was significantly higher in the saroglitazar group (least square mean = -55.3%; SE = 4.9) compared with the fenofibrate group (least square mean = -41.1%; SE = 4.9; P = 0.048). Overall, 37 treatment-emergent adverse events (AEs) were reported in 24 patients (saroglitazar: 13; fenofibrate: 11). No serious AEs were reported, and no patient discontinued the study because of AEs. We conclude that saroglitazar (4 mg) is noninferior to fenofibrate (160 mg) in reducing TG levels after 12 weeks of treatment, was safe, and well tolerated.

Association of Fenofibrate Use and the Risk of Progression to Vision-Threatening Diabetic Retinopathy.

Importance: Diabetic retinopathy (DR) may progress from nonproliferative DR (NPDR) to vision-threatening DR (VTDR). Studies have investigated fenofibrate use as a protective measure with conflicting results, and fenofibrate is not typically considered by ophthalmologists in the management of DR currently. Objective: To assess the association between fenofibrate use and the progression from NPDR to VTDR, proliferative DR (PDR), or diabetic macular edema (DME). Design, Setting, and Participants: This multicenter cohort study used medical claims data from a large US insurer. Cohorts were created from all patients with NPDR 18 years or older who had laboratory values from January 1, 2002, to June 30, 2019. Exclusion criteria consisted of any previous diagnosis of PDR, DME, proliferative vitreoretinopathy, or treatment used in the care of VTDR. Patients were also excluded if they had a diagnosis of VTDR within 2 years of insurance plan entry, regardless of when NPDR was first noted in the plan. Exposures: Fenofibrate use. Main Outcomes and Measures: The main outcomes were a new diagnosis of VTDR (a composite outcome of either PDR or DME) or DME and PDR individually. A time-updating model for all covariates was used in multivariate Cox proportional hazard regression to determine hazards of progressing to an outcome. Additional covariates included NPDR severity scale, systemic illnesses, demographics, kidney function (based on estimated glomerular filtration rate level), hemoglobin A1c, hemoglobin, and insulin use. Results: A total of 5835 fenofibrate users with NPDR at baseline (mean [SD] age, 65.3 [10.4] years; 3564 [61.1%] male; 3024 [51.8%] White) and 144 417 fenofibrate nonusers (mean [SD] age, 65.7 [12.3] years; 73 587 [51.0%] male; 67 023 [46.4%] White) were included for analysis. Of these, 27 325 (18.2%) progressed to VTDR, 4086 (2.71%) progressed to PDR, and 22 750 (15.1%) progressed to DME. After controlling for all covariates, Cox model results showed fenofibrates to be associated with a decreased risk of VTDR (hazard ratio, 0.92 [95% CI, 0.87-0.98]; P = .01) and PDR (hazard ratio, 0.76 [95% CI, 0.64-0.90]; P = .001) but not DME (hazard ratio, 0.96 [95% CI, 0.90-1.03]; P = .27). Conclusions and Relevance: In this study, fenofibrate use was associated with a decreased risk of PDR and VTDR but not DME alone. These findings support the rationale for additional clinical trials to determine if these associations may be representative of a causal relationship between fenofibrate use and reduced risk of PDR or VTDR.

Fenofibrate mitigates testosterone induced benign prostatic hyperplasia via regulation of Akt/FOXO3a pathway and modulation of apoptosis and proliferation in rats.

