Hyperlipidemias: Farnier M

Sicard D, Chanu B, Badoc G, Beucler I, Chauvenet M, Clavel J, Cocaul-André M, Denolle T, Desson J, Ducimetière P, Farnier M, Fontbonne A, Gautier J, Hoog-Labouret N, Janowski M, Krempf M, Le Goaziou M, Marechaud M, Mottier D, Ribier A, Signeyrole D, Veyssier-Belot C, Mlika-Cabanne N, Anonymous00274. · No affiliation provided · Ann Endocrinol (Paris). · Pubmed #11240408 No free full text.

This publication has no abstract.

Farnier M. · Endocrinologie maladies métaboliques, Point Médical, F-21000, Dijon, France. · Presse Med. · Pubmed #19376680 No free full text.

Abstract: Plasma lipids should - and can reliably - be measured within 24 hours of the onset of symptoms of acute coronary syndrome. They should again be measured from 1 to 3 months after the event. The level of low-density lipoproteins(LDL) cholesterol remains the marker for treatment initiation and for evaluation of therapeutic goals. The total number of atherogenic particles is a better determinant of cardiovascular risk than the LDL-cholesterol level, as are the levels of non-high-density lipoprotein (HDL)-cholesterol and apolipoprotein B. The use of apolipoprotein B by primary care physicians is limited by the lack of standardization and must be restricted to specific clinical cases. Non-HDL-cholesterol can be recommended as a secondary target in patients with high triglyceride levels. In coronary patients treated with a statin, management of abnormal levels of triglycerides and HDL-cholesterol is important to minimize the risk of recurrence.

Corsini A, Windler E, Farnier M. · Department of Pharmacological Sciences, University of Milan, Milan, Italy. · Eur J Cardiovasc Prev Rehabil. · Pubmed #19237992 No free full text.

Abstract: Several recent meta-analyses of numerous lipid-lowering outcome trials confirm the direct relationship between low-density lipoprotein-cholesterol (LDL-C) lowering and cardiovascular risk reduction. As a consequence, LDL-C goals are continuously being set lower. To achieve lipid lowering, several efficient drugs are available, however, the current pharmacopoeia remains limited for some critical patient situations. Colesevelam hydrochloride is a specifically engineered bile acid sequestrant that features a more favourable tolerability and drug interaction profile than traditional bile acid sequestrants, because of a better affinity and binding capacity to bile acids. In addition, colesevelam retains the nonsystemic mode of action of bile acid sequestrants. Moreover, colesevelam lowers LDL-C by 15-19% and 10-16%, respectively, in monotherapy and in combination to various lipid-lowering drugs, such as statins, ezetimibe and fenofibrates. Along with an efficient and sustainable effect on lipid profiles, colesevelam - as other bile acid sequestrants - has been shown to lower the glycosylated haemoglobin HbA1c by 0.5% on average in patients with type 2 diabetes. Overall, colesevelam represents an interesting add-on treatment to be used in high-risk patients with hypercholesterolaemia for whom standard lipid-lowering therapies are not enough or not well tolerated.

Farnier M. · Point Médical, Rond Point de la Nation, 21000 Dijon, France. · Fundam Clin Pharmacol. · Pubmed #18001317 No free full text.

Abstract: Ezetimibe with simvastatin in combination inhibits both the absorption and production of cholesterol. This dual mechanism of inhibition substantially increases the capacity to decrease levels of atherogenic low-density lipoproteins, compared with that observed when either drug is used alone. Ezetimibe/simvastatin is more effective than atorvastatin or rosuvastatin monotherapy treatments in low-density lipoprotein cholesterol lowering and getting more patients to goals. Ezetimibe/simvastatin offers an important treatment alternative to patients who respond inadequately even to high-dose statin therapy.

Farnier M. · Point Médical, Rond Point de la Nation, 21000 Dijon, France. · Expert Opin Pharmacother. · Pubmed #17563268 No free full text.

Abstract: Mixed hyperlipidaemia is an important risk factor for the development of cardiovascular disease. The global management of mixed hyperlipidaemia is often more difficult than the treatment of pure hypercholesterolaemia in terms of goal attainments. Despite the significant clinical benefits provided by statins, many patients with mixed hyperlipidaemia do not achieve their recommended low-density and non-high-density lipoprotein cholesterol target goals with statin monotherapy. The combination of ezetimibe plus fenofibrate is a new alternative to improve the overall atherogenic lipid profile of patients with mixed hyperlipidaemia. However, the absence of comparative data with statin monotherapy and of long-term clinical studies suggests reservation of the combination of ezetimibe plus fenofibrate as a second-line therapy. Nevertheless, this combination therapy of ezetimibe plus fenofibrate seems particularly useful for patients with a poor response or intolerance to statin monotherapy.

Shepherd J, Bassand JP, Milon H, Farnier M. · No affiliation provided · Presse Med. · Pubmed #15523280 No free full text.

This publication has no abstract.

