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Glycogen storage disease type Ia (GSDIa) is a rare metabolic disease caused by glucose-6-phosphatase (G6Pase) deficiency, due to mutations on the gene encoding G6Pase catalytic subunit (G6PC). This enzyme confers to the liver, kidneys and intestine the ability to produce glucose. Thus, patients with GSDIa are unable to ensure endogenous glucose production and suffer from severe hypoglycemia during fasting in the absence of nutritional control. In addition, G6Pase deficiency causes intracellular accumulation of glucose-6 phosphate in the liver and kidneys, leading to metabolic defects and the accumulation of glycogen and lipids. Over time, most adult patients suffer from chronic kidney disease (CKD), which can progress to kidney failure, requiring dialysis or kidney transplantation. This nephropathy is characterized in particular by tubulo-interstitial fibrosis and glomerulosclerosis, as well as by the development of cysts in the late stages. Moreover, patients develop hepatomegaly and hepatic steatosis that may progress to the development of hepatocellular adenomas or carcinomas. The aim of my thesis was to identify the molecular mechanisms involved in the establishment of renal pathology and cyst formation in GSDIa, by using mouse models where G6pc gene is specifically deleted in the kidneys (K.G6pc-/- mice). While GSDIa is a disease characterized by glycogen accumulation in the liver and kidneys, we first showed that the development of fibrosis, which causes progressive loss of kidney function, was induced by intracellular accumulation of lipids, regardless of glycogen content. The molecular mechanism probably involved is the activation of the renin angiotensin system by lipid derivatives such as diacylglycerol, which induced the expression of the profibrotic factor TGFβ1 and an epithelial-mesenchymal transition. In addition, the use of a PPARα agonist, i.e. fenofibrate, by decreasing renal lipid content, reduced the development of fibrosis and CKD evolution. Similarly, fenofibrate treatment prevented the accumulation of lipids in the liver and the development of liver damages that cause tumor development. Thus, the activation of lipid catabolism by PPARα agonists such as fenofibrate seems to be an interesting therapeutic strategy to reduce the progression of renal and hepatic diseases of GSDIa. The second part of my results suggest that the development of renal cysts in GSDI patients may be caused by an alteration of the primary cilia, a non-motile organelle that plays a key role in maintaining normal kidney structure and function. Indeed, defects in the primary cilia are involved in many polycystic kidney diseases. In summary, an increase in the length of the primary cilia was observed in the kidneys of K.G6pc-/- mice, which could be explained by a deregulation of the expression of different proteins involved in cilia structure and function, compared to control mice. We also demonstrated a metabolic reprogramming leading to a Warburg metabolism, characterized by the increased activation of aerobic glycolysis and the inhibition of mitochondrial pyruvate oxidation and lipid production in K.G6pc-/- mice. Thus, all these disorders would promote cell proliferation and cyst development, and could lead to the development of renal tumor, as recently observed in one K.G6pc-/- mouse (out of 36 studied mice). In conclusion, we have shown that, in GSDI, the accumulation of lipids in the kidneys and liver that occurs secondary to G6Pase deficiency plays a key role in the development of hepatic and renal long-term complications. In addition, the Warburg like metabolic reprogramming taking place in the GSDIa kidneys, associated with a defect in the primary cilia, could be at the origin of cysts formation and renal tumors. These new studies, by providing a better understanding of the pathophysiology of long-term complications of GSDIa, offer new perspectives on therapeutic strategies to be developed for better management of patients; La glycogénose de type Ia (GSDIa) est une maladie métabolique rare causée par une déficience en glucose-6-phosphatase (G6Pase), due à des mutations de la sous-unité catalytique (G6PC). Cette enzyme confère au foie, aux reins et à l’intestin la capacité de produire du glucose. Les patients atteints de GSDIa sont donc incapables de produire du glucose et souffrent d’hypoglycémies sévères lors de jeûnes courts. De plus, la déficience en G6Pase provoque une accumulation de glucose-6 phosphate dans le foie et les reins, conduisant à l’accumulation de glycogène et de lipides. A long terme, la plupart des patients souffre d’une maladie chronique rénale (MCR), qui peut évoluer en insuffisance rénale, nécessitant une mise sous dialyse ou une transplantation rénale. Cette MCR se caractérise par une fibrose, ainsi que par le développement de kystes dans les stades tardifs. Au niveau du foie, les patients développent une hépatomégalie et une stéatose hépatique qui peut évoluer vers le développement d’adénomes ou carcinomes hépatocellulaires. Le but de mes travaux de thèse a été d’identifier les mécanismes moléculaires impliqués dans l’établissement de la pathologie rénale et la formation des kystes, à l’aide de modèles murins invalidés pour le gène G6pc spécifiquement dans les reins (souris K.G6pc-/-). Alors que la GSDIa est une maladie caractérisée par l’accumulation hépatique et rénale de glycogène, nous avons d’abord montré que le développement de la fibrose, à l’origine de la perte de la fonction rénale, était induit par l’accumulation de lipides, indépendamment du contenu en glycogène. De plus, l’utilisation d’un agoniste de PPARα, le fénofibrate, en diminuant le contenu lipidique rénal, a ralenti l’installation de la fibrose et l’évolution de la MCR. Le mécanisme moléculaire impliqué est l’activation du système rénine angiotensine par les dérivés lipidiques, qui induit l’expression du facteur profibrotique TGFβ1. De même, le fénofibrate en limitant l’accumulation de lipides hépatiques a prévenu le développement d’atteintes hépatiques caractéristiques de la GSDI. Ainsi, l’activation du catabolisme des lipides par des agonistes de PPARα semble une stratégie thérapeutique intéressante pour réduire la progression des maladies rénales et hépatique de la GSDI. La deuxième partie de mes résultats suggèrent que le développement de kystes rénaux chez les patients atteints de la GSDI pourrait être causé par une altération du cil primaire, organelle jouant un rôle clé dans le maintien d’une structure et fonction normale des reins. En effet, une augmentation de la longueur du cil primaire a pu être observée dans les reins des souris K.G6pc-/- associée à une dérégulation de différentes protéines impliquées dans sa structure et sa fonction, par rapport aux souris contrôles. Nous avons également mis en évidence une reprogrammation métabolique de type Warburg, caractérisée par une activation accrue de la glycolyse aérobie, une inhibition de l’oxydation mitochondriale du pyruvate et une production de lipides. Ainsi, l’ensemble de ces perturbations va favoriser la prolifération cellulaire et le développement de kystes, et pourrait mener au développement de tumeur rénale comme observée chez une souris K.G6pc-/-. En conclusion nous avons démontré que, dans le cadre de la GSDI, l’accumulation de lipides dans les reins et le foie, secondaire à la déficience en G6Pase, joue un rôle clé dans le développement des complications hépatiques et rénales à long terme. Également, la reprogrammation métabolique rénale de type Warburg, prenant place dans le cadre de la GSDI, associée à un défaut du cil primaire pourrait être à l’origine de la formation des kystes et de tumeurs rénales. Ces études, en permettant une meilleure compréhension de la physiopathologie des complications à long terme de la GSDIa, offrent de nouvelles perspectives concernant les stratégies thérapeutiques à développer pour une meilleure prise en charge des patients atteints de GSDIa

