Hyperlipidemias: Mikhailidis DP

Paraskevas KI, Bessias N, Papas TT, Gekas CD, Andrikopoulos V, Mikhailidis DP. · No affiliation provided · Angiology. · Pubmed #18505745 No free full text.

Abstract: Established vascular risk factors (ie, smoking, hypertension, diabetes mellitus, and dyslipidemia) play an important role in the development of vascular disease. Emerging evidence suggests that some of these risk factors may have a more intense effect on specific arterial beds, a finding that holds implications for a prognostic role for certain types of vascular disease.

Athyros VG, Kakafika A, Tziomalos K, Karagiannis A, Mikhailidis DP. · No affiliation provided · Expert Opin Investig Drugs. · Pubmed #18363511 No free full text.

Abstract: Statins effectively lower plasma low-density lipoprotein cholesterol (LDL-C) levels and reduce the risk of vascular events. However, this benefit might be improved by dealing with other vascular risk factors such as high-density lipoprotein cholesterol (HDL-C). It follows that there has been an interest in drugs that raise plasma HDL-C levels. Among these drugs are the cholesteryl ester transfer protein (CETP) inhibitors. The first CETP inhibitor to be evaluated in an event-based trial was torcetrapib. This drug can considerably elevate serum HDL-C levels (e.g., by 72%). However, a recently published trial (ILLUMINATE) showed that torcetrapib used in combination with atorvastatin was associated with significantly more vascular events and deaths than atorvastatin alone. This finding resulted in the discontinuation of the torcetrapib development programme. The cause(s) of the adverse outcome remain speculative. It has been suggested that a significant rise in systolic blood pressure and possibly the quality of the HDL produced may be relevant. Despite this disappointing outcome it seems to be too early to close the book on CETP inhibitors because two other members of this class are being evaluated. These drugs (JTT-705 and anacetrapib) may be devoid of the adverse effect on systolic blood pressure. Eventually only appropriately designed, event-based trials, will settle the issue of whether CETP inhibitors are clinically useful.

Daskalopoulou SS, Mikhailidis DP. · No affiliation provided · Curr Med Res Opin. · Pubmed #17022863 No free full text.

Abstract: Recent guidelines recommend strict goals for low density lipoprotein cholesterol (LDL-C) (70-100 mg/dL; 1.8-2.6 mmol/L). These goals were set following the publication of several trials. In the current issue of the journal, a study compares different doses of the combination tablet (ezetimibe/simvastatin) with statin monotherapy (rosuvastatin). In keeping with previous literature, the combination therapy was more effective in achieving LDL-C goals. This editorial comments on the potential disadvantages of using monotherapy with high-dose statins and considers the issue of statin-induced proteinuria. Combination therapy may need to be increasingly used to achieve the LDL-C targets set by recent guidelines.

Athyros VG, Kakafika AI, Tziomalos K, Karagiannis A, Mikhailidis DP. · Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, HippocrationHospital, Thessaloniki, Greece. · Curr Pharm Des. · Pubmed #19199976 No free full text.

Abstract: The present review considers the potential pleiotropic effects of statins and the evidence indicative of the "real world" benefit from these effects in patients with cardiovascular disease (CVD). Some of these cholesterol-independent effects of statins involve improved endothelial function, stability of atherosclerotic plaques, attenuation of oxidative stress and inflammation, as well as inhibition of the thrombogenic response. Clinical evidence from early statin administration in acute coronary syndromes and in revascularisation procedures is reported. Moreover, the "metabolic" effects of statin treatment, such as renal function improvement and reduction in serum uric acid levels, in patients with stable coronary heart disease are discussed. Evidence suggests that in high CVD risk patient groups pleiotropic effects of statins may play a role in the reduction of morbidity and mortality. However, this concept requires proof in appropriately designed trials that will include clinically relevant end points in order to set specific targets in new CVD-related biomarkers, in addition to lipid levels, that should be used to fully assess the statin contribution to CVD treatment.

Liberopoulos EN, Florentin M, Mikhailidis DP, Elisaf MS. · University of Ioannina, Medical School, Department of Internal Medicine, Ioannina, Greece. · Expert Opin Drug Saf. · Pubmed #18983218 No free full text.