Dallongeville J, Ferrières J, Schuster H, Farnier M, Lepen C. · INSERM U508, Institut Pasteur, Lille, France. · Presse Med. · Pubmed #15523276 No free full text.

This publication has no abstract.

Farnier M. · Point Médical, Rond Point de la Nation, Dijon, France. · Am J Cardiovasc Drugs. · Pubmed #14727929 No free full text.

Abstract: It has been clearly shown that lowering low density lipoprotein-cholesterol (LDL-C) [most often with an HMG-CoA reductase inhibitor] decreases the risk of a cardiovascular event. However, this risk reduction was, at most, 35% in clinical trials, meaning that many events could not be prevented. Moreover, reaching target lipid values as recommended by the current guidelines is often difficult, mainly in high-risk situations such as secondary prevention or type 2 diabetes mellitus. As the two main classes of lipid-lowering drugs (HMG-CoA reductase inhibitors and fibric acid derivatives) have complementary effects on lipid parameters, it seems logical to combine both treatments particularly in patients with combined hyperlipidemia. In fact, combination therapy with an HMG-CoA reductase inhibitor and a fibric acid derivative induces a further decrease in LDL-C levels compared with monotherapy and improves other lipid values such as high density lipoprotein-cholesterol (HDL-C) and triglyceride (TG) levels. Unfortunately, there are currently no available randomized, prospective clinical data on the reduction of the incidence of cardiovascular events with such a combination. This is mainly because the use of HMG-CoA reductase inhibitor and fibric acid derivative combinations was initially described as dangerous. It is true that such a combination increases the risk of muscle toxicity that already exists with monotherapy. Muscle toxicity can eventually lead to life-threatening rhabdomyolysis and some precautions of use are required; however, the risk seems actually lower than what has been initially reported. The use of combined therapy with an HMG-CoA reductase inhibitor and a fibric acid derivative requires the respect of some rules such as avoiding the prescription in patients with concomitant conditions like renal failure and avoiding the use of gemfibrozil as a fibric acid derivative in such a combination. It is now imperative to design clinical trials to determine the clinical efficacy and precise safety of this combined treatment especially in patients with abnormalities in every parameter of the lipid triad (LDL, HDL and TG) and a high vascular risk such as patients with type 2 diabetes mellitus.

Farnier M. · · Therapie. · Pubmed #12822207 No free full text.

Abstract: The field of new lipid-lowering drug research is very active, with researchers, looking to make the currently available drugs more powerful and safer, and to develop new classes of drugs. Among the statins, development has gone the farthest for rosuvastatin and pitavastatin. Colesevelam is a new bile acid sequestrant with a better digestive tolerance. Among the new classes of drugs, the most promising molecules are the cholesterol absorption inhibitors--with ezetimibe as the first in line--and the PPAR-alpha and PPAR-gamma activators. Among the other classes, the acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, and ileal bile acid transporter inhibitors, have to be mentioned. In most of the cases, those new compounds are being developed mainly as a combined treatment with statins. However, these combination therapies differ depending on the lipid abnormalities of the patient. The statin-ezitimibe and the statin-bile acid sequestrant combinations have been the most studied treatments in pure hypercholesterolaemia. On another hand, the statin-PPAR-alpha and -gamma activator combination were the first to be developed for patients with combined hyperlipidaemia or type 2 diabetes mellitus. However, the clinical benefit of ACAT or CETP inhibitors remains to be determined and the development of MTP inhibitors has been restricted so far, because of problems of digestive intolerance and hepatic steatosis. Finally, the discovery of new specific lipoprotein receptors, such as the ABCA1 and SRB1 receptors, means that we can work towards developing new potential targets for pharmacological intervention.

Farnier M, Picard S. · Point Medical, Rond-Point de la Nation, Dijon, F-21000, France. · Curr Atheroscler Rep. · Pubmed #11123844 No free full text.

Abstract: Cardiovascular disease is the leading cause of mortality in patients with type 2 diabetes. Among the many factors that are involved in the pathogenesis of atherosclerosis in diabetic patients, dyslipidemia plays a major role. It is characterized by an increase in triglycerides, a decrease in high-density lipoprotein cholesterol and normal or mildly elevated low-density lipoprotein cholesterol. The management of patients with diabetic dyslipidemia is difficult because we lack studies specifically designed for diabetic patients. Thus, strategy has to rely on post hoc analyses of landmark intervention trials, which usually include only a small number of diabetic patients, or on rare trials enrolling small cohorts of diabetic patients. When lifestyle changes fail, monotherapy should be tried first with either a statin or a fibrate, depending on triglyceride level. If lipid target values are not reached, a combination therapy can then be initiated, with close follow-up of potential side effects.

Farnier M. · Point Médical, Rond-Point de la Nation, Dijon. · Presse Med. · Pubmed #10599269 No free full text.

