Hyperlipidemias: Wierzbicki AS

Wierzbicki AS, Humphries SE, Minhas R, Anonymous00232. · St Thomas' Hospital, London SE1 7EH. · BMJ. · Pubmed #18753174 No free full text.

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Viljoen A, Wierzbicki AS. · No affiliation provided · Int J Clin Pract. · Pubmed #18324945 No free full text.

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Wierzbicki AS. · No affiliation provided · Br J Hosp Med (Lond). · Pubmed #17554938 No free full text.

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Wierzbicki AS. · No affiliation provided · Int J Clin Pract. · Pubmed #15529513 No free full text.

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Wierzbicki AS. · No affiliation provided · Int J Clin Pract. · Pubmed #14627172 No free full text.

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Wierzbicki AS. · No affiliation provided · Int J Clin Pract. · Pubmed #11321864 No free full text.

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Wierzbicki AS. · No affiliation provided · Int J Clin Pract. · Pubmed #10824358 No free full text.

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Wierzbicki AS, Graham CA, Young IS, Nicholls DP. · St. Thomas' Hospital, London SE 1 7EH, UK. · Curr Vasc Pharmacol. · Pubmed #18220935 No free full text.

Abstract: Familial combined hyperlipidaemia (FCH) was identified in early genetic studies of populations as a dominant condition associated with mixed hyperlipidaemia and early onset coronary heart disease. Later studies extended the phenotype and noted that this genetic hyperlipidaemia was sensitive to environmental effects. This article reviews the definitions, animal models and genetics of FCH. In contrast to familial hypercholesterolaemia, which is caused by mutations in a limited number of affected genes, the genetics of FCH have remained obscure and very few definite candidate genes have been identified. A strong role for the apoA-I, A-IV, A-V, C-III cluster on chromosome 11 was identified early on and multiple associations have been found to hyperlipidaemia in this region and more strongly to adjacent sections of the chromosome. More recently quantitative trait mapping has identified a number of candidate genes including upstream transcription factor -1 (USF-1) on 1 q21 and CD-36 on chromosome 4. Of these the strongest evidence, based on 4 analyses, links the lipid components of FCH to intronic variants in the USF-1 gene on chromosome 1q21-23. Unfortunately USF-1 yet fails to show clear associations with diabetes and the metabolic syndrome which co-map to this region and are also associated with mixed hyperlipidaemia. Large scale validation of USF-1 variants in other populations is still awaited. It is likely that FCH is a heterogeneous condition, that is subject to wide-scale environmental confounding from common traits such as obesity and the metabolic syndrome, and that the resolution of its genetics is going to prove a severe challenge.

Kulasekaram R, Peters BS, Wierzbicki AS. · HIV Medicine, St. Thomas' Hospital, London, UK. · Curr Med Res Opin. · Pubmed #16307691 No free full text.

Abstract: Cardiovascular disease is increasingly recognised as a consequence of human immunodeficiency virus (HIV) infection in the era of highly active antiretroviral therapy (HAART). Dyslipidaemia is also a feature of HIV infection itself and the antiretroviral drugs from the protease inhibitor classes. Increased rates of atherosclerotic disease and diabetes have been associated with lipodystrophy and now from one of the major causes of morbidity in HIV and acquired immunodeficiency syndrome (AIDS).This review, based on a multi-database keyword search, summarises the lipid changes observed in the course of HIV infection and its treatment, and puts them into the context of other risk factors for cardiac disease, and other causes of cardiovascular disease in HIV.

Liberopoulos EN, Daskalopoulou SS, Mikhailidis DP, Wierzbicki AS, Elisaf MS. · Department of Internal Medicine, Medical School, University of Ioannina, Greece. · Curr Med Res Opin. · Pubmed #15801994 No free full text.

Abstract: BACKGROUND: Statin therapy has been shown to significantly decrease vascular events and overall mortality in primary and secondary prevention trials. This review considers the pharmacology, nonlipid-lowering effects and clinical trial evidence of fluvastatin based on a survey of PubMed entries. FINDINGS: Recent clinical data show that treatment with fluvastatin is associated with a variety of benefits in different high-risk populations along with a good safety profile. Fluvastatin exerts non-lipid lowering-associated pleiotropic effects in both clinical and experimental studies. Furthermore, an extended-release formulation of fluvastatin with a favourable pharmacokinetic profile is available. CONCLUSION: Treatment with fluvastatin offers a convenient, safe and evidence-based approach to managing dyslipidaemias and preventing vascular events.