Glycogen storage disease type Ia (GSDIa) is a rare metabolic disease caused by glucose-6-phosphatase (G6Pase) deficiency, due to mutations on the gene encoding G6Pase catalytic subunit (G6PC). This enzyme confers to the liver, kidneys and intestine the ability to produce glucose. Thus, patients with GSDIa are unable to ensure endogenous glucose production and suffer from severe hypoglycemia during fasting in the absence of nutritional control. In addition, G6Pase deficiency causes intracellular accumulation of glucose-6 phosphate in the liver and kidneys, leading to metabolic defects and the accumulation of glycogen and lipids. Over time, most adult patients suffer from chronic kidney disease (CKD), which can progress to kidney failure, requiring dialysis or kidney transplantation. This nephropathy is characterized in particular by tubulo-interstitial fibrosis and glomerulosclerosis, as well as by the development of cysts in the late stages. Moreover, patients develop hepatomegaly and hepatic steatosis that may progress to the development of hepatocellular adenomas or carcinomas. The aim of my thesis was to identify the molecular mechanisms involved in the establishment of renal pathology and cyst formation in GSDIa, by using mouse models where G6pc gene is specifically deleted in the kidneys (K.G6pc-/- mice). While GSDIa is a disease characterized by glycogen accumulation in the liver and kidneys, we first showed that the development of fibrosis, which causes progressive loss of kidney function, was induced by intracellular accumulation of lipids, regardless of glycogen content. The molecular mechanism probably involved is the activation of the renin angiotensin system by lipid derivatives such as diacylglycerol, which induced the expression of the profibrotic factor TGFβ1 and an epithelial-mesenchymal transition. In addition, the use of a PPARα agonist, i.e. fenofibrate, by decreasing renal lipid content, reduced the development of fibrosis and CKD evolution. Similarly, fenofibrate treatment prevented the accumulation of lipids in the liver and the development of liver damages that cause tumor development. Thus, the activation of lipid catabolism by PPARα agonists such as fenofibrate seems to be an interesting therapeutic strategy to reduce the progression of renal and hepatic diseases of GSDIa. The second part of my results suggest that the development of renal cysts in GSDI patients may be caused by an alteration of the primary cilia, a non-motile organelle that plays a key role in maintaining normal kidney structure and function. Indeed, defects in the primary cilia are involved in many polycystic kidney diseases. In summary, an increase in the length of the primary cilia was observed in the kidneys of K.G6pc-/- mice, which could be explained by a deregulation of the expression of different proteins involved in cilia structure and function, compared to control mice. We also demonstrated a metabolic reprogramming leading to a Warburg metabolism, characterized by the increased activation of aerobic glycolysis and the inhibition of mitochondrial pyruvate oxidation and lipid production in K.G6pc-/- mice. Thus, all these disorders would promote cell proliferation and cyst development, and could lead to the development of renal tumor, as recently observed in one K.G6pc-/- mouse (out of 36 studied mice). In conclusion, we have shown that, in GSDI, the accumulation of lipids in the kidneys and liver that occurs secondary to G6Pase deficiency plays a key role in the development of hepatic and renal long-term complications. In addition, the Warburg like metabolic reprogramming taking place in the GSDIa kidneys, associated with a defect in the primary cilia, could be at the origin of cysts formation and renal tumors. These new studies, by providing a better understanding of the pathophysiology of long-term complications of GSDIa, offer new perspectives on therapeutic strategies to be developed for better management of patients; La glycogénose de type Ia (GSDIa) est une maladie métabolique rare causée par une déficience en glucose-6-phosphatase (G6Pase), due à des mutations de la sous-unité catalytique (G6PC). Cette enzyme confère au foie, aux reins et à l’intestin la capacité de produire du glucose. Les patients atteints de GSDIa sont donc incapables de produire du glucose et souffrent d’hypoglycémies sévères lors de jeûnes courts. De plus, la déficience en G6Pase provoque une accumulation de glucose-6 phosphate dans le foie et les reins, conduisant à l’accumulation de glycogène et de lipides. A long terme, la plupart des patients souffre d’une maladie chronique rénale (MCR), qui peut évoluer en insuffisance rénale, nécessitant une mise sous dialyse ou une transplantation rénale. Cette MCR se caractérise par une fibrose, ainsi que par le développement de kystes dans les stades tardifs. Au niveau du foie, les patients développent une hépatomégalie et une stéatose hépatique qui peut évoluer vers le développement d’adénomes ou carcinomes hépatocellulaires. Le but de mes travaux de thèse a été d’identifier les mécanismes moléculaires impliqués dans l’établissement de la pathologie rénale et la formation des kystes, à l’aide de modèles murins invalidés pour le gène G6pc spécifiquement dans les reins (souris K.G6pc-/-). Alors que la GSDIa est une maladie caractérisée par l’accumulation hépatique et rénale de glycogène, nous avons d’abord montré que le développement de la fibrose, à l’origine de la perte de la fonction rénale, était induit par l’accumulation de lipides, indépendamment du contenu en glycogène. De plus, l’utilisation d’un agoniste de PPARα, le fénofibrate, en diminuant le contenu lipidique rénal, a ralenti l’installation de la fibrose et l’évolution de la MCR. Le mécanisme moléculaire impliqué est l’activation du système rénine angiotensine par les dérivés lipidiques, qui induit l’expression du facteur profibrotique TGFβ1. De même, le fénofibrate en limitant l’accumulation de lipides hépatiques a prévenu le développement d’atteintes hépatiques caractéristiques de la GSDI. Ainsi, l’activation du catabolisme des lipides par des agonistes de PPARα semble une stratégie thérapeutique intéressante pour réduire la progression des maladies rénales et hépatique de la GSDI. La deuxième partie de mes résultats suggèrent que le développement de kystes rénaux chez les patients atteints de la GSDI pourrait être causé par une altération du cil primaire, organelle jouant un rôle clé dans le maintien d’une structure et fonction normale des reins. En effet, une augmentation de la longueur du cil primaire a pu être observée dans les reins des souris K.G6pc-/- associée à une dérégulation de différentes protéines impliquées dans sa structure et sa fonction, par rapport aux souris contrôles. Nous avons également mis en évidence une reprogrammation métabolique de type Warburg, caractérisée par une activation accrue de la glycolyse aérobie, une inhibition de l’oxydation mitochondriale du pyruvate et une production de lipides. Ainsi, l’ensemble de ces perturbations va favoriser la prolifération cellulaire et le développement de kystes, et pourrait mener au développement de tumeur rénale comme observée chez une souris K.G6pc-/-. En conclusion nous avons démontré que, dans le cadre de la GSDI, l’accumulation de lipides dans les reins et le foie, secondaire à la déficience en G6Pase, joue un rôle clé dans le développement des complications hépatiques et rénales à long terme. Également, la reprogrammation métabolique rénale de type Warburg, prenant place dans le cadre de la GSDI, associée à un défaut du cil primaire pourrait être à l’origine de la formation des kystes et de tumeurs rénales. Ces études, en permettant une meilleure compréhension de la physiopathologie des complications à long terme de la GSDIa, offrent de nouvelles perspectives concernant les stratégies thérapeutiques à développer pour une meilleure prise en charge des patients atteints de GSDIa