Abstract: MECHANISM OF ACTION: Statins act by competitive inhibition of HMG-CoA reductase, a key enzyme regulating cholesterol synthesis. Reduction in serum LDL, the crucial biological expression dependent on this mechanism, varies in intensity as a function of the type and of the dose of statin. PLEIOTROPIC EFFECTS: Besides their lipid lowering effect, statins have also been demonstrated to have pleiotropic effects mostly directly related to HMG-CoA reductase inhibition. CARDIOVASCULAR IMPACT: Several clinical studies investigating prevention of cardiovascular disease have established that statins decrease cardiovascular morbidity and mortality. Results have been very coherent for both primary and secondary prevention with statins. The cardiovascular benefit is most likely partly related to its pleiotropic effects, particularly those inducing a stabilization of the atheromatous plaques. INDICATIONS: Interventional studies have clearly established the role of statins in comparison with other lipid lowering agents for the prevention of cardiovascular events in most situations although a few therapeutic choices remain a subject of debate. Globally, the primary indications of statins are hypercholesterolemia and mixed hyperlipidemia with moderately elevated triglycerides. There are still some questions concerning the therapeutic goals of statin therapy.

Farnier M, Averna M, Missault L, Vaverkova H, Viigimaa M, Massaad R, Vandormael K, Johnson-Levonas AO, Brudi P. · Point Medical, Rond Point de Nation, Dijon, France. · Int J Clin Pract. · Pubmed #19222610 No free full text.

Abstract: AIMS: To evaluate the efficacy of switching from a previous statin monotherapy to ezetimibe/simvastatin (EZE/SIMVA) 10/20 mg vs. rosuvastatin (ROSUVA) 10 mg. METHODS: In this randomised, double-blind study, 618 patients with documented hypercholesterolaemia [low-density lipoprotein cholesterol (LDL-C) > or = 2.59 and < or = 4.92 mmol/l] and with high cardiovascular risk who were taking a stable daily dose of one of several statin medications for > or = 6 weeks prior to the study randomisation visit entered a 6-week open-label stabilisation/screening period during which they continued to receive their prestudy statin dose. Following stratification by study site and statin dose/potency, patients were randomised to EZE/SIMVA 10/20 mg (n = 314) or ROSUVA 10 mg (n = 304) for 6 weeks. RESULTS: EZE/SIMVA produced greater reductions in LDL-C (-27.7% vs. -16.9%; p < or = 0.001), total cholesterol (-17.5% vs. -10.3%; p < or = 0.001), non-high-density lipoprotein cholesterol (HDL-C) (-23.4% vs. -14.0%; p < or = 0.001) and apolipoprotein B (-17.9% vs. -9.8%; p < or = 0.001) compared with ROSUVA, while both treatments were equally effective at increasing HDL-C (2.1% vs. 3.0%; p = 0.433). More patients achieved LDL-C levels < 2.59 mmol/l (73% vs. 56%), < 2.00 mmol/l (38% vs. 19%) and < 1.81 mmol/l (25% vs. 11%) with EZE/SIMVA than ROSUVA (p < or = 0.001). A borderline significantly greater reduction in triglycerides (p = 0.056) was observed for EZE/SIMVA (-11.0%) vs. ROSUVA (-5.3%). There were no between-group differences in the incidences of adverse events or liver transaminase and creatine kinase elevations. CONCLUSION: EZE/SIMVA 10/20 mg produced greater improvements in LDL-C, total cholesterol, non-HDL-C and apoB with a similar safety profile as for ROSUVA 10 mg.

Farnier M, Volpe M, Massaad R, Davies MJ, Allen C. · Point Medical, Rond Point de la Nation, 21000 Dijon, France. · Int J Cardiol. · Pubmed #15982505 No free full text.

Abstract: OBJECTIVE: To determine whether co-administering ezetimibe with on-going simvastatin treatment was more effective than placebo plus on-going simvastatin in achieving an LDL-C treatment target of < or = 2.60 mmol/l (100 mg/dl) in hypercholesterolemic patients with coronary heart disease (CHD). METHODS: Men and women (age > or = 18 years) with documented CHD and on a stable dose of simvastatin 10 mg or 20 mg for at least 6 weeks were recruited for this study. After a 4-week simvastatin 10 or 20 mg plus placebo and diet run-in period, patients were eligible for randomization if LDL-C > 2.60 and < or = 4.20 mmol/l and triglycerides (TG) < or = 4.00 mmol/l. Eligible patients were randomized to a double-blind comparative study with ezetimibe 10 mg co-administered with on-going simvastatin 10 mg or 20 mg (n=181) versus placebo to match ezetimibe co-administered with simvastatin 10 mg or 20 mg (n=191) for 6 weeks. RESULTS: At baseline, mean LDL-C was comparable between the ezetimibe (3.14 mmol/l) and placebo (3.19 mmol/l) groups. With the addition of ezetimibe or placebo to on-going simvastatin therapy, the percentage of patients achieving the LDL-C goal of < or = 2.60 mmol/l after 6 weeks of treatment was significantly (p < or = 0.001) greater in the ezetimibe group (74.3%) than in the placebo group (16.7%). The addition of ezetimibe to on-going simvastatin treatment also resulted in a significantly (p < or = 0.001) larger mean percent reduction in LDL-C from baseline (25.2%) compared with placebo (0.9%). Ezetimibe was generally well tolerated compared to placebo when added to on-going simvastatin treatment. CONCLUSIONS: Co-administering ezetimibe with on-going simvastatin 10 or 20 mg treatment allowed more hypercholesterolemic patients with CHD to reach the LDL-C treatment target of < or = 2.60 mmol/l.