Abstract: BACKGROUND: Hypercholesterolemia is a major risk factor for cardiovascular disease. OBJECTIVE: Treatment with hypolipidemic agents reduces the risk of vascular events both in primary and secondary prevention. Although compliance with lipid-lowering therapy is an important determinant of cardiovascular clinical outcomes, relatively little attention is being paid to this issue by physicians. METHODS: We searched the literature using Pubmed up to 5 August 2008. RESULTS: Compliance with lipid-lowering therapy is poor in clinical practice, especially in primary prevention. As many as 6 out of 10 patients may stop taking statins during the first 6 months following initiation of treatment. Poor compliance has been associated with worse clinical outcome and increased cardiovascular morbidity and mortality. Importantly, statin withdrawal may be even worse compared with not taking statins at all. Several strategies may increase treatment adherence. CONCLUSIONS: Poor compliance with lipid-lowering treatment is an important health issue that has been associated with unfavorable cardiovascular outcome. Increasing adherence rates should become a major concern for physicians.

Athyros VG, Tziomalos K, Mikhailidis DP, Pagourelias ED, Kakafika AI, Skaperdas A, Hatzitolios A, Karagiannis A. · Aristotle University of Thessaloniki, Second Propedeutic Department of Internal Medicine, Medical School, Thessaloniki, Greece. · Expert Opin Pharmacother. · Pubmed #17927482 No free full text.

Abstract: This review considers the treatment for combined hyperlipidaemia (CH) with a combination formulation of three drugs: a statin, nicotinic acid (NA) and aspirin--a mini-polypill. CH is a highly atherogenic dyslipidaemia manifested either as familial combined hyperlipidaemia or dyslipidaemia related to the metabolic syndrome or Type 2 diabetes mellitus. These types of dyslipidaemia are highly prevalent in the general population. Statin plus extended-release NA is a promising treatment option for the normalisation of these atherogenic lipid alterations, regression of atherosclerosis, as well as for primary or secondary prevention of cardiovascular disease (CVD) events. The addition of aspirin might prove a useful adjunct that might reduce the cutaneous side effects of NA while also acting as an antiplatelet agent in high-CVD-risk patients. However, the effective dose of aspirin may need to be at least 160 mg/day. This triple combination might improve patient compliance when compared with the three drugs administered separately.

Tziomalos K, Athyros VG, Karagiannis A, Mikhailidis DP. · University of London, Department of Clinical Biochemistry, Royal Free Hospital, Pond Street, London NW3 2QG, UK. · Expert Opin Ther Targets. · Pubmed #17845142 No free full text.

Abstract: The endothelium is a dynamic organ that plays a pivotal role in cardiovascular homeostasis. Alteration in endothelial function precedes the development of atherosclerosis and contributes to its initiation, perpetuation and clinical manifestations. It has been suggested that the assessment of endothelial function could represent a barometer of vascular health that could be used to gauge cardiovascular risk. This review summarises the various methods used to assess endothelium-dependent vasodilatation and their potential prognostic implications. In addition, the techniques used to evaluate arterial stiffness are discussed. The latter is to some extent controlled by the endothelium and has been the subject of considerable research in recent years. This paper also discusses the effects of lipid lowering treatment on both endothelial function and arterial stiffness.

Milionis HJ, Liberopoulos EN, Elisaf MS, Mikhailidis DP. · Department of Clinical Biochemistry, Vascular Disease Prevention Clinics, Royal Free Hospital, Pond Street, London NW3 2QG, UK. · Curr Hypertens Rep. · Pubmed #17519121 No free full text.

Abstract: Hypertension and hyperlipidemia, two powerful risk factors of cardiovascular disease (CVD), often coexist. Therefore, treatment should consider the beneficial properties of drugs used to treat either condition. Statins, the mainstay of lipid-lowering therapy, result in a significant clinical benefit both in primary and secondary CVD prevention. In addition to their hypolipidemic capacity, other properties may contribute to statin-induced benefits. Clinical and experimental evidence indicates that statins may modulate blood pressure (BP). The mechanisms by which statins reduce BP seem to be largely independent of their lipid effects. Although small, reductions in BP are possibly clinically relevant. Large landmark studies confirm that statins can reduce CVD risk in hypertensive patients. These findings suggest that statins could be prescribed as an adjunct in treating hypertension with dyslipidemia or even in patients with "normal" cholesterol levels. Whether the effect of statins on BP is accompanied by an additional decrease in clinical outcomes needs to be investigated in long-term, large-scale trials.