Wierzbicki AS. · St Thomas' Hospital Campus, London, UK. · Int J Clin Pract. · Pubmed #15605675 No free full text.

Abstract: Lipid-lowering is established as proven intervention to reduce atherosclerosis and its complications. This article summarises novel developments in the lipid-altering therapies under development. It also discusses other therapeutic targets, such as squalene synthase, microsomal transfer protein, acyl-cholesterol acyl transferase, cholesterol ester transfer protein, peroxosimal proliferator-activating receptors and lipoprotein (a), for which compounds have been developed and have at least reached trials in animal models. Lipid-altering drugs are likely to prove a fast-developing area for novel treatments, as possible synergies exist between new and established compounds for the treatment of atherosclerosis.

Wierzbicki AS, Mikhailidis DP, Wray R. · Department of Chemical Pathology, St. Thomas' Hospital, London, UK. · Am J Cardiovasc Drugs. · Pubmed #14728015 No free full text.

Abstract: Combined hyperlipidemia is increasing in frequency and is the most common lipid disorder associated with obesity, insulin resistance and diabetes mellitus. It is associated with other features of the metabolic syndrome including hypertension, hyperuricemia, hyperinsulinemia and highly atherogenic subfractions of lipoprotein remnant particles including small dense low density lipoprotein-cholesterol. This review examines the mechanisms by which combined hyperlipidemia arises and the various drugs including fibric acid derivatives, hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, and nicotinic acid which can be used either as monotherapy or in combination to manage it and to improve prognosis from atherosclerotic disease in diabetes mellitus, insulin resistant states and primary combined hyperlipidemia. The therapeutic approach to combined hyperlipidemia involves determination of whether the cause is hepatocyte damage or metabolic derangements. Combined hyperlipidemia due to hepatocyte damage should be treated by attention to the primary cause. In the case of metabolic dysfunction because of imbalance in glucose and fat metabolism, therapy of diabetes mellitus and obesity should be optimised prior to commencement of lipid lowering drugs. Both fibric acid derivatives and HMG-CoA reductase inhibitors can be used in the treatment of combined hyperlipidemia with fibric acid derivatives having greater effects on triglycerides and HMG-CoA reductase inhibitors on LDL-C though both have effects on the other cardiovascular risk factors. There is some evidence of benefit with both interventions in mild combined hyperlipidemias and large scale trials are underway. Fibric acid derivatives and HMG-CoA reductase inhibitor therapy can be combined with care, provided that gemfibrozil is avoided, fibric acid derivatives are given in the mornings and shorter half -life HMG-CoA reductase inhibitors are used at night. Combined hyperlipidemia emergencies occur with predominant hypertriglyceridemia in pregnancy or as a cause of pancreatitis. Therapy in the former should aim to reduce chylomicron production by a low fat diet and intervention to suppress VLDL-C secretion using omega-3 fatty acids. In the latter case, fluid therapy alone and medium chain plasma triglyceride infusions usually reduce levels satisfactorily though apheresis may be required. Blood glucose levels also need aggressive management in these conditions. Combined hyperlipidemia is likely to become an increasing problem with the increase in the prevalence of obesity and diabetes mellitus and needs aggressive management to reduce cardiovascular risk.

Wierzbicki AS, Mikhailidis DP, Wray R, Schacter M, Cramb R, Simpson WG, Byrne CB. · Department of Chemical Pathology, St. Thomas' Hospital, London, UK. · Curr Med Res Opin. · Pubmed #12814127 No free full text.

Abstract: Statins and fibrates are well-established treatments for hyperlipidaemias and the prevention of vascular events. However, fibrate + statin therapy has been restricted following early reports of rhabdomyolysis that mainly involved gemfibrozil, originally with bovastatin, and recently, with cerivastatin. Despite this limitation, several reports describing combination therapy have been published. This review considers these studies and the relevant indications and contraindications. Statin + fibrate therapy should be considered if monotherapy or adding other drugs (e.g. cholesterol absorption inhibitors, omega-3 fatty acids ornicotinic acid) did not achieve lipid targets or is impractical. Combination therapy should be hospital-based and reserved for high-risk patients with a mixed hyperlipidaemia characterised by low density lipoprotein cholesterol (LDL) >2.6 mmol/l(100 mg/dl, high density lipoprotein cholesterol (HDL) <1.0 mmol/l (40 mg/dl) and/or triglycerides> 5.6 mmol/l (500 mg/dl. These three 'goals' are individually mentioned in guidelines. Patients should have normal renal, liver and thyroid function tests and should not be receiving therapy with cyclosporine, protease inhibitors or drugs metabolised through cytochrome P450 (especially 3A4). Combination therapy is probably best conducted using drugs with short plasma half-lives; fibrates should be prescribed in the morning and statins at night to minimise peak dose interactions. Both drug classes should be progressively titated from low doses. Regular (3-monthly) monitoring of liver function and creatine kinase is required. In conclusion, fibrate + statin therapy remains an option in high-risk patents. However, long-term studies involving safety monitoring and vascular endpoints are required to demonstrate the efficacy of this regimen.