Farnier M, Freeman MW, Macdonell G, Perevozskaya I, Davies MJ, Mitchel YB, Gumbiner B, Anonymous00319. · Point Medical, Rond Point de la Nation, Dijon F-21 000, France. · Eur Heart J. · Pubmed #15781429 links to  free full text

Abstract: AIMS: To examine the efficacy and safety of coadministered ezetimibe (EZE) with fenofibrate (FENO) in patients with mixed hyperlipidaemia. METHODS AND RESULTS: This was a multicentre, randomized, double-blind, placebo-controlled, parallel arm trial in patients with mixed hyperlipidaemia [LDL-cholesterol (LDL-C), 3.4-5.7 mmol/L (2.6-4.7 mmol/L for patients with type 2 diabetes); triglycerides (TG), 2.3-5.7 mmol/L] and no history of coronary heart disease (CHD), CHD-equivalent disease (except for type 2 diabetes), or CHD risk score>20%. A total of 625 patients was randomized in a 1:3:3:3 ratio to one of four daily treatments for 12 weeks: placebo; EZE 10 mg; FENO 160 mg; FENO 160 mg plus EZE 10 mg (FENO+EZE). The primary endpoint compared the LDL-C lowering efficacy of FENO+EZE vs. FENO alone. LDL-C, non-HDL-cholesterol (non-HDL-C), and apolipoprotein B were significantly (P<0.001) reduced with FENO+EZE when compared with FENO or EZE alone. TG levels were significantly decreased and HDL-C was significantly increased with FENO+EZE and FENO treatments when compared with placebo (P<0.001). Coadministration therapy reduced LDL-C by 20.4%, non-HDL-C by 30.4%, TG by 44.0%, and increased HDL-C by 19.0%. At baseline, >70% of all patients exhibited the small, dense LDL pattern B profile. A greater proportion of patients on FENO+EZE and FENO alone treatments shifted from a more atherogenic LDL size pattern to a larger, more buoyant, and less atherogenic LDL size pattern at study endpoint than those on placebo or EZE. All three active therapies were well tolerated. CONCLUSION: Coadministration of EZE with FENO provided a complementary efficacy therapy that improves the atherogenic lipid profile of patients with mixed hyperlipidaemia.

Stein EA, Farnier M, Waldstreicher J, Mercuri M, Anonymous00310. · Medical Research Laboratories, 2 Tesseneer Drive, Highland Heights, KY 41076, USA. · Nutr Metab Cardiovasc Dis. · Pubmed #11434192 No free full text.

Abstract: BACKGROUND AND AIM: Recently, several studies have indicated there may be differences among statins regarding a possible association between therapy and a reduction in risk of fractures. No data from prospective randomised clinical trials designed to assess either biochemical or clinical effects on bone metabolism are yet available. We assayed levels of biochemical markers of bone formation in stored serum samples from a recently completed randomised clinical trial conducted to compare the effects of simvastatin and atorvastatin on the lipid profile of patients with hypercholesterolaemia. METHODS AND RESULTS: This 12-week, randomised, multicenter, open-label study was designed to compare the safety and lipid-lowering efficacy of simvastatin 40 mg or 80 mg with that of atorvastatin 20 mg or 40 mg in 846 hypercholesterolaemic patients. Stored serum samples from this study were analysed to compare the effects of simvastatin and atorvastatin on 2 biomarkers of bone turnover, bone-specific alkaline phosphatase (BSAP), a marker of bone formation, and C-teleopeptide of type 1 collagen (CTx), a marker of bone resorption. Treatment with simvastatin 40 and 80 mg/day, but not atorvastatin 20 and 40 mg/day, led to significant (p < 0.05) reductions in BSAP in both men (4.1-5.4% reduction) and women (4.2-7.4% reduction). In addition, there appeared to be a dose-dependent effect with greater reductions in BSAP seen with the 80 mg dose of simvastatin. Treatment with either 20 mg or 40 mg of atorvastatin had no significant effect on BSAP levels on the groups as a whole or in the gender-specific subgroups. CTx showed a small, but not statistically significant, decrease with simvastatin, again with an apparent dose-related trend. Atorvastatin treatment generally resulted in small, non significant increases in CTx. CONCLUSIONS: The present serum bone biomarker results show that treatment with simvastatin, but not atorvastatin, decreases BSAP and suggest that simvastatin may have a beneficial effect on bone turnover.

Farnier M, Dejager S. · Point Médical, Dijon, France. · Am J Cardiol. · Pubmed #11078237 No free full text.

