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Fenofibrate for Diabetic Retinopathy.
Stewart, S, Lois, N
Asia-Pacific journal of ophthalmology (Philadelphia, Pa.). 2018;(6):422-426
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Fenofibrate is a safe and inexpensive orally administered fibric acid derivative conventionally used to treat dyslipidemia. Two large randomized clinical trials, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies, demonstrated the benefit of oral fenofibrate in the treatment of patients with type 2 diabetes and diabetic retinopathy (DR), including reduced disease progression and need for laser treatment for diabetic macular edema and proliferative diabetic retinopathy. These findings are supported by results of experimental studies, which have demonstrated beneficial effects of fenofibrate ameliorating retinal vascular leakage and leukostasis, downregulating vascular endothelial growth factor, and reducing endothelial cell and pericyte loss, among others; all of these are characteristic features of DR. In spite of this evidence, fenofibrate is not prescribed routinely for treating patients with diabetes and DR. In FIELD and ACCORD studies, retinopathy was not the primary outcome and this may explain, at least partly, its lack of use for this indication. New trials are now underway to specifically address the effects of fenofibrate in DR; these trials will provide additional and robust data that may support current evidence favoring the use of fenofibrate in this common microvascular complication of diabetes.
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Fenofibrate monotherapy-induced rhabdomyolysis in a patient with hypothyroidism: A rare case report and literature review.
Wang, D, Wang, Y
Medicine. 2018;(14):e0318
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RATIONALE Fenofibrate is a fibric acid derivative indicated for use in hypertriglyceridemia and mixed dyslipidemia treatment among adults. Rhabdomyolysis is a syndrome characterized by muscle necrosis and the release of intracellular muscle contents into the systemic circulation, which is the most serious and fatal side effect of fenofibrate. The objective of this paper is to discuss fatal side effect of fenofibrate and keep safe medication. PATIENT CONCERNS A patient with hypothyroidism who presented with rhabdomyolysis during fenofibrate monotherapy for hypertriglyceridemia was reported. DIAGNOSES Fenofibrate Monotherapy Induced Rhabdomyolysis. INTERVENTIONS Fenofibrate was stopped. Adequate fluid resuscitation, mannitol diuresis, myocardium protection, hepatoprotection and urine alkalinization with sodium bicarbonate were performed. OUTCOMES Blood tests were normal and the patient was good and discharged 2 weeks later. LESSONS 13 cases associated with fenofibrate monotherapy-induced rhabdomyolysis were reviewed, which had been published in the English literature. The severity of fenofibrate muscle toxicity may be the result of the combination of two rhabdomyolysis enhancers, such as hypothyroidism and female gender. To avoid it, strict clinical and laboratory monitoring should be maintained, particularly hypothyroidism. Patients should be informed of possible potentially irreversible effects after taking fibrates.
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Fenofibrate and Diabetic Retinopathy.
Knickelbein, JE, Abbott, AB, Chew, EY
Current diabetes reports. 2016;(10):90
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Diabetic retinopathy, a common and sight-threatening microvascular complication of diabetes mellitus, is a leading cause of blindness among working-aged adults. Medical therapies including intensive control of hyperglycemia and hypertension have been shown to reduce the incidence and progression of diabetic retinopathy. The association of dyslipidemia and treatment with statins with diabetic retinopathy is inconsistent in epidemiologic studies. However, two recent randomized clinical trials have demonstrated beneficial effects of systemic fenofibrate therapy in reducing the progression of diabetic retinopathy independently of serum lipid levels. These findings suggest that fenofibrate may be an effective strategy for reducing the progression of diabetic retinopathy, thus reducing the large and growing public health burden of treating the sight-threatening complications of diabetic retinopathy.
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Plasma uric acid concentrations are reduced by fenofibrate: A systematic review and meta-analysis of randomized placebo-controlled trials.
Derosa, G, Maffioli, P, Sahebkar, A
Pharmacological research. 2015;:63-70
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BACKGROUND Hyperuricaemia increases the risk of gout, but it is also a risk factor for cardiovascular diseases. PURPOSE To conduct a systematic review and meta-analysis of relevant randomized clinical trials to ascertain the effect size of fibrates in modulating plasma uric acid concentrations. DATA SOURCES Medline (http://www.ncbi.nlm.nih.gov/pubmed), SCOPUS, Web of Science and Google Scholar databases were searched. STUDY SELECTION Studies were included if they met the following inclusion criteria: (i) being a randomized placebo-controlled trial with either parallel or cross-over design, (ii) investigating the impact of fibrate therapy on plasma uric acid concentrations, (iii) presentation of sufficient information on uric acid values at baseline and at the end of follow-up in each group or providing the net change values. DATA EXTRACTION The following data were extracted: (1) first author's name; (2) year of publication; (3) study location; (4) study design; (5) number of participants in the fibrate and placebo groups; (6) type and dose of fibrate; (7) duration of treatment; (8) age, gender and body mass index (BMI) of study participants; (9) baseline levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, high-sensitivity C-reactive protein (hs-CRP) and glucose; (10) systolic and diastolic blood pressure; and (11) data regarding baseline and follow-up uric acid. DATA SYNTHESIS There was a significant reduction in plasma uric acid concentrations following fenofibrate therapy. LIMITATIONS Few eligible studies, and most had small population sizes. CONCLUSIONS Fenofibrate, but not bezafibrate is effective in reducing serum acid uric levels.