Daskalopoulou SS, Daskalopoulos ME, Mikhailidis DP, Liapis CD. · Department of Medicine, Division of Clinical Epidemiology, McGill University, Montreal, Quebec, Canada. · Curr Drug Targets. · Pubmed #17430127 No free full text.

Abstract: Peripheral arterial disease (PAD) is a common disorder usually associated with silent or symptomatic arterial disease elsewhere in the circulation and a "cluster" of cardiovascular risk factors (e.g. smoking, dyslipidemia, hypertension, and insulin resistance/diabetes mellitus). The medical management of PAD should focus on both the relief of symptoms and prevention of secondary cardiovascular complications. This approach must include smoking cessation, optimal cholesterol levels, blood pressure and glycemic control as well as prescribing antiplatelet therapy. This review focuses on the evidence supporting the use of lipid-lowering drugs in PAD. Several trials indicate that getting low density lipoprotein-cholesterol levels to target (<2.6 mmol/l; 100 mg/dl), or even lower, is associated with improvement of symptoms and a reduction in vascular events in patients with PAD.

Kolovou GD, Anagnostopoulou KK, Salpea KD, Daskalopoulou SS, Mikhailidis DP. · Cardiology Department, Onassis Cardiac Surgery Center, Athens, Greece. · Curr Drug Targets. · Pubmed #17430126 No free full text.

Abstract: Several studies showed that postprandial plasma triglyceride (TG) concentrations are higher in patients with coronary heart disease. TG-rich lipoprotein remnants accumulated in the postprandial state are involved in atherogenesis and in events leading to thrombosis. Lipid lowering drugs, such as 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) are of significant benefit in the primary and secondary prevention of atherosclerosis. Statins can decrease total cholesterol and low density lipoprotein cholesterol as well as TG concentrations and improve postprandial lipoprotein metabolism. Since abnormal postprandial lipemia is associated with pathological conditions, its treatment is relevant. This review considers the effect of statins on postprandial lipemia.

Gazi IF, Mikhailidis DP. · Royal Free Hospital, Department of Clinical Biochemistry, Royal Free and University College of Medicine, University of London, Pond Street, London NW3 2QG, UK. · Expert Opin Ther Targets. · Pubmed #17105372 No free full text.

Abstract: Ezetimibe, an intestinal cholesterol absorption inhibitor, lowers circulating low-density lipoprotein cholesterol (LDL-C) levels both when administered as monotherapy and in combination with other hypolipidaemic drugs, mostly statins. This review focuses on the effects of ezetimibe on non-LDL-C-associated variables. In most studies, ezetimibe effectively reduced triglyceride and increased high density lipoprotein cholesterol levels. The authors also consider the effect of ezetimibe on other variables such as C-reactive protein levels, insulin sensitivity and endothelial function. Ezetimibe is useful in patients with sitosterolaemia (a rare inherited disorder) as it significantly reduces plasma phytosterol concentrations. Ezetimibe fulfils two of the three essential characteristics of any drug (efficacy and safety). However, clinical studies are required to provide evidence of its ability to reduce vascular events.

Kalantzi KJ, Milionis HJ, Mikhailidis DP, Goudevenos JA. · Department of Cardiology, School of Medicine, University of Ioannina, 451 10 Ioannina, Greece. · Curr Pharm Des. · Pubmed #17073689 No free full text.

Abstract: The rising number of elderly people has a major impact on healthcare systems. Advancing age is a risk factor for the development of cardiovascular disease (CVD), which represents a major global healthcare problem. The clinical efficacy and safety of lipid lowering treatment (especially statins) is well established following a series of large-scale, randomised controlled trials, which mainly recruited patients under the age of 70 years. Subgroup analyses together with the findings of trials involving sufficient numbers of elderly participants, such as the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) and the Heart Protection Study (HPS) offer a basis for considering statin therapy in this population. Furthermore, since this population is at greater absolute risk of CVD, substantial benefits from adequate treatment may be anticipated. However, underevaluation and undertreatment appear to be common in the elderly. In this review, we provide a survey of potentially modifiable cardiovascular risk factors in association with old age, and discuss the relevant findings of large-scale end-point clinical studies as well as major considerations regarding lipid-lowering treatment in this population. It is concluded that the decision whether to treat hypercholesterolaemia in the elderly is currently individualised, depending upon the degree of risk, general health, willingness to receive treatment and financial concerns. Further, prospective randomised trials are required to guide physicians towards an effective management of older individuals at increased atherosclerotic risk.