Abstract: This double-blind study was designed to assess the efficacy and safety of fluvastatin-fenofibrate combination therapy compared with fenofibrate monotherapy in severe primary hypercholesterolemia (low-density lipoprotein [LDL] cholesterol > or =190 mg/dl [4.9 mmol/L], triglycerides < or =350mg/dl [3.9 mmol/l]). After a 10-week placebo and dietary baseline period, 102 patients were randomized to receive micronized fenofibrate 200 mg, fluvastatin 20 mg plus micronized fenofibrate 200 mg, or fluvastatin 40 mg plus micronized fenofibrate 200 mg. At week 16, fenofibrate 200 mg alone lowered LDL cholesterol from baseline by 21% compared with 32% for fluvastatin 20 mg plus fenofibrate 200 mg and 41% for fluvastatin 40 mg plus fenofibrate 200 mg (p <0.001). Triglycerides decreased by 29% with fenofibrate 200 mg alone, 39% with fluvastatin 20 mg plus fenofibrate 200 mg, and 40% with fluvastatin 40 mg plus fenofibrate 200 mg (p <0.05). Safety was assessed by recording adverse events and measuring clinical laboratory parameters. The adverse event profile was similar for the 3 treatment groups. One patient withdrew due to an increase in transaminase levels. No significant increase in creatine phosphokinase levels was observed with combination therapy. In conclusion, the addition of fluvastatin to micronized fenofibrate results in substantial improvement in atherogenic plasma lipids and is well tolerated.

Krempf M, Rohmer V, Farnier M, Issa-Sayegh M, Corda C, Sirugue I, Gerlinger C, Masseyeff-Elbaz MF. · Clinique d'Endocrinologie et Nutrition, Hôtel-Dieu, 44093 Nantes Cedex 1, France. · Diabetes Metab. · Pubmed #10880891 links to  free full text

Abstract: The aim of this study was to evaluate the efficacy on LDL-cholesterol (LDL-C) of micronised fenofibrate given for three months at doses ranging from 200 to 400 mg once daily, compared with placebo. A double-blind, randomised, parallel-group, multi-centre trial was performed in four centers of France in 340 hypercholesterolemic patients (163M, 177F) aged 18-75 years. After a 2-3 month single-blind run-in period on placebo and diet, patients with LDL-C greater than or equal to 4.65 mmol/l (180 mg/dl) maintained on the same diet throughout the study were randomly allocated to placebo or to 200, 267, 340 or 400 mg micronised fenofibrate, given once daily with the evening meal for 3 months. LDL-C, total cholesterol (TC), total triglycerides (TG) and apolipoprotein B (Apo B) significantly decreased compared with placebo in all four fenofibrate groups. For all randomised patients, the decrease in the fenofibrate groups ranged from 31.6-38.8% for LDL-C, 24.5-31.9% for TC, 26.7-40.8% for TG, and 27.3-35.0% for Apo B. An increase in HDL-cholesterol of 4.1-8.2% was observed in the fenofibrate groups, but did not reach statistical significance. Lipid values in the placebo group remained unchanged. The therapeutic goal of LDL-C<3.36 mmol/l (130 mg/dl) was reached in 27% in the 200 mg group and increased to 56% in the 300 mg group. There were no major clinical or biological adverse events in the dose interval from 200 mg to 400 mg of micronised fenofibrate per day. This study showed treatment for 3 months with micronised fenofibrate at doses up to 400 mg per day is effective and can reduce LDL-cholesterol up to 30% allowing further evaluation of these doses on longer trials.

Farnier M, Portal JJ, Maigret P. · Point Médical, Dijon, France. · J Cardiovasc Pharmacol Ther. · Pubmed #10687671 No free full text.

Abstract: BACKGROUND: Atorvastatin, a new enantiomerically pure synthetic statin, has shown a marked low-density lipoprotein (LDL) cholesterol reduction at doses ranging from 10 to 80 mg/d. This trial was designed to compare the efficacy of atorvastatin 10 mg with simvastatin 10 mg and 20 mg, the latter dose being commonly used in some countries. METHODS AND RESULTS: A parallel group, randomized, PROBE, multicenter study was conducted to compare the efficacy of 10 mg/d atorvastatin with that of 10 mg/d simvastatin and 20 mg/d simvastatin in patients with primary hypercholesterolemia. After a 6-week diet-placebo lead-in period, 272 patients with LDL cholesterol > or = 160 mg/dL and triglycerides < or = 300 mg/dL were randomized to 6 weeks of treatment with atorvastatin 10 mg (109 patients), simvastatin 20 mg (109 patients), or simvastatin 10 mg (54 patients). In the main analysis, which tested the equivalence of atorvastatin 10 mg and simvastatin 20 mg, the mean percent change in LDL cholesterol for atorvastatin 10 mg (-37.0%) was greater than and not equivalent to simvastatin 20 mg (-33.8%). In the secondary analysis, which compared the efficacy of atorvastatin 10 mg with that of simvastatin 10 mg, the mean decrease in LDL cholesterol was significantly greater (P < .001) for atorvastatin 10 mg than for simvastatin 10 mg (-37.0% vs. -28.9%). The two drugs were well tolerated, with an incidence of clinical and biochemical side effects similar among the 3 treatment groups. CONCLUSION: In primary hypercholesterolemia, atorvastatin 10 mg was more effective and nonequivalent to simvastatin 20 mg and significantly more effective than simvastatin 10 mg for reducing LDL cholesterol levels.