Benign prostatic hyperplasia (BPH) is one of the most age-related health problems that commonly affect men. Regrettably, many individuals may not respond to current medical therapies or develop resistance to them. Accordingly, this study aimed to uncover how potentially fenofibrate, a lipid lowering agent, can ameliorate the induced BPH in rats. Forty rats were categorized randomly into four groups; the control group was given the vehicle (olive oil); the BPH model received testosterone propionate (20 mg/kg daily; s.c.) for 4 weeks; BPH-induced group received finasteride (10 mg/kg daily; p.o.) and BPH-induced group received fenofibrate (80 mg/kg daily; p.o.). After testosterone administration, both weight and relative weight of the prostate increased. Additionally, testosterone upregulated androgen receptor (AR), 5α-reductase gene expression and increased prostate proliferation. Histopathological examination confirmed that testosterone disrupted the histo-architecture of the prostate and caused marked hyperplasia of glands and stroma. On the other hand, fenofibrate administration reverted most hyperplastic changes of testosterone, it significantly reduced weight, relative weight of the prostate and dihydrotestosterone (DHT) level compared to BPH group. Also fenofibrate significantly decreased AR and 5α-reductase gene expression. Fenofibrate significantly suppressed ps473 Akt expression causing FOXO3a nuclear inclusion, which triggered induction of apoptosis. As well, Bax/Bcl2 ratio and caspase 3 content were significantly enhanced. Fenofibrate significantly diminished cyclin D1 immunoexpression and restored normal histo-architecture. In conclusion, this study emphasizes the preventive effect of fenofibrate in BPH rat model. This can be accredited, at least partly, to inhibiting AR and 5α-reductase expressions, the anti-proliferative, and pro-apoptotic activity of fenofibrate via modulation of Akt/FOXO3a pathway.

Event Monitoring and Evaluation by Community Pharmacists in Japan: A Pilot Study on Fenofibrate and Pemafibrate.

BACKGROUND: The Japan Pharmaceutical Association has conducted drug event monitoring to detect drug events related to pemafibrate. As there are a few studies on the safety of pemafibrate in clinical settings, a pilot study evaluating the association between drug use and detected events was performed in Japan. AIMS: In this study, the association between detected events and the use of pemafibrate, utilizing pharmacy records maintained by community pharmacists, was investigated. We identified the newuser cohort using a test and active comparison drug and collected the baseline information. An active comparison group comprising new users was used to assess the events. METHODS: A retrospective cohort study using questionnaires regarding baseline and event data was conducted by community pharmacists belonging to the Japan Pharmaceutical Association. The incidence of event and estimated hazard ratio were calculated using the Cox proportional hazards model that was adjusted for confounding factors, such as age and sex. RESULTS: A total of 1294 patients using pemafibrate and 508 patients using fenofibrate were identified as new drug users. The most reported events involving suspected adverse reactions and add-on drugs were increased blood pressure and lipid-lowering effects with pemafibrate use, and nasopharyngitis, pruritus, dizziness, and lipid-lowering effects with fenofibrate use. No significant differences were found in commonly occurring events, except that an add-on anti-hypertensive drug has been used by pemafibrate users compared to fenofibrate users. CONCLUSION: This study conducted by pharmacists can facilitate the safety assessment of newly marketed drugs, as few drug use investigations with a comparator are carried out by the Japanese authority for pharmaceutical companies. However, further research is required.

Efficacy and Safety of Fenofibrate-Statin Combination Therapy in Patients With Inadequately Controlled Triglyceride Levels Despite Previous Statin Monotherapy: A Multicenter, Randomized, Double-blind, Phase IV Study.

PURPOSE: Residual cardiovascular risk reduction by fenofibrate in patients with high serum triglyceride (TG) levels despite previous statin monotherapy is not well characterized. The purpose of this study was to evaluate the efficacy and safety of a combination of choline fenofibrate and statin in patients with inadequately controlled TG levels despite previous statin monotherapy. METHODS: This prospective, multicenter, randomized, double-blind study was conducted in Korea. A total of 133 patients with controlled LDL-C but elevated TG levels, already receiving statin monotherapy, were enrolled in the study, which was conducted from July 2018 to December 2019. Patients were randomly assigned to receive combination therapy with choline fenofibrate and statin or statin monotherapy in a 1:1 ratio. After 8 weeks of treatment, the lipid profiles and safety parameters of the patients in the 2 groups were compared. FINDINGS: The study included 127 patients (64 in the combination group and 63 in the control group) older than 19 years. After 8 weeks of therapy, mean serum TG levels significantly decreased from 269.8 to 145.5 mg/dL (P < 0.0001) in the combination therapy group, whereas no significant changes occurred in the statin monotherapy group (from 271.1 to 280.5 mg/dL). Contrarily, the mean serum HDLC levels significantly increased from 45.0 to 50.4 mg/dL (P = 0.0004) in the combination therapy group, whereas there were no significant changes in the monotherapy group (from 44.3 to 44.7 mg/dL). There were no additional serious adverse events in the combination therapy group compared with the statin monotherapy group. IMPLICATIONS: The combination therapy using choline fenofibrate and statin was found to be effective in serum TG control and likely tolerable in patients with high TG levels despite statin monotherapy. A larger study, conducted for a longer duration, is needed to evaluate the effectiveness of this combination in reducing cardiovascular risk. ClinicalTrials.gov identifier: NCT03874260.