Hypertriglyceridaemia is a common finding in medical practice. The reduction of triglyceride levels may contribute to reduce the cardiovascular risk (at least in patients with low HDL cholesterol) and to avoid the occurrence of acute pancreatitis (in case of severe hypertriglyceridaemia). The discovery of causes of hypertriglyceridaemia (comorbidities, medications) may lead to specific measures. Otherwise, the focus should be put on dietary advises first (reduced caloric intake to promote weight loss, less alcohol, less sucrose), which, if well conducted, may result in spectacular results. If they fail, some pharmacological approaches may be considered, but with generally a limited success rate. Among them, fenofibrate is the best studied and has been shown to be useful for cardiovascular prevention, especially if low HDL cholesterol is associated with hypertriglyceridaemia in patients with type 2 diabetes.Le médecin est souvent confronté à une hypertriglycéridémie, soit découverte de façon fortuite, soit recherchée dans le cadre d’une approche spécifique. Réduire le taux de triglycérides, à jeun et en post-prandial, peut contribuer à diminuer le risque cardiovasculaire (au moins chez les patients avec cholestérol HDL abaissé) et à limiter le risque de pancréatite aiguë (en cas d’hypertriglycéridémie sévère). Rechercher des causes connues d’hypertriglycéridémie (comorbidités, médicaments) permet de proposer des mesures spécifiques. Sinon, il convient d’envisager, en première intention, des mesures hygiéno-diététiques (réduction pondérale, abstinence d’alcool, évitement des glucides à index glycémique élevé) qui, si elles sont bien respectées, peuvent donner des résultats remarquables. En cas d’échec, des traitements pharmacologiques peuvent être éventuellement envisagés, mais avec un succès souvent limité. Parmi les médicaments, c’est le fénofibrate qui a été le plus étudié et s’est révélé utile en prévention cardiovasculaire, surtout si un taux de cholestérol HDL bas est associé à l’hypertriglycéridémie chez le patient diabétique de type 2.