Hanefeld M, Deslypere JP, Ose L, Durrington PN, Farnier M, Schmage N. · Institute and Polyclinic for Clinical Metabolism Research, University Clinic Carl Gustav Carus of the Technology University, Dresden, Germany. · J Int Med Res. · Pubmed #10505301 No free full text.

Abstract: This study examined the action of cerivastatin, a new statin, in subjects with primary hypercholesterolaemia. The effects of two oral doses of cerivastatin (400 micrograms/day or 300 micrograms/day) were compared with placebo in 349 patients using a multicentre, randomized, double-blind, placebo-controlled study design. Cerivastatin treatment lasted 8 weeks and produced significant reductions in low density lipoprotein-cholesterol (LDL-C) levels from baseline compared with placebo. The reduction in LDL-C was significantly greater with 400 micrograms than with 300 micrograms cerivastatin. When responder rates were examined, the higher (400 micrograms/day) cerivastatin dose was found to be more effective in producing larger (> 40%) reductions in LDL-C levels. Cerivastatin treatment was well tolerated. Only two withdrawals due to adverse events during active treatment occurred, neither of which was considered to be due to the study medication. In addition, no clinically relevant increases in the levels of creatine phosphokinase and hepatic transaminases (alanine transaminase and aspartate transaminase) compared with placebo were seen in this study. In conclusion, cerivastatin treatment produced a significant lowering of LDL-C levels, with the higher dose providing the greatest benefit.

Lagrost L, Athias A, Lemort N, Richard JL, Desrumaux C, Châtenet-Duchêne L, Courtois M, Farnier M, Jacotot B, Braschi S, Gambert P. · Laboratoire de Biochimie des Lipoprotéines, INSERM U498, Faculté de Médecine, Hôpital du Bocage, Dijon, France. · Atherosclerosis. · Pubmed #10217372 No free full text.

Abstract: The aim of the present study was to search in type IIb hyperlipidemic patients for putative concomitant effects of simvastatin on the physicochemical characteristics of low density lipoproteins (LDL) and high density lipoproteins (HDL), as well as on the activities of the cholesteryl ester transfer protein (CETP) and the phospholipid transfer protein (PLTP) that were determined in both endogenous lipoprotein-dependent and endogenous lipoprotein-independent assays. In a double-blind, randomized trial, patients received either placebo (one tablet/day; n = 12) or simvastatin (20 mg/day; n = 12) for a period of 8 weeks after a 5-week run-in period. Simvastatin, unlike placebo, reduced the lipid and apolipoprotein B contents of the most abundant LDL-1, LDL-2, and LDL-3 subfractions without inducing significant changes in the overall size distribution of LDL and HDL. Whereas simvastatin significantly increased PLTP activity in an endogenous lipoprotein-dependent assay (P < 0.01), no variation was observed in a lipoprotein-independent assay. Simvastatin significantly decreased plasma CETP activity in an endogenous lipoprotein-dependent assay (P < 0.01), and the reduction in plasma cholesteryl ester transfer rates was explained by a 16% drop in CETP mass concentration (P < 0.01). In contrast, the specific activity of CETP was unaffected by the simvastatin treatment reflecting at least in part the lack of significant alteration in plasma triglyceride-rich lipoprotein acceptors. The simvastatin-induced changes in plasma CETP mass levels correlated positively with changes in plasma CETP activity (r = 0.483, P = 0.0561), in total cholesterol levels (r = 0.769; P < 0.01), and in LDL-cholesterol levels (r = 0.736; P < 0.01). Whereas the observations suggest that simvastatin might exert concomitant beneficial effects on plasma CETP and LDL levels, neither plasma cholesteryl ester transfer activity nor plasma phospholipid transfer activity appeared as the main determinants of the LDL and HDL distribution profiles in type IIb hyperlipidemic patients.

Steg PG, Verdier JC, Carré F, Darne B, Ducardonnet A, Jullien G, Farnier M, Giral P, Haïat R, Anonymous00017. · Inserm U-698, université Paris-VII-Denis-Diderot, hôpital Bichat-Claude-Bernard, AP-HP, 46, rue Henri-Huchard 75018 Paris, France. · Arch Cardiovasc Dis. · Pubmed #19059567 No free full text.