The relationship of neutrophil elastase and proteinase 3 with risk factors, and chronic complications in type 2 diabetes: A Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) sub-study.

INTRODUCTION: Neutrophil elastase (NE) and proteinase 3 (PR3) are novel inflammation biomarkers. We investigated their associations with chronic complications, determinants of biomarker levels and effects of fenofibrate in patients with type 2 diabetes mellitus (T2DM) from Fenofibrate Intervention and Event Lowering in Diabetes study. METHODS: Plasma NE and PR3 levels were quantified at baseline (n = 2000), and relationships with complications over 5-years assessed. Effects of fenofibrate on biomarker levels (n = 200) were determined at four follow-up visits. RESULTS: Higher waist-to-hip ratio, homocysteine and C-reactive protein and lower apoA-II were determinants of higher NE and PR3 levels. Higher NE levels were associated with on-trial stroke and cardiovascular mortality, and higher PR3 levels with on-trial stroke, but associations were not significant after adjustment for confounding factors. Although higher NE and PR3 levels were associated with baseline total microvascular disease, only NE levels were associated with on-trial neuropathy or amputation. These associations were not significant after adjusting for multiple comparisons. NE and PR3 levels did not change with fenofibrate. CONCLUSIONS: In T2DM plasma NE and PR3 levels are associated with vascular risk factors, and total microvascular disease at baseline, but on rigorous analyses were not associated with on-trial complications. Levels were not changed by fenofibrate.

Liver injury caused by fenofibrate within 48 h after first administration: a case report.

BACKGROUND: Fenofibrate is commonly used in the treatment of dyslipidemia. Fenofibrate is related to mild aminotransferase elevations and in some cases severe chronic injury such as fibrosis or cirrhosis, resulting in liver transplantation or death. The latency of disease has been reported to range between weeks to years. CASE PRESENTATION: A 63 years old male with hypertriglyceridemia developed symptoms of fatigue and anorexia 48 h after taking fenofibrate for the first time. The patient's aminotransferase level was more than 10 times ULN. Immediately, fenofibrate was discontinued and aminotransferase level returned to normal 23 days later. To assess causality between the drug and liver damage, the standardized Roussel Uclaf Causality Assessment Method (RUCAM) was used. The patient's RUCAM score was 7, which fell in the group of "probable". Eight months later, follow-up examination suggested the liver function was normal. CONCLUSIONS: Weakness, fatigue and abnormal liver function during fenofibrate therapy should be closely monitored and trigger prompt withdrawal if these symptoms occur.

Effects of fenofibrate therapy on renal function in primary gout patients.