Wierzbicki AS, Poston R, Ferro A. · Department of Chemical Pathology, GKT School of Medicine, King's College London, London, UK. · Pharmacol Ther. · Pubmed #12804701 No free full text.

Abstract: The 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors, more commonly known as statins, are a class of drug widely used for the treatment of hypercholesterolaemia in patients with established cardiovascular disease as well as those at high risk of developing atherosclerosis. Their predominant action is to reduce circulating levels of low-density lipoprotein (LDL) cholesterol; to a smaller degree, they also increase high-density lipoprotein (HDL) cholesterol and reduce triglyceride concentrations. In recent years, however, there has been an increasing body of evidence that their effects on lipid profile cannot fully account for their cardiovascular protective actions: their beneficial effects are too rapid to be easily explained by their relatively slow effects on atherogenesis and too large to be accounted for by their relatively small effects on plaque regression. Experimental models have revealed that statins exert a variety of other cardiovascular effects, which would be predicted to be of clinical benefit: they possess anti-inflammatory properties, as evidenced by their ability to reduce the accumulation of inflammatory cells in atherosclerotic plaques; they inhibit vascular smooth muscle cell proliferation, a key event in atherogenesis; they inhibit platelet function, thereby limiting both atherosclerosis and superadded thrombosis; and they improve vascular endothelial function, largely through augmentation of nitric oxide (NO) generation. The relative importance of the lipid- and non-lipid-related effects of the statins in the clinical situation remains the subject of much continuing research.

Wierzbicki AS. · St. Thomas' Hospital, London SE1 7EH. · Hosp Med. · Pubmed #12572329 No free full text.

Abstract: Lipid lowering forms part of the treatment of atherosclerosis. Primary prevention is dependent on identification and treatment of patients at high risk of which patients with diabetes are the clearest example. This article reviews the role of lipid lowering in high-risk individuals.

Wierzbicki AS. · Department of Chemical Pathology, St Thomas' Hospital, London, UK. · J Hum Hypertens. · Pubmed #12444536 links to  free full text

Abstract: Modern management of cardiovascular risk depends on assessment of cardiovascular risk factors. Hypertension and hyperlipidaemia are synergistic risk factors for cardiovascular events. Both show a degree of cross-correlation through sharing mechanisms of pathogenesis including insulin resistance and endothelial dysfunction. This article reviews the common pathways leading to dyslipidaemia and hypertension and the effects diet and lipid-lowering drug therapies have had on correcting blood pressure in patients with essential hypertension. Both statins and fibrates have shown a capability to lower blood pressure by up to 8/5 and 15/10 mmHg respectively, in some small-scale clinical trials and have effects on arterial wall structure and hence pulse wave velocity. This blood pressure action may account for some of the clinical effects of lipid-lowering drugs on cardiovascular risk. Thus, lipid lowering may provide an additional method of correcting hypertension in some high-risk patients. However, data from large-scale intervention trials are either absent or ambiguous. Definitive large-scale trials to investigate the antihypertensive effects of lipid-lowering drugs are required, although end point studies examining the interaction of lipid-lowering and antihypertensive drugs to determine optimum combinations are already under way.

Nair DR, Wierzbicki AS, Mikhailidis DP. · Department of Molecular Pathology and Clinical Biochemistry, Royal Free and University College Medical School, Royal Free Campus, London NW3 2QG, England. · J R Soc Promot Health. · Pubmed #11467215 No free full text.

Abstract: There is convincing epidemiological evidence indicating that the serum levels of high density lipoprotein (HDL) cholesterol are inversely related to the risk of vascular events. Similarly, intervention trials, involving healthy populations and patients with coronary heart disease (CHD), have shown that raising the serum levels of HDL is associated with a significant decrease in the risk of vascular events. It follows that serum HDL levels must be considered when assessing risk and setting therapeutic goals. Some of the currently available national treatment guidelines reflect this view. The present review considers the place of serum HDL measurement in the prevention of vascular events.

Wierzbicki AS. · Department of Chemical Pathology, St. Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, United Kingdom. · Expert Opin Pharmacother. · Pubmed #11336625 No free full text.