Several studies have investigated the occurrence of venous thromboembolic events (phlebitis and pulmonary embolism) [VTE] and fibrates. Fibrates could be associated with VTE although published data are contradictory. The objective of this study is to confirm the link between VTE and fibrates.Retrospective disproportionality analysis (case/non-case method) from observations recorded consecutively in the French pharmacovigilance database between 1985 and 2016. Cases were defined as embolic and thrombotic events, thrombophlebitis; Non-cases were other adverse events reported over the same period. We measured the disproportionality of exposure to each fibrate among cases and no-cases. The analysis was validated with a positive control (drospirenone) and a negative control (paracetamol).We compared 19,436 cases (including 161 mentioning fibrates) to 563,310 non-cases (including 3228 fibrates). Reports of VTE were significantly associated with fenofibrate (ROR=1.83; 95% CI=[1.53; 2.2]) but not with other fibrates: bézafibrate (ROR=0.44; 95% CI=[0.2; 0.99]), ciprofibrate (ROR=1.15; 95% CI=[0.76; 1.73]) and gemfibrozil (ROR=0.91; 95% CI=[0.45; 1.84]).With this study, we confirm the link between VTE and fenofibrate. It is therefore advisable to remain cautious when prescribing fenofibrate, in particular in case of past history of VTE and to declare systematically any venous thromboembolic adverse events observed with these drugs.

Ischemic cholangitis in intensive care unit is a recently reported liver disease in patients who have had a prolonged mechanical ventilation and vasopressive drug support for multiple organ deficiency. Prognosis is usually poor and the only life-saving therapy is liver transplantation despite ursodesoxycholic acid treatment.We report a 63-year-old man who presented with a sclerosis cholangitis after a month in intensive care unit, effectively treated with fenofibrate and ursodesoxycholic acid. Recent reports underline fenofibrate efficacy in the treatment of primary biliary cirrhosis, especially in association with ursodesoxycholic acid. This treatment has prevented liver transplantation for our patient with a correct quality of life.The addition of fibrate to ursodesoxycholic acid improves persistent cholestasis in sclerosing cholangitis.

Multiple cutaneous osteomas are a rare complication of chronic inflammatory acne that often goes unrecognized. We report a case concerning a 35-year-old woman.A 35-year-old woman had been treated for acne since the age of 22 years, as part of which she received two courses of oral isotretinoin. We noted the secondary appearance of several microcysts on the face for which the excision was very difficult. Curiously, these small formations did not contain keratin but were very callous. Histological examination revealed foci of osseous metaplasia, probably of postinflammatory origin. Treatment consisted solely of excision of the lesions.Osteoma cutis comprises two distinct groups (primary and secondary). In our case, there were multiple cutaneous osteomas of the face resulting from chronic acne. The differential diagnosis was idiopathic miliary osteomatosis of the face, but this was ruled out by the young age of the patient, the improvement of the acneiform lesions under isotretinoin (confirming the initial diagnosis of acne) and the subsequent appearance of microcysts. Although there are as yet no codified treatments, excision appears to yield good results.

Fenofibrate has been evaluated in the ACCORD trial, in combination with a statin, to prevent vascular complications in patients with type 2 diabetes. In ACCORD-Lipid, the addition of fenofibrate was not able to significantly reduce the incidence of a composite cardiovascular endpoint (no positive effect was also observed with the intensification of blood glucose or blood pressure control in this population). However, an interaction effect was observed according to basal lipid profile, suggesting a better protection by fenofibrate in patients with hypertriglyceridaemia and low HDL cholesterol (so-called atherogenic dyslipidaemia). In ACCORD-Eye, the addition of fenofibrate to a basal statin therapy resulted in a significant reduction of the progression of diabetic retinopathy, in a similar manner as that observed with intensifying blood glucose control (but with a good safety profile and without increasing the risk of hypoglycaemia). These observations, confirming earlier results from FIELD also with this fibrate, open new perspectives for a useful prescription of fenofibrate in patients with type 2 diabetes.

In the acute stage of gout, the hallux is most commonly involved followed by the mediotarsal joints and the Achilles tendons. Diagnosis of gout is established when typical monosodium urate crystals can be identified. Apart from NSAIDs, colchicine can be used when there is no renal impairment. Hypouricemic agents (allopurinol or uricosuric drugs) must be initiated one or two weeks after the acute attack of gout because there are risks of exacerbation. Losartan as well as fenofibrate have uricosuric properties. Chondrocalcinosis of the foot can be observed in hemochromatosis. Diffuse idiopathic skeletal hyperostosis (DISH) can cause severe talagia. Hypercholesterolemia can induce xanthomas of the Achilles tendons. Apatite rheumatism can be observed in chronic dialysis patients.