Alnaeb ME, Alobaid N, Seifalian AM, Mikhailidis DP, Hamilton G. · Vascular Unit, Department of Surgery, Royal Free Hospital and University College Medical School, Pond Street, London, NW3 2QG, UK. · Ann Vasc Surg. · Pubmed #16841271 No free full text.

Abstract: Peripheral arterial disease (PAD) is a manifestation of widespread atherosclerosis. Lipid modification (especially with statins) is a component of the treatment of patients with PAD since this condition is considered a coronary heart disease equivalent. This review considers the mechanism of action of statins in PAD. Statins have been shown to reduce the incidence of new coronary events in patients with PAD. However, surveys suggest that many such patients remain undertreated. Statins can also increase walking distance in patients with PAD. There is also evidence that statins can improve renal function in these patients. Several other actions of statins are considered in this review. PAD patients have an increased morbidity and mortality, largely due to myocardial infarction and stroke. Recognizing and treating these high-risk patients as early as possible should be a priority.

Daskalopoulou SS, Mikhailidis DP. · Department of Clinical Biochemistry, Royal Free Hospital, Royal Free and University College School of Medicine, London NW3 2QG, UK. · Curr Med Res Opin. · Pubmed #16574035 No free full text.

Abstract: Lowering serum cholesterol levels reduces the risk of coronary heart disease (CHD)-related events. Statins are commonly prescribed as first-line treatment but many patients at high-risk for CHD still fail to reach their cholesterol or low-density lipoprotein cholesterol (LDL-C) goals with statin monotherapy. National and international guidelines for the prevention of CHD recommend the modification of lipid profiles and particularly LDL-C [e.g. the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III; 2001) and Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice (2003) Guidelines]. Several recent clinical trials indicated an added benefit from aggressive lowering of LDL-C levels. Based on these findings, the NCEP ATP III revised the LDL-C target from < 100 mg/dL (2.6 mmol/L) to < 70 mg/dL (1.8 mmol/L) (optional target) for very high-risk patients and < 130 mg/dL (3.4 mmol/L) to < 100 mg/dL (2.6 mmol/L) for moderately high-risk patients. For patients who fail to achieve their LDL-C target, inhibiting the two main sources of cholesterol - synthesis and uptake - can produce more effective lipid lowering, allowing more patients to reach their LDL-C goal. Ezetimibe is a highly-selective inhibitor of cholesterol absorption and simvastatin is an evidence-based inhibitor of cholesterol synthesis. The LDL-C-lowering efficacy of targeting both major sources of cholesterol with ezetimibe plus simvastatin was demonstrated in several multicentre, double-blind, placebo-controlled trials in patients with hypercholesterolaemia. For patients who do not reach their cholesterol goal with a statin, adding ezetimibe 10 mg significantly reduces LDL-C compared with statin monotherapy. Thus, this treatment option may help patients reach the new 'stricter' cholesterol goals. This review, based on a Medline database search from January 2000 to August 2005, considers the LDL-C-lowering efficacy of ezetimibe and discusses the role of this agent for patients who fail to achieve guideline cholesterol goals with statin monotherapy.

Milionis HJ, Liberopoulos EN, Achimastos A, Elisaf MS, Mikhailidis DP. · Department of Internal Medicine, Medical School, University of Ioannina, Ioannina, Greece. · J Hum Hypertens. · Pubmed #16511505 No free full text.

Abstract: The assessment of global cardiovascular risk is an essential step in the management of atherosclerotic disease prevention. Among the risk factors to be addressed are hypertension and hyperlipidaemia; these commonly coexist. A neutral or lipid-friendly antihypertensive agent is probably useful in the presence of lipid abnormalities. Similarly, statins have been shown to decrease cardiovascular risk in hypertensive patients. There is also experimental and clinical evidence that statins have blood pressure (BP)-lowering effects. In this review, we discuss the beneficial effects of statins on BP, and provide an overview of the underlying pathophysiology. We also consider the evidence justifying the use of statins in the management of hypertensive patients.

Milionis HJ, Elisaf MS, Mikhailidis DP. · Department of Molecular Pathology and Clinical Biochemistry, Royal Free and University College Medical School, University College, Royal Free Campus (University of London), London. · Curr Med Res Opin. · Pubmed #16422031 No free full text.