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Should we start all patients with diabetic retinopathy on fenofibrates?
Koshy, J, Koshy, JM, Thomas, S, Kaur, G, Mathew, T
Middle East African journal of ophthalmology. 2013;(4):309-14
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There remains a need for strategies that are effective in preventing diabetic retinopathy (DR) or slowing down its progression, which is safe, well-tolerated, and more effective, have a lower risk profile, easy to perform, have more predictable results with less morbidity than the current regimens. Physicians caring for diabetic patients not only need to maximize glycemic control, but also closely monitor and treat other systemic conditions. The consistency of clinical data from the fenofibrate studies showed consistent beneficial effects with fenofibrate in slowing the progression of DR. They demonstrated significant benefit on micro-vascular (i.e., retinopathy and nephropathy) outcome, possibly independent of lipid levels. Can we combine the effectiveness of the current standard procedures with the prevention and slowing down of progression of DR that fenofibrates can offer? Knowledge of the primary mode of action of fenofibrate will be useful for both physicians and patients in determining how best to use this drug as an adjunct in the management of DR and ultimately facilitating the translation of clinical trial data to clinical practice.
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The case for intraocular delivery of PPAR agonists in the treatment of diabetic retinopathy.
Treacy, MP, Hurst, TP
BMC ophthalmology. 2012;:46
Abstract
BACKGROUND Systemic therapeutics targeting the peroxisome proliferator-activated receptors have been found to be beneficial in the treatment of diabetic retinopathy. In this paper, we provide a rationale for the use of these therapeutics as intraocular agents. In addition, we introduce the peroxisome proliferator-activated receptors and describe their functions in response to the drugs. DISCUSSION Based on the evidence of large-scale clinical studies investigating the systemic administration of fenofibrate, this ligand for peroxisome proliferator-activated receptor-α is potentially a good candidate for intraocular delivery. Here, we describe the mechanisms by which it might be acting to improve diabetic retinopathy, its relative safety and we speculate on how it could be developed for intraocular delivery. SUMMARY In this paper, we provide a rationale for the further investigation of peroxisome proliferator-activated receptor-α agonists as intraocular agents for the treatment of diabetic retinopathy.
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Medical management of diabetic retinopathy: fenofibrate and ACCORD Eye studies.
Wright, AD, Dodson, PM
Eye (London, England). 2011;(7):843-9
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The approach of all ophthalmologists, diabetologists and general practitioners seeing patients with diabetic retinopathy should be that good control of blood glucose, blood pressure and plasma lipids are all essential components of modern medical management. The more recent data on the use of fenofibrate in the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye studies is reviewed. In FIELD, fenofibrate (200 mg/day) reduced the requirements for laser therapy and prevented disease progression in patients with pre-existing diabetic retinopathy. In ACCORD Eye, fenofibrate (160 mg daily) with simvastatin resulted in a 40% reduction in the odds of retinopathy progressing over 4 years, compared with simvastatin alone. This occurred with an increase in HDL-cholesterol and a decrease in the serum triglyceride level in the fenofibrate group, as compared with the placebo group, and was independent of glycaemic control. We believe fenofibrate is effective in preventing progression of established diabetic retinopathy in type 2 diabetes and should be considered for patients with pre-proliferative diabetic retinopathy and/or diabetic maculopathy, particularly in those with macular oedema requiring laser.
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Non-invited review: prevention of microvascular diabetic complications by fenofibrate: lessons from FIELD and ACCORD.