Ezetimibe is the first cholesterol absorption inhibitor, a novel class of lipopenic drugs that inhibit intestinal absorption of biliary and dietary cholesterol. From a pathophysiological point of view, combining complementary drugs that act on different cholesterol metabolism pathways is particularly interesting. This interest has been confirmed in clinical studies combining ezetimibe and statins, which inhibit cholesterol synthesis in the liver. Adding ezetimibe (10 mg/d) to statin therapy decreased LDL cholesterol by as much as an additional 20%. It may thus be especially useful in patients who are unable to reach the LDL cholesterol target with diet and statins alone. Ezetimibe is well tolerated and is indicated alone in statin-intolerant patients.

This year, two prospective randomized studies aimed at the reduction of composite cardiovascular endpoints in type 2 diabetic patients. The PROactive study estimated the impact of pioglitazone in the secondary prevention. The significant reduction of the primary composite endpoint was not obtained: reduction of the relative risk (RR) of 10 % (p= 0.095). However, the secondary composite endpoint was significantly reduced RR 16 % (p = 0.027). The FIELD study also had the same objectives. The primary composite endpoint was not significantly reduced in spite of a RR of 11% while the reduction of RR was significant for the secondary composite endpoint (p = 0.035). These studies reveal the difficulties and the complexity of the secondary prevention of atherosclerosis for patients already treated with effective molecules.

FIELD ("Fenofibrate Intervention and Events Lowering in Diabetes") study compared the incidence of coronary and cardiovascular events in 4895 patients with type 2 diabetes treated with fenofibrate (micronized fomulation, 200 mg/day) and in 4900 patients treated with placebo. After a mean 5-year follow-up, the fenofibrate group did not have less coronary events (primary endpoint), neither present a significant reduction in cardiovascular or total mortality as compared to the placebo group. However, it had significantly less non-fatal myocardial infarctions and cardiovascular events in general as well as less coronary and total revascularization procedures (secondary endpoints). The higher rate of starting statin therapy in patients allocated placebo might have masked a larger treatment benefit of fenofibrate on macrovascular complications. The tolerance of fenofibrate was good, even in combination with statins. More surprisingly, fenofibrate exerted a favourable effect on microangiopathy complications, with less albuminuria progression and less retinopathy needing laser treatment (tertiary endpoints).

Rhabdomyolysis with fibrate have been reported when fibrate are associated with statin or during renal insufficiency or hypothyroidism.We describe one patient with diabetes mellitus treated by fenofibrate monotherapy since several years; 48 h after gliclazide therapy was introduced, rhabdomyolysis occurred.Responsibilities of deshydratation and / or drug interaction with gliclazide. are discussed.

Rhabdomyolysis and myositis are rare, dose-related complications of statins and fenofibrates. The outcome is favorable as a rule with rapid regression after stopping the responsible drug. Recently, various auto-immune disease with evidence of hypersensitivity to HMG-CoA reductase inhibitors or fibrates drugs have been reported. Less than ten cases of dermatomyositis and polymyositis due to cholesterol-lowering drugs (CLD) have been previously reported. Five more cases polymyositis associated with CLD are reported.Symptoms were compatible with diagnosis of polymyositis according to Bohan and Peter and with previous reported criteria for drug-induced myopathy in all cases. None of these patients had previous other connective tissue disorders.Five patients (median age 68 [54-78], female N =4) with CLD treatment (statin N =4, fenofibrates N =1) have developed iatrogenic polymyositis. All of them presented both proximal muscular weakness and increased muscle enzyme levels. One patient had iatrogenic antisynthetase syndrome characterized by mechanic's hand, Raynaud's phenomenon and anti JO1 antibodies. One other had sclerodermic hand oedema. Antinuclear antibodies were positive in 4 cases and muscle biopsy revealed polymyositis infiltrate in 4 cases. CLD treatment was discontinued with partial clinical improvement in 3 cases. Clinical remission was obtained with corticosteroid (N =5) in association with immunosuppresive agents in 3 cases.Muscular symptoms in patient with CLD treatment could be the first symptom of a polymyositis revealed or increased by this treatment and must encourage physician with antinuclear antibodies screening especially in case of proximal muscular weakness and increased muscle enzyme levels.

Fenofibrate is a potent hypolipemic agent, widely used in patients with mild to severe renal failure in whom hyperlipoproteinemia is frequent. A moderate reversible increase in creatinine plasma levels has been reported with fenofibrate therapy; however, it is not known whether this increased creatininemia reflects a fenofibrate induced alteration of renal function or if fenofibrate interferes with creatinine tubular handling. We prospectively examined the effect of 2 weeks fenofibrate treatment (200 mg daily) on renal function in thirteen hyperlipidemic patients with normal renal function or mild to moderate renal failure (Creat Cl: 110 to 30 ml/min). This study confirms that fenofibrate therapy significantly increases creatininemia in patients with mild to moderate renal failure (147 +/- 12 versus 170 +/- 15 mmol/l; p = 0.014), but does not alter renal hemodynamic nor glomerular filtration rate as assessed by the stability of PAH (304 +/- 56 versus 311 +/- 49 ml/min; p = NS) and inulin clearances (51.7 +/- 6 versus 52.3 +/- 7 ml/min; p = NS). The increase in creatininemia is neither due to an inhibition of creatinine tubular excretion, since no change in creatinine clearance was observed (69 +/- 8 versus 68 +/- 8 ml/min; p = NS), but appears to be associated to a parallel increase in creatinine daily urinary excretion (13.7 +/- 5 versus 15.4 +/- 4 mmol; p = 0.03). In conclusion, fenofibrate therapy in renal patients does not worsen renal function, nor diminish the reliability of creatinine clearance for its follow-up in spite of a significant rise in creatininemia. The mechanism of the fenofibrate-induced increase in urinary creatinine excretion remains to be determined.