OBJECTIVE: To investigate the incidence and potential risk factors for development of fenofibrate-associated nephrotoxicity in gout patients. METHODS: A total of 983 gout patients on fenofibrate treatment who visited the dedicated Gout Clinic at the Affiliated Hospital of Qingdao University between September 2016 and June 2020 were retrospectively enrolled from the electronic records system. Fenofibrate-associated nephrotoxicity was defined as an increase in serum creatinine (SCr) ≥0.3 mg/dl within 6 months of fenofibrate initiation. The change trend of SCr and uric acid levels during the treatment period were assessed by a generalised additive mixed model (GAMM). Multivariate analysis was performed for risk factors affecting elevated SCr. RESULTS: A total of 100 (10.2%) patients experienced an increase in SCr ≥0.3 mg/dl within 6 months after fenofibrate initiation. The median change of SCr in the whole cohort was 0.11 mg/dl [interquartile range (IQR) 0.03-0.20], whereas it was 0.36 (0.33-0.45) in the fenofibrate-associated nephrotoxicity group. In a multivariable regression model, chronic kidney disease (CKD) [odds ratio (OR) 2.39 (95% CI 1.48, 3.86)] and tophus [OR 2.29 (95% CI 1.39, 3.78)] were identified to be risk predictors, independent of measured covariates, of fenofibrate-associated nephrotoxicity. During the treatment period, although SCr temporarily increased, serum urate and triglyceride concentrations decreased using the interaction analysis of GAMM. Of those with fenofibrate withdrawal records, the SCr increase in 65% of patients was reversed after an average of 49 days off the drug. CONCLUSIONS: This observational study implied that fenofibrate-associated nephrotoxicity occurs frequently in gout patients, especially in patients with tophi or CKD. The potential renal risks of fenofibrate usage in gout needs additional research.

Effects of fenofibrate and its combination with lovastatin on the expression of genes involved in skeletal muscle atrophy, including FoxO1 and its targets.

Fibrates and statins have been widely used to reduce triglyceride and cholesterol levels, respectively. Besides its lipid-lowering effect, the side effect of muscle atrophy after fibrate administration to humans has been demonstrated in some studies. Combination therapy with fibrates and statins also increases the risk of rhabdomyolysis. FoxO1, a member of the FoxO forkhead type transcription factor family, is markedly upregulated in skeletal muscle in energy-deprived states and induces muscle atrophy via the expression of E3-ubiquitine ligases. In this study, we investigated the changes in FoxO1 and its targets in murine skeletal muscle with fenofibrate treatment. High doses of fenofibrate (greater than 0.5% (wt/wt)) over one week increased the expression of FoxO1 and its targets in the skeletal muscles of mice and decreased skeletal muscle weight. These fenofibrate-induced changes were diminished in the PPARα knockout mice. When the effect of combination treatment with fenofibrate and lovastatin was investigated, a significant increase in FoxO1 protein levels was observed despite the lack of deterioration of muscle atrophy. Collectively, our findings suggest that a high dose of fenofibrate over one week causes skeletal muscle atrophy via enhancement of FoxO1, and combination treatment with fenofibrate and lovastatin may further increase FoxO1 protein level.

Fenofibrate treatment for severe hypertriglyceridemia in dogs.

Lipid disorders are relatively common in dogs. Hyperlipidemia can be primary or secondary to other diseases. In humans, fenofibrate is used to control hypertriglyceridemia. In dogs, there are no studies evaluating fenofibrate in hypertriglyceridemia. The aim of the study was to evaluate the safety and efficacy of fenofibrate to control severe hypertriglyceridemia in dogs. A total of 124 dogs (n = 124) with severe hypertriglyceridemia (>300 mg/dL, 3.39 mmol/L) were randomly distributed in the fenofibrate group (n = 64) and the diet group (n = 60). Dogs of the fenofibrate group were treated with fenofibrate (10 mg/Kg) once daily. Dogs of the diet group were treated with low-fat diet (10%). Serum triglycerides (TGs), total cholesterol (TC), liver enzymes, and creatine kinase concentrations were evaluated, before and after 1 mo of medical or dietary treatment. Triglyceride concentrations were reduced with fenofibrate (P < 0.001), and 85.93% of the dogs normalized their levels. Triglyceride concentrations also decreased with low-fat diet (P < 0.001), but only 26.6% of the dogs normalized their levels. Triglyceride concentrations were reduced with fenofibrate (P < 0.01) and with low-fat diet (P < 0.01). Of the cases with hypercholesterolemia, 53.7% and 50% of the dogs normalized their TC concentrations, with fenofibrate and diet, respectively. No significant adverse effects were observed (3% showed diarrhea). Fenofibrate was safe and effective in reducing and normalizing TG concentrations in dogs with severe hypertriglyceridemia, regardless of the cause of hyperlipidemia. The low-fat diet was effective in reducing, but not normalizing, TG concentrations. Fenofibrate and low-fat diet were effective in reducing TC concentrations. This is the first study evaluating fibrates in dogs with severe hypertriglyceridemia and comparing results with a low-fat diet.