Abstract: Atorvastatin (Lipitor, Pfizer) is a safe and effective 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (statin). It is the most potent currently available statin in terms of lowering low-density lipoprotein (LDL) and total cholesterol levels. It was the first statin shown to lower triglycerides in patients with isolated hypertriglyceridaemia. It has a good safety profile. In common with other statins, it has non-lipid-lowering effects including improving endothelial function, antiproliferative actions on smooth muscle and reducing platelet aggregation. It also has anti-inflammatory effects and may reduce plasma glucose levels. Clinical trial evidence with this statin is currently limited. It did slightly reduce events in the AVERT trial comparing patients receiving coronary angioplasty with those receiving high-dose atorvastatin therapy and in the MIRACL study reduced ischemia in patients with acute coronary syndromes. Other end point trials are in progress.

Wierzbicki AS. · Department of Chemical Pathology, St Thomas' Hospital, London, UK. · Int J Clin Pract. · Pubmed #10344068 No free full text.

Abstract: Transplantation is an increasingly common procedure. Yet the contribution of accelerated atherosclerosis to the reduction of graft life is often underestimated. This review examines the evidence for the involvement of hyperlipidaemia and other cardiovascular disease risk factors in the aetiology of chronic graft failure in renal, cardiac, liver and pancreatic transplantation. The evidence for the role of lipid lowering therapy in the prevention of accelerated atheroma in these patients is reviewed.

Wierzbicki AS, Doherty E, Lumb PJ, Chik G, Crook MA. · Department of Chemical Pathology, St. Thomas' Hospital, London, UK. · Curr Med Res Opin. · Pubmed #15811200 No free full text.

Abstract: OBJECTIVE: To investigate the efficacy of the cholesterol absorption inhibitor ezetimibe in patients with refractory familial hyperlipidaemia or intolerant to statin therapy. METHODS: This prospective study assessed the safety and efficacy of ezetimibe in 200 patients with refractory familial hyperlipidaemias not achieving a low-density-lipoprotein (LDL) cholesterol < 3 cholesterol < 3 mmol/L (116 mg/dL) including 22% intolerant to all statin therapy, many consuming intolerant to all statin therapy, many consuming sterol-containing products. RESULTS : Ezetimibe monotherapy resulted in 7% and 11% reductions in LDL-cholesterol and apolipoprotein B respectively. Ezetimibe-statin combination therapy reduced LDL-cholesterol by an additional 11 +/- 27% and apolipoprotein B by 11 (+79 to -18)%. There was a similar response between various sub-groups but a wide variation within groups with the greatest effect seen in patients groups with the greatest effect seen in patients under-responding to statins. The number of patients achieving the LDL-C target of 3 mmol/L rose from 5.5% to 18%. Non-significant effects included a 5 (+78 to -470)% reduction in triglycerides, 8 +/- 36% increment in HDL-cholesterol, 21 (+35 to -82)% reduction in C-reactive protein and a 1 (+20 to -50)% increase in alanine transaminase. No effects were seen on creatinine, creatine kinase, or insulin resistance. Fourteen patients (7%) discontinued ezetimibe: seven due to gastrointestinal side-effects, one patient developed an ezetimibe-induced hypercholesterolaemia (x 1.5), one developed ezetimibe-induced hypertriglyceridaemia (x 7) and five discontinued for other reasons. CONCLUSION: Ezetimibe is a useful addition to statins in patients with familial hyperlipidaemias but shows a highly variable response profile.

Marteau T, Senior V, Humphries SE, Bobrow M, Cranston T, Crook MA, Day L, Fernandez M, Horne R, Iversen A, Jackson Z, Lynas J, Middleton-Price H, Savine R, Sikorski J, Watson M, Weinman J, Wierzbicki AS, Wray R, Anonymous00031. · Psychology & Genetics Research Group, King's College London, London, United Kingdom. · Am J Med Genet A. · Pubmed #15216550 No free full text.