Long term treatment by fibrates could induce chronic hepatitis associated with auto-antibodies. The aim of this study was to assess the features of this hepatitis.Baseline clinical and biological features, and liver biopsy in 5 patients with fibrate-induced chronic hepatitis were studied, as well as their outcome.At enrollment, patients (4 men, mean age 65 years) had highly (n = 3) or mildly (n = 2) increased serum aminotransferase activity, hypergammaglobulinemia and high titers of anti-nuclear antibodies (with homogenous fluorescence in 3 cases). Liver biopsies demonstrated a lympho-plasmocytic infiltrate in all cases. Hepatocellular necrosis was multilobular in 2 cases, and mild to moderate, located in lobular and periportal areas in 3 cases. Cirrhosis was found at presentation in 3 cases and developed within a few months in the 2 other patients. After discontinuation of fibrates, aminotransferase activity normalized within 6 weeks either spontaneously (n = 3) or under immunosuppressive treatment (n = 2). Immunosuppression was rapidly withdrawn in 2 patients (18 months) without relapse, while one patient was treated for 4 years because of relapse after early withdrawal. A second liver biopsy performed 6 months after discontinuation of fibrates in an untreated-patient showed no inflammation or necrosis.These observations suggest that fibrates could trigger chronic liver disease resembling type I auto-immune chronic hepatitis, which resolves after drug withdrawal.

Since 1983, several cases of allergy and photoallergic contact dermatitis to ketoprofen gel have been reported in Italy and Spain. In France, this drug has been available for topic applications since 1989 and no cases of photoallergy have been reported.We observed two cases of photoallergic contact dermatitis to ketoprofen (Profenid gel, Ketum gel). Imputability was suggested by clinical history and proven by patch-tests showing evidence of crossed photoallergy with fenofibrate in both cases. Photoallergic dermatitis to oxybenzone was associated in one case.Ketoprofen is the predominant nonsteroid anti-inflammatory drug responsible for allergic and/or photoallergic contact dermatitis resulting from topic applications. Its prevalence is probably underestimated in France in light of the number of cases reported in certain Mediterranean countries. Cross reactive photoallergy to ketoprofen and fenofibrate can be explained by the common benzoly-ketone structure of these compounds. In case of skin reaction, the other drug should not be prescribed and benzophenone-containing cosmetics discouraged.

We report a case of chronic intra-hepatic cholestasis observed after 5 months treatment of fenofibrate, a drug extensively prescribed in the treatment of dyslipidemia. Clinically asymptomatic liver injury was revealed by a marked elevation of GGT activity, associated with a moderate increase in alkaline phosphatase and aminotransferases activities. GGT activity remained moderately increased 2 years after discontinuation of treatment. Examination of a liver biopsy showed a reduction in the number of interlobular bile ducts. This case emphasizes the need for systematic and repeated control of blood liver tests in patients receiving fenofibrate therapy.

Photosensitization to lipid-lowering fibric acid derivatives are rare. We report a case of photoallergy induced by fenofibrate, proved by a positive UVA photo-patch-test. Evolution towards persistent photosensitization is probable, since photobiological abnormalities persisted during four months after fenofibrate was discontinued. The fact that patch-tests to various benzophenones were negative is not in favour of the benzophenone group being responsible for the photosensitization reaction.

The authors report a case of biological myolysis related to combined fenofibrate-pravastatin therapy in the course of a change in treatment. This case suggests that the risk of myolysis is not specific to the association of some compounds of the two classes but is inherent in possible combinations of drugs from these two families. One must therefore abstain from prescribing these two classes of drugs, since there is no evidence that the combination is preferable to the HMG CoA inhibitor administered alone and the risk of iatrogenic complications is increased. Finally, during the passage from fibrate to HMG CoA reductase a treatment-free interval of about one week should be mandatory.

We report the case of acute hepatitis probably due to fenofibrate. Clinical features included abdominal pain and fever. Serum aminotransferases and alkaline phosphatase activities were moderately increased. Rechallenge induced a relapse of the symptoms and liver test abnormalities. High levels of eosinophils were present in the blood and in the liver suggesting an immunoallergic mechanism. Fenofibrate withdrawal was rapidly followed by favorable outcome.

In a 65-year old man complaining of myalgias and loss of muscular strength, the creatine phosphokinase level was found to be 35 times higher than normal values. The electromyogram was of the diffuse myogenic type. Muscle biopsy showed necrotic lesions of the muscle fibres associated with perivascular infiltrates of mononuclear cells, leading to the diagnosis of polymyositis. This patient had been treated for 10 years with fenofibrate for hyperlipidaemia; during the last 32 months he had taken this drug in doses of 600 mg per day. Eight days after fenofibrate was discontinued, all clinical and laboratory abnormalities had disappeared. A reintroduction test performed 6 weeks later raised the creatine phosphokinase level up to 43 times the normal value. Withdrawal of fenofibrate therapy resulted in rapid and lasting recovery. This case shows that fenofibrate should be added to the list of drugs that are responsible for iatrogenic polymyositis.