Abstract: The key 'statin trials' focussed on the beneficial effect of lowering the circulating concentrations of low-density lipoprotein cholesterol (LDL). However, epidemiological surveys, mainly based on healthy populations, indicate that other lipid-related variables, such as high-density cholesterol (HDL), triglycerides (TG), dense LDL subfraction distribution, and possibly lipoprotein (a) (Lp(a)), are also predictors of vascular events. Furthermore, TG and HDL levels influenced outcome within some of the statin trials. Plasma fibrinogen levels have also been shown to be powerful predictors of vascular risk in healthy subjects and patients with established ischaemic heart disease. The fibrates exert beneficial effects on all these variables that predict vascular events. The results from recent trials, the Bezafibrate Infarction Prevention (BIP) study and the Veterans Administration HDL Intervention Trial (VA-HIT) have revived our interest in fibrates. These trials involved bezafibrate and gemfibrozil that have a relatively poor LDL-lowering capacity. Therefore, the benefits reported in BIP and VA-HIT must be attributed to actions on variables other than a reduction in LDL quantity. Ciprofibrate and fenofibrate have significantly greater LDL-lowering capacity than bezafibrate or gemfibrozil. This advantage may render them more effective, especially since they retain the additional beneficial actions associated with this class of lipid-lowering drugs.

Kolovou GD, Anagnostopoulou KK, Daskalopoulou SS, Mikhailidis DP, Cokkinos DV. · Cardiology Department, Onassis Cardiac Surgery Center, Athens, Greece. · Curr Med Chem. · Pubmed #16101498 No free full text.

Abstract: Several studies showed that after a fatty meal, plasma triglyceride (TG) levels are higher in patients with coronary heart disease. This abnormality may explain why some individuals develop atherosclerotic disease despite normal fasting lipid values. TG-rich lipoproteins are involved in atherosclerosis and thrombosis. TG, remnant-like particle (RLP) cholesterol (RLP-C) and RLP-TG increase after fat load and could contribute to atherothrombosis. Postprandial lipaemia is not a uniform abnormality. Its pathophysiology is not yet entirely clarified; possibly, the response to dietary fat is a polygenic phenomenon. However, a link with insulin resistance is likely; this link as well as that with obesity is discussed. A substantial part of life is spent in the postprandial state. Therefore, several investigators described fat load tests. However, it is still difficult to establish normal postprandial TG ranges since only small numbers of subjects were studied and there is as yet no standardised method. A more simplified fat load test should be established for 'routine' use. In this review, we consider the metabolic features, prevalence and management of postprandial lipaemia. Treatment may involve lifestyle measures as well as the use of lipid lowering (e.g. fibrates or statins), weight reducing and hypoglycaemic drugs.

Tsouli SG, Kiortsis DN, Argyropoulou MI, Mikhailidis DP, Elisaf MS. · University of Ioannina, Greece. · Eur J Clin Invest. · Pubmed #15816992 No free full text.

Abstract: Tendon xanthomatosis often accompanies familial hypercholesterolaemia, but it can also occur in other pathologic states. Achilles tendons are the most common sites of tendon xanthomas. Low-density lipoprotein (LDL) derived from the circulation accumulates into tendons. The next steps leading to the formation of Achilles tendon xanthomas (ATX) are the transformation of LDL into oxidized LDL (oxLDL) and the active uptake of oxLDL by macrophages within the tendons. Although physical examination may reveal Achilles tendon xanthomas (ATX), there are several imaging methods for their detection. It is worth mentioning that ultrasonography is the method of choice in everyday clinical practice. Although several treatments for Achilles tendon xanthomas (ATX) have been proposed (LDL apheresis, statins, etc.), they target mostly in the treatment of the basic metabolic disorder of lipid metabolism, which is the main cause of these lesions. In this review we describe the formation, detection, differential diagnosis and treatment of ATX as well as the relationship between tendon xanthomas and atheroma.

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.

Daskalopoulou SS, Mikhailidis DP, Elisaf M. · Department of Clinical Biochemistry (Vascular Disease Prevention Clinics), Royal Free Hospital, London, UK. · Angiology. · Pubmed #15547646 No free full text.