Abstract: This trial tests the hypothesis that confirming a clinical diagnosis of familial hypercholesterolemia (FH) by finding a genetic mutation reduces patients' perceptions of control over the disease and adherence to risk-reducing behaviors. Three hundred forty-one families, comprising 341 hypercholesterolemia probands and 128 adult relatives, were randomized to one of two groups: (a) routine clinical diagnosis; (b) routine clinical diagnosis plus genetic testing (mutation searching in probands and direct gene testing in relatives). The main outcome measures were perceptions of control over hypercholesterolemia, adherence to cholesterol-lowering medication, diet, physical activity, and smoking. There was no support for the main hypothesis: finding a mutation had no impact on perceived control or adherence to risk-reducing behavior (all P-values > 0.10). While all groups believed that lowering cholesterol was an effective way of reducing the risk of a heart attack, participants in whom a mutation was found believed less strongly in the efficacy of diet in reducing their cholesterol level (P = 0.02 at 6 months) and showed a trend in believing more strongly in the efficacy of cholesterol-lowering medication (P = 0.06 at 6 months). In conclusion, finding a mutation to confirm a clinical diagnosis of FH in a previously aware population does not reduce perceptions of control or adherence to risk-reducing behaviors. The pattern of findings leads to the new hypothesis that genetic testing does not affect the extent to which people feel they have control over a condition, but does affect their perceptions of how control is most effectively achieved. Further work is needed to determine whether similar results will be obtained in populations with little previous awareness of their risks.

Wierzbicki AS, Lumb PJ, Chik G. · Department of Chemical Pathology, St Thomas' Hospital, London, UK. · Int J Clin Pract. · Pubmed #11777291 No free full text.

Abstract: High-dose preparations of simvastatin and atorvastatin have recently become available to treat resistant hypercholesterolaemia aggressively, but few studies have compared these two agents. This study compared the efficacy of simvastatin 80 mg and 120 mg in 22 patients with severe familial hypercholesterolaemia over a three-month period using an open label format. Simvastatin 120 mg was reasonably well tolerated and delivered a further 8% reduction in LDL over 80 mg, giving a total reduction of 55 +/- 13%, while further decreasing triglycerides (18%) and continuing to raise HDL (13%) further than the 80 mg dose. However, transient adverse changes were noted in both lipoprotein (a) and fibrinogen and 20% of patients were unable to tolerate the higher dose. One late case of rhabdomyolysis was observed, suggesting patients on the 120 mg dose require continued regular review.

Wierzbicki AS, Lumb PJ, Chik G, Crook MA. · Department of Chemical Pathology, King's College London, Guy's, King's & St. Thomas' Medical School, United Kingdom. · Am J Cardiol. · Pubmed #11165973 No free full text.

Abstract: The clinical and biochemical determinants of the fibrinogen response to simvastatin or atorvastatin therapy were assessed in 130 patients with severe polygenic or familial hypercholesterolemia treated in a randomized open-trial format design. Hyperfibrinogenemia was associated with atorvastatin, baseline fibrinogen, and initial concentration and change in concentration of apolipoprotein B or low-density lipoprotein cholesterol.

Wierzbicki AS, Lumb PJ, Chik G, Crook MA. · Department of Chemical Pathology, King's College London, Guy's, King's & St Thomas' Medical School, United Kingdom. · Am J Cardiol. · Pubmed #11009276 No free full text.

Abstract: The clinical and biochemical determinants of high-density lipoprotein (HDL) and triglyceride response to simvastatin and atorvastatin were assessed in 150 patients with severe hyperlipidemia treated in a randomized open-trial format design. Triglyceride reduction was only dependent on HDL:apolipoprotein A1, change in apolipoprotein B, and dose response, whereas an increase in HDL was dependent on initial LDL, change in LDL or dose response, and therapy with simvastatin.

Wierzbicki AS, Lumb PJ, Chik G, Crook MA. · Department of Chemical Pathology, St Thomas' Hospital, London. · Int J Clin Pract. · Pubmed #10692755 No free full text.

Abstract: This study compared the efficacy of simvastatin 80 mg and atorvastatin 80 mg in the treatment of 26 patients with familial hypercholesterolaemia over 12 weeks using an open crossover trial format. Both, similarly, reduced LDL by 47 +/- 13% and 43 +/- 16% and median triglycerides by 22% and 27% respectively. However, atorvastatin reduced HDL by 2 +/- 24% compared with 8 +/- 30% increase with simvastatin (p = 0.05) affecting the LDL:HDL ratio achieved (4.478 +/- 1.56 vs 3.74 +/- 0.93, p = 0.001). Atorvastatin raised median fibrinogen by 15% compared with a non-significant 5% increase with simvastatin (p = 0.05). Simvastatin reduced lipoprotein (a) by a median 20% compared with baseline (p = 0.05) compared with 5% for atorvastatin. Side-effects, mostly gastrointestinal, were seen in four patients (16%) with atorvastatin compared with one case of myalgia with simvastatin (4%). We conclude both drugs are equally effective in LDL reduction but that simvastatin is superior in raising HDL and causes fewer side-effects. These results require confirmation in larger studies.