The effects of simvastatin and fenofibrate on blood lipids and the side-effects of these two drugs were compared in a double-blind trial involving 184 adults with primary hypercholesterolemia (total cholesterol levels: 3.87 +/- 1.02 g/l in the simvastatin group, 3.78 +/- 0.79 g/l in the fenofibrate group; N.S.). During a 10-week period, the patients received either fenofibrate 200 mg twice daily or simvastatin 20 mg once daily with doubling of the dosage at week 6 if the LDL-cholesterol level remained above 1.40 g/l. Simvastatin significantly (P less than 0.01) reduced total cholesterol by -29.9 percent, LDL-cholesterol by -35.4 percent, apoprotein B by -27.3 percent and triglycerides by -16.7 percent. Fenofibrate significantly (P less than 0.01) reduced total cholesterol by -19.2 percent, LDL-cholesterol by -22.3 percent apoprotein B by 13.9 percent and triglycerides by 28.9 percent. Reduction of the first 3 parameters was significantly (P less than 0.01) greater with simvastatin and reduction of triglycerides significantly greater with fenofibrate. Apoprotein A1 levels were increased by fenofibrate (+ 7.4 percent) but not by simvastatin. Side-effects occurred with a frequency of 6 percent under simvastatin and 9 percent under fenofibrate.

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The active metabolite of fenofibrate is fenofibric acid, which is strongly bound to serum proteins. Following a single oral dose of 300 mg fenofibrate there is a diphasic decrease in plasma levels of fenofibric acid, and most of the drug is excreted as conjugate in the urine. Following daily oral administration of 300 mg during 10 days, a state of equilibrium is obtained within 2 to 3 days and persists throughout the observation period; the mean elimination half-life and urinary excretion rate are very similar to those measured after a single dose, and the drug does not accumulate. In patients with renal insufficiency, the plasma half-life of fenofibric acid is very substantially prolonged and considerable accumulation takes place, as the compound is virtually not dialyzable. Doses of 100 mg/day produce plasma levels similar to those obtained with 300 mg/day. The lipid-lowering activity mostly affects triglycerides. Concomitant administration of colestipol has no effect on blood kinetics and urinary excretion of fenofibrate but results in very important reduction of all lipoprotein fractions.

The authors list the principal normolipidemic drugs. Only cholestyramine (Questran) and some fibrates (fenofibrate: Lipanthyl for instance) are registered for pediatrics. Cholestyramine acts by sequestering biliary acids, and thereby inhibiting intestinal cholesterol resorption. It is the primary drug used for children, when diet has been unable to restore normal cholesterol values.

A study of blood lipids and platelet functions was conducted in north-eastern (Moselle) and southeastern (Var) France, among populations with widely different dietary habits and coronary disease mortality rates. Striking variations were found between the two populations with regard to platelet coagulation activity and response to various aggregation agents. On the other hand, plasma cholesterol, HDL-cholesterol and triglyceride levels were identical. Voluntary reduction by 53 subjects from Moselle in the consumption of saturated fats resulted, within one year, in remarkable improvement in platelet functions, thus demonstrating that the differences were due to diet and not to genetic factors. This being established, two studies were undertaken comparing healthy, normolipaemic subjects (control group) with two groups of type IIb hyperlipaemic subjects following the same pre-established diet and either untreated or treated with fenofibrate. They showed platelet hyperaggregation response to epinephrine in untreated subjects, whereas platelet functions in fenofibrate-treated subjects were identical with those in the control group. It would therefore seem that for many coronary disease patients changes in dietary habits combined with fenofibrate treatment might be one of the simplest and quickest ways of preventing the recurrence of myocardial infarction.

Fenofibrate is one of several compounds with substituted-2-phenoxy-isobutyric acids and esters. In ageing rats receiving a hyperlipidaemic diet or injections of triton, fenofibrate lowers blood lipids as much as, or more than other antilipaemic agents. It is active in man against the main types (IIa, IIb and IV) of hyperlipoproteinaemia (HLP), and this activity is sustained throughout treatment (20 months in one study). In comparative studies, the effects of fenofibrate (400 mg/day) on the lipoprotein fractions tested were superior to those of clofibrate (2 g/day) and slightly superior to those of gemfibrosil (800 mg/day) and bezafibrate (600 mg/day). The drug also enhanced the lipid-lowering effects of colestipol. In doses of 300 mg/day fenofibrate produced a significant 13-15% decrease in apoprotein B with a concomitant 19-28% increase in apoprotein A. Fenofibrate was also found to normalize platelet aggregation in patients with type IIb HLP. In animals fenofibrate is excreted in equal amounts in the urine and faeces; in man, urinary excretion predominates (85-90%). The serum half-life curve is diphasic, with a rapid (5 hours) slope and a slow (17 hours) slope. In a 10-day study conducted on 10 volunteers serum levels of fenofibric acid remained remarkably constant, indicating lack of accumulation. New data on the mode of action are needed to further differentiate fenofibrate from clofibrate.

Fenofibrate in doses of 300 mg/day was administered for 3 consecutive months to 31 patients with type IIa, IIb, III or IV hyperlipoproteinaemia (HLP). Mean plasma cholesterol levels decreased by 22% in type IIa (n = 15), by 19% in type IIb (n = 10), by 51% in type III (n = 2) and by 5% in type IV (n = 4) HLP. Mean plasma triglyceride levels were reduced by 32, 38, 60 and 52% respectively in these four types of HLP. Apo-A, measured in 11 patients with type IIa, HLP increased by up to 28% after three months' treatment, whereas alphalipoprotein cholesterol only slightly rose by a mean 11%. Apo-B decreased by 14%. Fenofibrate was well tolerated. Only one patient developed a pruriginous rash at the end of the treatment period.