Abstract: The prevalence of the metabolic syndrome is increasing owing to lifestyle changes leading to obesity. This syndrome is a complex association of several interrelated abnormalities that increase the risk for cardiovascular disease and progression to diabetes mellitus (DM). Insulin resistance is the key factor for the clustering of risk factors characterizing the metabolic syndrome. The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III defined the criteria for the diagnosis of the metabolic syndrome and established the basic principles for its management. According to these guidelines, treatment involves the improvement of the underlying insulin resistance through lifestyle modification (eg, weight reduction and increased physical activity) and possibly by drugs. The coexistent risk factors (mainly dyslipidemia and hypertension) should also be addressed. Since the main goal of lipid-lowering treatment is to achieve the NCEP low-density lipoprotein cholesterol (LDL-C) target, statins are a good option. However, fibrates (as monotherapy or in combination with statins) are useful for the treatment of the metabolic syndrome that is commonly associated with hypertriglyceridemia and decreased high-density lipoprotein cholesterol (HDL-C) levels. The blood pressure target is < 140/90 mm Hg. The effect on carbohydrate homeostasis should possibly be taken into account in selecting an antihypertensive drug. Patients with the metabolic syndrome commonly have other less well-defined metabolic abnormalities (eg, hyperuricemia and raised C-reactive protein levels) that may also be associated with an increased cardiovascular risk. It seems appropriate to manage these abnormalities. Drugs that beneficially affect carbohydrate metabolism and delay or even prevent the onset of DM (eg, thiazolidinediones or acarbose) could be useful in patients with the metabolic syndrome. Furthermore, among the more speculative benefits of treatment are improved liver function in nonalcoholic fatty liver disease and a reduction in the risk of acute gout.

Lau DH, Mumtaz FH, Thompson CS, Mikhailidis DP. · Department of Urology, Royal Free and University College Medical School, University College London, Royal Free Campus, Rowland Hill Street, London NW3 2PF, England. · J R Soc Promot Health. · Pubmed #15493779 No free full text.

Abstract: Research has led to effective treatment regimes for erectile dysfunction (ED). Convincing evidence links vascular risk factors (hypertension, diabetes mellitus, hyperlipidaemia and smoking) with ED. This association is not surprising since the corpus cavernosum is a modified vascular tissue. This review presents a brief account of the aetiology, diagnosis and treatment of ED. There is a need to raise awareness of this condition and to make appropriate treatment available to patients.

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.

Tsiara S, Elisaf M, Mikhailidis DP. · Internal Medicine Department, University of Ioannina Medical School, Ioannina, Greece. · Curr Med Res Opin. · Pubmed #14594527 No free full text.

Abstract: Large-scale trials established that statin administration in hypercholesterolaemic individuals and patients with coronary heart disease (CHD) significantly reduces the risk of vascular events and death. This benefit was primarily attributed to their actions on lipids. This review focuses on the benefits (clinical and experimental) of statins observed soon (approximately 12 weeks) after their administration. Statins rapidly increase nitric oxide production and improve endothelial function (e.g. increased flow-mediated dilatation). Similarly, antioxidant properties decrease the susceptibility of low density lipoprotein cholesterol to oxidation. Statins inhibit the migration of macrophages and smooth muscle cell proliferation leading to an antiproliferative effect and the stabilisation of atherosclerotic plaques. Anti-inflammatory effects include a reduction in serum C-reactive protein levels, inflammatory and proinflammatory cytokines (e.g. IL-6, IL-8), adhesion molecules (e.g. ICAM-1, VCAM-1) and other acute phase proteins. Statins influence the haemostatic system. They reduce tissue factor expression and platelet activity, whereas fibrinolysis can be enhanced. Statins improve microalbuminuria, renal function, hypertension and arterial wall stiffness. A significant reduction of the carotid intima media thickness (IMT) was also reported early after statin treatment. These early effects of statins probably contribute to the significant reduction in vascular events seen in some 'short-term' studies. There is a need to further elucidate the rapid and non-lipid lowering properties of statins.

Milionis HJ, Elisaf MS, Mikhailidis DP. · Department of Internal Medicine, Medical School, Universities of Ioannina, Greece. · Curr Pharm Des. · Pubmed #14529557 No free full text.

Abstract: There is growing evidence that the components of the haemostatic system play a significant role in the development and progression of atherosclerosis and its complications. Lipid-lowering interventions have been associated with a significant reduction of morbidity and mortality. However, the improvement in cardiovascular risk seen in several clinical trials is incompletely explained by cholesterol reduction. Therefore, the benefit from lipid lowering drugs may involve non-lipid mechanisms. These include beneficial effects on the arterial wall, improved endothelial function and a favourable influence on blood rheology and thrombogenesis. In this review, we consider the influence of lipid-lowering interventions on rheological and haemostatic parameters as well as the potential clinical relevance of these effects.

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.