Abstract: AIMS: To compare the impact of three patient counselling strategies for lifestyle changes and to assess the safety and efficacy of ezetimibe on top of statin therapy in hypercholesterolemic high risk patients. METHODS: Open, cluster randomized 3-parallel group trial. Physicians were randomized between patient motivation on: diet or physical exercise or both. Counselling was adapted to the patient's baseline Prochaska stage of change. High cardiovascular risk patients, with LDL-C above or equal to 3 mmol/L despite statin therapy for at least 3 months, were enrolled. Ezetimibe (10mg/day) and patient counselling were started at the same time. Target goal was defined as total cholesterol less than 5 mmol/L and LDL-C above 3 mmol/L. RESULTS: Overall 428 physicians enrolled 1,496 patients. At baseline, LDL-C was 3.9+/-0.9 mmol/L and total cholesterol was 6.1+/-1.1 mmol/L. LDL-C decreased by -30.4+/-19.3% and 869 (62%) patients achieved target goal. No difference was shown between randomisation groups. However, improvements in diet consumption patterns were more easily obtained than improvement in physical activity stage of change in non-active patient at baseline. CONCLUSIONS: The marked short-term impact (-30%) on LDL-C, although similar between the three groups, slightly exceeds usual LDL-C reductions achieved by this dose of ezetimibe. Decreasing fat consumption seems easier than increasing physical activity. This study confirms the good efficacy, short-term tolerability and safety of ezetimibe on top of statins.

Farnier M, Perevozskaya I, Taggart WV, Kush D, Mitchel YB. · Point Medical, Dijon, France. · J Lipid Res. · Pubmed #18669979 No free full text.

Abstract: This analysis evaluates the effects on lipoprotein subfractions and LDL particle size of ezetimibe/simvastatin with or without coadministration of fenofibrate in patients with mixed hyperlipidemia. This multicenter, double-blind, placebo-controlled, parallel-group study included 611 patients aged 18-79 years randomized in 1:3:3:3 ratios to one of four 12 week treatment groups: placebo; ezetimibe/simvastatin 10/20 mg/day; fenofibrate 160 mg/day; or ezetimibe/simvastatin 10/20 mg/day + fenofibrate 160 mg/day. At baseline and study endpoint, cholesterol associated with VLDL, intermediate density lipoprotein (IDL), LDL, and HDL subfractions was quantified using the Vertical Auto Profile II method. LDL particle size was determined using segmented gradient gel electrophoresis. Whereas fenofibrate reduced cholesterol mass within VLDL and IDL, and shifted cholesterol from dense LDL subfractions into the more buoyant subfractions and HDL, ezetimibe/simvastatin reduced cholesterol mass within all apolipoprotein B-containing particles without significantly shifting the LDL particle distribution profile. When administered in combination, the effects of the drugs were complementary, with more-pronounced reductions in VLDL, IDL, and LDL, preferential loss of more-dense LDL subfractions, and increased HDL, although the effects on most lipoprotein subfractions were not additive. Thus, ezetimibe/simvastatin + fenofibrate produced favorable effects on atherogenic lipoprotein subclasses in patients with mixed hyperlipidemia.

Tribble DL, Farnier M, Macdonell G, Perevozskaya I, Davies MJ, Gumbiner B, Musliner TA. · Merck Research Laboratories, Rahway, NJ 07065, USA. · Metabolism. · Pubmed #18502262 No free full text.

Abstract: Coadministration of fenofibrate and ezetimibe (FENO + EZE) produced complementary and favorable effects on the major lipids and lipoproteins, low-density lipoprotein cholesterol (LDL-C), triglycerides, high-density lipoprotein cholesterol (HDL-C), and non-HDL-C levels, and was well tolerated in patients with mixed hyperlipidemia. The current analysis evaluates the effects of FENO and EZE, as monotherapies and in coadministration, on lipoprotein subfractions and LDL particle size distributions in these patients. In a 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, patients with mixed hyperlipidemia were randomized in a 1:3:3:3 ratio to one of 4 treatment groups: placebo, FENO 160 mg/day, EZE 10 mg/day, or FENO 160 mg/day + EZE 10 mg/day. At baseline and study end point, the Vertical Auto Profile II method was used to measure the cholesterol associated with 2 very low-density lipoprotein (VLDL) subfractions (VLDL-C1 + 2 and VLDL-C3), intermediate-density lipoproteins (IDL-C), and 4 LDL subfractions (LDL-C1 through LDL-C4, from most buoyant to most dense), lipoprotein (Lp) (a), and 2 HDL-C subfractions (HDL-C2 and HDL-C3). The LDL particle size was determined using segmented gradient gel electrophoresis. Fenofibrate reduced cholesterol mass within VLDL, IDL, and dense LDL (primarily LDL-C4) subfractions, and increased cholesterol mass within the more buoyant LDL-C2 subfraction, consistent with a shift to a more buoyant LDL peak particle size. Ezetimibe reduced cholesterol mass within all of the apolipoprotein B-containing particles (eg, VLDL-C, IDL-C, and LDL-C) but did not lead to a shift in the LDL particle size distribution profile. Coadministration of FENO and EZE promoted more pronounced reductions in VLDL-C, IDL-C, and LDL-C, and a preferential decrease in dense LDL subfractions. Fenofibrate and FENO + EZE promoted similar increases in HDL-C2 and HDL-C3. Coadministration of FENO + EZE produced complementary and favorable changes in lipoprotein fractions and subfractions, as assessed by the Vertical Auto Profile II method, in patients with mixed hyperlipidemia. These changes reflected the combined effects of FENO in reducing triglycerides-rich lipoproteins and promoting a shift in the LDL particle distribution profile toward larger, more buoyant particles and of EZE in promoting reductions in cholesterol mass across the apolipoprotein B particle spectrum.