Since its discovery by Thorp and Waring in 1962, the clofibrate molecule has undergone various modifications. The all-important phenoxy-2-methyl-2-propionic acid chain was preserved, but it seemed reasonable to try and improve pharmacological activity by substituting for the Cl atom a group with different hydrophobic profile. However, none of the phenylketone derivatives produced had satisfactory antilipaemic properties, except for the benzoyl derivative. Grafting on this derivative a Cl atom in position 4 by an original method based on a vinylogy principle, and esterifying with propanol-2 yielded the most active and best tolerated compound: fenofibrate. Fenofibrate resembles clofibrate in that it has the same phenoxy-2-methyl-2-propionic chain but differs from it by the way electrons are distributed, by its lipophilia and by its supple structure, the mobile carbon links between the two rings allowing for spatial changes and facilitating adaptation to receptors. The strong individuality of the molecule is undoubtedly responsible for the significant pharmacokinetic and pharmacological differences between fenofibrate and clofibrate.

In vitro and in vivo studies using capillary column gas chromatography alone or coupled with mass spectrometry resulted in the identification of several metabolites of fenofibrate (LF 178). Fenofibric acid (LF 153) was omnipresent, being found in rats after acute, subacute and chronic administration, in human urine during chronic treatment, and in cultures of rat and human liver cells. Other metabolites were LF 433 (LF 153 benzhydrol), which increases in rats with the duration of treatment while LF 153 decreases, and LF - phenol" found in human urine. In hepatocyte cultures, fenofibric acid was predominant, but fenofibrate itself and LF 321 (LF 178 benzhydrol) were also present in addition to the above-mentioned metabolites. LF 321, however, was only found in human liver cell cultures.

Seven analogs of methyl-2 [chloro-4' benzoyl)-4 phenoxy]-2 propionic acid, (LF 153) have been tested for their effects on respiration and phosphorylation of rat liver mitochondria suspensions. They differ from one another by the sort of binding between both aromatic cycle as well as by the nature and position of the halogenated substitutions and alpha methylation in the propionic chain. All the compounds which have been tested acted as inhibitors of the electron transport chain and uncouplers of phosphorylations.

The effects on rat liver of probucol (250 or 500 mg/kg/24 h), clofibrate (250 mg/kg/24 h) and fenofibrate (100 mg/kg/24 h) were compared after 28 days' treatment. Th bodyweight of animals treated with probucol 250 mg/kg/24 h has increased, as compared with a control group of untreated animals. The increase in liver weight and live weight/bodyweight ratio was greater in rats treated with clofibrate or fenofibrate than in rats treated with probucol. Cholesterol and triglyceride plasma levels were lower in clofibrate-treated animals. There were no changes in SGOT and SGPT in any of the three groups. Alkaline phosphatases were increased only in rats treated with clofibrate (these enzymes were not assayed in rats which received fenofibrate). Electron microscope study of liver sections showed the following changes in clofibrate--and fenofibrate-treated rats as compared with the control group: increase in smooth-surfaced endoplasmic reticulum, ribosome detachment, slight glycogen depletion and increase in the number of peroxysomes. In the probucol-treated group, apart from an occasional increase in smooth-surfaced endoplasmic reticulum, liver cells were identical with those of the control group; in particular, there was no increase in the number of peroxysomes.

In a study started in 1973 and still in progress (1100 patient-years so far) fenofibrate in daily doses of 200-400 mg consistently proved effective, without any loss of activity with time. The drug lowered serum total cholesterol levels by 17-27% in type IIa, IIb and III primary hyperlipoproteinaemia (HLP) and serum triglyceride levels by 35-51% in type IIb and III HLP and by 46-54% in type IV HLP. Clinically and biologically fenofibrate was always well tolerated, even after 5 years' treatment. Side-effects were uncommon (4%) and mild, and they obliged to discontinue treatment in only 1% of the patients. Abnormal manifestations encountered during therapy appeared to be fortuitous. The effects of the drug on cardiovascular morbidity and mortality could not be determined from this trial. In a short-term study involving 21 patients with type IIa and IIb primary HLP, fenofibrate in doses of 200-400 mg/day produced a significant decrease in total cholesterol, LDL-cholesterol and apoprotein B. It is also reduced triglycerides and VLDL-triglycerides in type IIb HLP. The increase in HDL-cholesterol observed under fenofibrate was significant in type IIa HLP but not in type IIb HLP. In both types, there was a significant rise in HDL: LDL + VLDL ratio.

Clofibrate (250 mg/kg/day) and Procetofene (100 mg/kg/day) feedings determine a significant increase of the rat liver weight. After intravenous injection in treated and control rats of doubly labelled chylomicrons ([14C] glycerol and [3H] oleic acid) an enhancement of radioactive triglyceride hydrolysis was observed in the treated groups. The oxidation of exogenous oleic acid was increased by both drug feeding. Alterations of liver and blood lipids (especially large amounts of labelled diglycerides in the blood) could be probably related to the inhibition of the diglyceride acyltransferase in the liver.