Association of Fenofibrate and Diabetic Retinopathy in Type 2 Diabetic Patients: A Population-Based Retrospective Cohort Study in Taiwan.

Background and Objectives: Fenofibrate, a PPAR-α agonist, has been demonstrated to reduce the progression of diabetic retinopathy (DR) and the need for laser treatment in a FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) study. However, in the subgroup of patients without pre-existing DR, there was no significant difference in the progression of DR between the fenofibrate group and the placebo group. In this study, we aim to investigate whether fenofibrate can decrease the risk of incident DR in a population-based cohort study of type 2 diabetic patients in Taiwan. Materials and Methods: A total of 32,253 type 2 diabetic patients without previous retinopathy were retrieved from 892,419 patients in 2001-2002. They were then divided into two groups based on whether they were exposed to fenofibrate or not. The patients were followed until a diagnosis of diabetic retinopathy was made or until the year 2008. Results: With a follow-up period of 6.8 ± 1.5 years and 5.4 ± 2.6 years for 2500 fenofibrate users and 29,753 non-users, respectively, the Cox proportional hazard regression analysis revealed that the hazard ratio (HR) of new onset retinopathy was 0.57 (95% CI 0.57-0.62, p < 0.001). After adjusting for hypertension; the Charlson comorbidity index (CCI); and medications such as angiotensin-converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), anticoagulants, gemfibrozil, statins, and hypoglycemic agents, the adjusted HR was 0.75 (95% CI 0.68-0.82, p < 0.001). The need for laser treatment has an HR and adjusted HR of 0.59 (95% CI 0.49-0.71, p < 0.001) and 0.67 (95% CI 0.56-0.81, p < 0.001), respectively. Conclusion: Our study showed that the long-term and regular use of fenofibrate may decrease the risk of incident retinopathy and the need for laser treatment in type 2 diabetic patients. Since there are limitations associated with our study, further investigations are necessary to confirm such an association.

Peroxisome proliferator-activated receptor α agonist-induced histidine decarboxylase gene expression in the rat and mouse liver.

By analysis of the data from the Toxicogenomics Database (TG-GATEs), histidine decarboxylase gene (Hdc) was identified as largely and commonly upregulated by three fibrates, clofibrate, fenofibrate, and WY-14,643, which are known to induce hepatocellular hypertrophy and proliferation via stimulation of peroxisome proliferator-activated receptor α (PPARα) in rodents. As histamine has been reported to be involved in the proliferation of liver cells, the present study was conducted to focus on Hdc. Among other genes related to histidine and histamine, the expression of the gene of histamine ammonia lyase (Hal) was exclusively mobilized by the three fibrates. The expression of Hdc, which was usually very low in the liver, was increased with the repeated administration of fibrates, and concomitantly, the constitutive expression of Hal was suppressed. An interpretation is that the formation of urocanic acid from histidine under the normal condition switches to the formation of histamine. The mobilization of gene expression of Hdc and Hal by PPARα agonists could not be reproduced in primary cultured hepatocytes. The Hdc mRNA appeared to be translated to a protein which is processed differently from brain but similarly to gastric mucosa. Surprisingly, the fibrates caused hepatic hypertrophy but no induction of Hdc mRNA at all in mice. These results revealed that the changes in the histidine catabolism by PPARα agonists might be partially, but not directly, involved in the hepatocyte proliferation in rats, and there is a large genetic distance even between rat and mouse.

A Randomised Controlled Trial Assessing the Effects of Peri-operative Fenofibrate Administration on Abdominal Aortic Aneurysm Pathology: Outcomes From the FAME Trial.