Hermans, MP
Diabetes & vascular disease research. 2011;(3):180-9
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Microvascular complications are common in type 2 diabetes in primary care. Intensified management of glycaemia or blood pressure had little effect on microvascular complication rates in recent large trials (ADVANCE, VADT, ACCORD). In 2005, the FIELD study demonstrated a significant reduction in the need for laser treatment for retinopathy, and of progression of renal dysfunction, with fenofibrate versus placebo. The FIELD ophthalmology sub-study showed that fenofibrate reduced the risk of new retinopathy and progression of retinopathy. Also, fenofibrate versus placebo significantly reduced the risk of non-traumatic, diabetes-related amputations in a post-hoc analysis from FIELD. Recently, the results of the ACCORD Lipid study were consistent with these findings, as fenofibrate significantly reduced progression of retinopathy and albuminuria, apparently independent of effects on lipids. These findings suggest a role for fenofibrate in the prevention of major diabetic microvascular complications.
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Fenofibrate and metabolic syndrome.
Kraja, AT, Province, MA, Straka, RJ, Ordovas, JM, Borecki, IB, Arnett, DK
Endocrine, metabolic & immune disorders drug targets. 2010;(2):138-48
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The fibric acid derivative, fenofibrate (FF) has been used in the US since 1998 to manage patients with dyslipidemia. Typical changes in serum lipids as result a of FF treatment include clinically important mean reductions of serum triglycerides (TG) by a mean change of -93.7 mg/dL (-39.3%), increases of high density lipoprotein cholesterol (HDLC) by +5.5 mg/dL (+12.4%), and reductions in low density lipoprotein cholesterol (LDLC) by -17.9 mg/dL (-12.3%). The greatest reductions in serum TG are usually observed in subjects with elevated baseline TGs including those with the metabolic syndrome (MetS). Although statins remain the mainstay of therapy for most dyslipidemic patients, their combined use with FF would be expected to address residual risk resulting from less than optimal TG and HDLC levels in such patients. Clinical trials examining the cardiovascular benefits of FF alone or combined with statins have produced mixed results. These observations underscore our lack of understanding of which patients may benefit from FF therapy and which do not. Although FF's basic mechanism of action is known to involve PPAR-alpha agonist activity resulting in altered transcription of several genes, the actual genetic bases for variability in lipid response is poorly understood. Studies, such as our GOLDN study and others designed to better understand the genetic determinants of variability in the response to FF treatment and lipid levels. As a result several important genetic determinants of lipid levels have been identified. For example, in the GOLDN study SNPs from different genes were significantly associated with baseline lipid levels before treatment (APOA5- rs662799, rs3135506; APOC3- rs5128, rs2854117, rs4520); APOA4- rs5104; PPARA- rs9626730, rs135543, rs11703495; LPL- rs1801177), after treatment PPARA- rs11708495; LPL- rs1801177, and appeared to modulate overall response to FF treatment (NOS3- rs1799983). In this article, we will review the literature leading up to the contemporary use of FF as an agent to manage patients with dyslipidemia and focus on emerging understanding of the genetic variability in response to FF treatment. On the basis of the available evidence, we conclude that FF is of benefit in the treatment of dyslipidemia, especially among those with MetS. However, more work is needed to specifically identify which individuals derive a benefit from FF administration in terms of clinical outcomes and which do not - particularly in the context of type 2 diabetes.
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Vascular and metabolic effects of treatment of combined hyperlipidemia: focus on statins and fibrates.
Koh, KK, Quon, MJ, Rosenson, RS, Chung, WJ, Han, SH
International journal of cardiology. 2008;(2):149-59
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Combined hyperlipidemia results from overproduction of hepatically synthesized apolipoprotein B in very low-density lipoproteins in association with reduced lipoprotein lipase activity. Thus, this condition is typically characterized by concurrent elevations in total cholesterol and triglycerides with decreased high-density lipoprotein cholesterol. High levels of apolipoprotein B-containing lipoproteins, most prominently carried by low-density lipoprotein (LDL) particles, are an important risk factor for coronary heart disease. Statin therapy is highly effective at lowering LDL cholesterol. Despite the benefits of statin treatment for lowering total and LDL cholesterol, many statin-treated patients still have initial or recurrent coronary heart disease events. In this regard, combined therapy with statins and fibrates is more effective in controlling atherogenic dyslipidemia in patients with combined hyperlipidemia than either drug alone. Furthermore, statins and fibrates activate PPARalpha in a synergistic manner providing a molecular rationale for combination treatment in coronary heart disease. Endothelial dysfunction associated with cardiovascular diseases may contribute to insulin resistance so that there may also be additional beneficial metabolic effects of combined statin/fibrates therapy. However, there has been little published evidence that combined therapy is synergistic or even better than monotherapy alone in clinical studies. Therefore, there is a great need to study the effects of combination therapy in patients. When statins are combined with gemfibrozil therapy, this is more likely to be accompanied by myopathy. However, this limitation is not observed when fenofibrate, bezafibrate, or ciprofibrate are used in combination therapy.