Stein EA, Amerena J, Ballantyne CM, Brice E, Farnier M, Guthrie RM, Harats D, Ma PT, Le Maulf F, Melezínková H, Gold A, Sager P. · Metabolic & Atherosclerosis Research Center, Cincinnati, OH, USA. · Am J Cardiol. · Pubmed #17950795 No free full text.

Abstract: Patients with elevated low-density lipoprotein (LDL) cholesteral levels are at high risk of cardiovascular events but are often undertreated and fail to achieve lipid goals. This open-label, noncomparative, multicenter study assessed efficacy and safety of rosuvastatin 40 mg for < or =96 weeks in 1,380 patients with severe hypercholesterolemia, including heterozygous familial hypercholesterolemia. Patients > or =18 years old with fasting LDL cholesterol > or =190 and < or =260 mg/dl and triglycerides <400 mg/dl entered a 6-week dietary lead-in, before receiving rosuvastatin 40 mg for 48 weeks. An optional additional 48-week treatment period followed. The initial period had 2 primary end points: percentage of patients achieving National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III LDL cholesterol goals at 12 weeks, and long-term safety, assessed during 48 weeks by incidence and severity of adverse events (AEs) and abnormal laboratory values. Safety was the primary end point in the extension period. At 12 weeks, 83% of patients achieved NCEP ATP III LDL cholesterol goals, which were maintained during 48 and 96 weeks (81% and 84%, respectively). At 48 weeks, rosuvastatin 40 mg reduced LDL cholesterol from baseline by 52% and increased high-density lipoprotein (HDL) cholesterol by 11% (both p <0.0001). At 96 weeks, LDL cholesterol was reduced by 54% and HDL cholesterol increased by 13%. Rosuvastatin 40 mg was well tolerated during 96 weeks. The overall pattern and incidence of AEs and abnormal laboratory values were consistent with the published safety profile of rosuvastatin and higher doses of other statins. In conclusion, long-term treatment with rosuvastatin 40 mg is safe and effective in patients with severe hypercholesterolemia.

Farnier M, Roth E, Gil-Extremera B, Mendez GF, Macdonell G, Hamlin C, Perevozskaya I, Davies MJ, Kush D, Mitchel YB, Anonymous00370. · Point Medical, Dijon, France. · Am Heart J. · Pubmed #17239698 No free full text.

Abstract: BACKGROUND: Mixed hyperlipidemia is characterized by elevated low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and TG-rich lipoprotein levels. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel arm trial, eligible patients were 18 to 79 years of age, with mixed hyperlipidemia (LDL-C 130-220 mg/dL, TG 150-500 mg/dL). Patients with type 2 diabetes were limited to those with LDL-C of 100 to 180 mg/dL. Patients (N = 611) were randomized in a 3:3:3:1 ratio to one of 4 treatment arms for 12 weeks: ezetimibe/simvastatin 10/20 mg (EZE/SIMVA) + fenofibrate 160 mg (FENO), EZE/SIMVA 10/20 mg, FENO 160 mg, or placebo. The primary objective was to evaluate the LDL-C-lowering efficacy of EZE/SIMVA + FENO versus FENO monotherapy. RESULTS: Low-density lipoprotein cholesterol level was significantly (P < .05) reduced with EZE/SIMVA + FENO (-45.8%) compared with FENO (-15.7%) or placebo (-3.5%), but not when compared with EZE/SIMVA (-47.1%). High-density lipoprotein cholesterol and apolipoprotein A-I levels were significantly increased with EZE/SIMVA + FENO (18.7% and 11.1%, respectively) treatment compared with EZE/SIMVA (9.3% and 6.6%) or placebo (1.1% and 1.6%), but not when compared with FENO (18.2% and 10.8%). Triglyceride, non-high-density lipoprotein cholesterol, and apolipoprotein B levels were significantly reduced with EZE/SIMVA + FENO (-50.0%, -50.5%, and -44.7%, respectively) versus all other treatments. Treatment with EZE/SIMVA + FENO was generally well tolerated with a safety profile similar to the EZE/SIMVA and FENO therapies. CONCLUSIONS: Coadministration of EZE/SIMVA + FENO effectively improved the overall atherogenic lipid profile of patients with mixed hyperlipidemia. Clinical trial registry number: NCT 00093899 (http://www.ClinicalTrials.gov).