OBJECTIVE: Experimental studies suggest that fenofibrate prevents abdominal aortic aneurysm (AAA) development by lowering aortic osteopontin (OPN) concentration and reducing the number of macrophages infiltrating the aortic wall. The current study examined the effects of a short course of fenofibrate on AAA pathology in people with large AAAs awaiting aortic repair. METHODS: This randomised double blind parallel trial included male and female participants aged ≥ 60 years who had an asymptomatic AAA measuring ≥ 50 mm and were scheduled to undergo open AAA repair. Participants were allocated to fenofibrate (145 mg/day) or matching placebo for at least two weeks before elective AAA repair. Blood samples were collected at recruitment and immediately prior to surgery. AAA biopsies were obtained during aortic surgery. The primary outcomes were (1) AAA OPN concentration; (2) serum OPN concentration; and (3) number of AAA macrophages. Exploratory outcomes included circulating and aortic concentrations of other proteins previously associated with AAA. Outcomes assessed at a single time point were compared using logistic regression. Longitudinal outcomes were compared using linear mixed effects models. RESULTS: Forty-three participants were randomised. After three withdrawals, 40 were followed until the time of surgery (21 allocated fenofibrate and 19 allocated placebo). As expected, serum triglycerides reduced significantly from recruitment to the time of surgery in participants allocated fenofibrate. No differences in any of the primary and exploratory outcomes were observed between groups. CONCLUSION: A short course of 145 mg of fenofibrate/day did not lower concentrations of OPN or aortic macrophage density in people with large AAAs.

Cumulative non-HDL-cholesterol burden in patients with hypertriglyceridemia receiving long-term fibrate therapy: Real life data from a lipid clinic cohort.

OBJECTIVE: Though epidemiological data suggest that an elevated triglyceride (TG) level may be a risk factor for coronary artery disease (CAD), there is still insufficient clinical evidence. This study was designed to evaluate the real-life efficacy and side effects of fibrate treatment for hypertriglyceridemia seen in a lipid clinic, as well as cardiovascular and diabetic outcomes. METHODS: This retrospective study evaluated patients who were followed-up for a diagnosis of hypertriglyceridemia at the lipid outpatient clinic of the Ege University Cardiology Department between 1997 and 2018. Data of demographic and clinical characteristics were obtained from hospital records. All patients (n=240) with at least 1 year of follow-up were included in the analysis. During follow-up, patients were treated with fenofibrate, and less frequently, gemfibrozile (14 patients), at different doses according to the TG level and disease severity. RESULTS: Of the study population, 23% had CAD, 21% were diabetic, and 52% were obese. On admission, 20% were using fibrates and 17% were on statins. The mean admission lipid levels were TG: 281±194 mg/dL, low-density lipoprotein cholesterol: 115±37 mg/dL, high-density lipoprotein (HDL) cholesterol: 43±13 mg/dL, and non-HDL cholesterol: 166±42 mg/dL. The mean length of follow-up was 5.3±4.7 years (range: 1-16 years). A total of 8 (4.3%) patients had adverse effects during follow-up (1 on statin combination and 7 on fibrates alone). The side effects observed were an elevation of liver enzymes in 3, myalgia in 2, insomnia in 1, malaise in 1, and a skin rash in 1 patient. No rhabdomyolysis or myopathy was seen. During follow-up, diabetes developed in 14 and cardiovascular disease (CVD) in 14 patients. The cumulative non-HDL cholesterol level was significantly high in patients who developed diabetes or CVD. Receiver operating curve analysis indicated that a cumulative non-HDL cholesterol value of 1016 mg/dL was predictive of the development of diabetes mellitus or CVD with 85% sensitivity and 70% specificity. CONCLUSION: In real life, long-term fibrate use is effective and safe. The cumulative non-HDL cholesterol burden can be used to assess the efficacy of treatment as a simple and easily calculated method. Large studies are needed to further clarify the value of this parameter in predicting the development of both diabetes and CVD.