Is there a role of lipid-lowering therapies in the management of fatty liver disease?

Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol concentrations. It is highly prevalent in non-alcoholic fatty liver disease (NAFLD) and contributes to the increased cardiovascular risk associated with this condition. Alongside insulin resistance it plays an important pathogenetic role in NAFLD/non-alcoholic steatohepatitis (NASH) development and progression. It has been shown that cholesterol-lowering reduces cardiovascular risk more in NAFLD vs non-NAFLD high-risk individuals. This evidence highlights the importance of effective lipid modulation in NAFLD. In this narrative review the effects of the most commonly used lipid-lowering therapies on liver outcomes alongside their therapeutic implications in NAFLD/NASH are critically discussed. Preclinical and clinical evidence suggests that statins reduce hepatic steatosis, inflammation and fibrosis in patients with NAFLD/NASH. Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities, steatosis/fibrosis scores, and imaging evidence of steatosis as surrogates. Also, relevant histologic benefits were noted in small biopsy studies. Atorvastatin and rosuvastatin showed greater benefits, whereas data for other statins are scarce and sometimes conflicting. Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis. However, no significant anti-inflammatory and anti-fibrotic actions of ezetimibe have been shown. Preclinical studies showed that fibrates through peroxisome proliferator-activated receptor (PPAR)α activation may have a role in NAFLD prevention and management. Nevertheless, no relevant benefits have been noted in human studies. Species-related differences in PPARα expression and its activation responsiveness may help explain this discrepancy. Omega-3 fatty acids reduced hepatic steatosis in numerous heterogeneous studies, but their benefits on hepatic inflammation and fibrosis have not been established. Promising preliminary data for the highly purified eicosapentaenoic acid require further confirmation. Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD, though this needs to be established by future prospective studies.     

Comparison of biochemical effects of statins and fish oil in brain: the battle of the titans

Neural membranes are composed of glycerophospholipids, sphingolipids, cholesterol and proteins. The distribution of these lipids within the neural membrane is not random but organized. Neural membranes contain lipid rafts or microdomains that are enriched in sphingolipids and cholesterol. These rafts act as platforms for the generation of glycerophospholipid-, sphingolipid-, and cholesterol-derived second messengers, lipid mediators that are necessary for normal cellular function. Glycerophospholipid-derived lipid mediators include eicosanoids, docosanoids, lipoxins, and platelet-activating factor. Sphingolipid-derived lipid mediators include ceramides, ceramide 1-phosphates, and sphingosine 1-phosphate. Cholesterol-derived lipid mediators include 24-hydroxycholesterol, 25-hydroxycholesterol, and 7-ketocholesterol. Abnormal signal transduction processes and enhanced production of lipid mediators cause oxidative stress and inflammation. These processes are closely associated with the pathogenesis of acute neural trauma (stroke, spinal cord injury, and head injury) and neurodegenerative diseases such as Alzheimer disease. Statins, the HMG-CoA reductase inhibitors, are effective lipid lowering agents that significantly reduce risk for cardiovascular and cerebrovascular diseases. Beneficial effects of statins in neurological diseases are due to their anti-excitotoxic, antioxidant, and anti-inflammatory properties. Fish oil omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have similar anti-excitotoxic, antioxidant and anti-inflammatory effects in brain tissue. Thus the lipid mediators, resolvins, protectins, and neuroprotectins, derived from eicosapentaenoic acid and docosahexaenoic acid retard neuroinflammation, oxidative stress, and apoptotic cell death in brain tissue. Like statins, ingredients of fish oil inhibit generation of beta-amyloid and provide protection from oxidative stress and inflammatory processes. Collective evidence suggests that antioxidant, anti-inflammatory, and anti-apoptotic properties of statins and fish oil contribute to the clinical efficacy of treating neurological disorders with statins and fish oil. We speculate that there is an overlap between neurochemical events associated with neural cell injury in stroke and neurodegenerative diseases. This commentary compares the neurochemical effects of statins with those of fish oil.     

Statin plus ezetimibe treatment in clinical practice: the SI-SPECT (Slovenia (SI) Statin Plus Ezetimibe in Cholesterol Treatment) monitoring of clinical practice study

ABSTRACT

Background: Poor results from lipid-lowering therapy are mainly due to inadequate dosing and increased adverse effects with high-dose statin monotherapy or drug combinations.

Objectives: The SI-SPECT (Slovenia (SI) Statin Plus Ezetimibe in Cholesterol Treatment) study evaluated the effectiveness of either ezetimibe (EZE) 10?mg as monotherapy or co-administered with on-going statin treatment (S?+?EZE) in clinical practice.

Design and methods: A total of 1053 dyslipidaemic patients (52% men, age 60.3 years, 42.9% with CHD, 32.0% with diabetes mellitus and 69.6% with hypertension) were enrolled. The majority (n?=?986; 93.6%) were treated with EZE as ‘add-on’ to their already prescribed statin, the rest only received EZE (n?=?67).

Main outcome measures: Baseline lipid levels were compared with those obtained 16 weeks after initiating treatment.

Results: Total (TC) and low density lipoprotein cholesterol (LDL-C), as well as triglycerides (TG) decreased significantly with S?+?EZE (by 25.3%, 31.4% and 28.9%, respectively; p?<?0.0001 for all comparisons), while monotherapy with EZE resulted in a decrease of 20.8% for TC (?p?<?0.0001), 28.0% for LDL-C (?p?<?0.0001) and 28.8% for TG (?p?=?0.016). At the end of the study 43.9% of patients achieved target TC (<?5.0?mmol/L for primary prevention and <?4.5?mmol/L for secondary prevention), 50.5% target LDL-C (<?3.0?mmol/L for primary prevention and <?2.5?mmol/L for secondary prevention) and 61.6% target TG (<?2.0?mmol/L). The overall incidence of adverse effects during the treatment period, and probably related to EZE use, was low (n?=?6, 0.6% of patients).

Conclusions: (1) S?+?EZE combination therapy was effective and safe irrespective of the statin used, (2) the S?+?EZE combination resulted in significantly more patients reaching their recommended target lipid levels and (3) the lipid-lowering efficacy of EZE in monotherapy as well as of the S?+?EZE combination was related to initial lipid values. The much greater decrease of TG than expected could be, at least in part, due to better control/compliance regarding diet and drug treatment during the study and adherence to the need for an overnight fast before sampling.     

Cost-effectiveness of intensive atorvastatin therapy in secondary cardiovascular prevention in the United Kingdom, Spain, and Germany, based on the Treating to New Targets study

The Treating to New Targets (TNT) clinical trial found that intensive 80 mg atorvastatin (A80) treatment reduced cardiovascular events by 22% when compared to 10 mg atorvastatin (A10) treatment. We evaluated the cost-effectiveness of intensive A80 vs A10 treatment in the United Kingdom (UK), Spain, and Germany. A lifetime Markov model was developed to predict cardiovascular disease-related events, costs, survival, and quality-adjusted life-years (QALYs). Treatment-specific event probabilities were estimated from the TNT clinical trial. Post-event survival, health-related quality of life, and country-specific medical-care costs were estimated using published sources. Intensive treatment with A80 increased both the per-patient QALYs and corresponding costs of care, when compared to the A10 treatment, in all three countries. The incremental cost per QALY gained was € 9,500, € 21,000, and € 15,000 in the UK, Spain, and Germany, respectively. Intensive A80 treatment is estimated to be cost-effective when compared to A10 treatment in secondary cardiovascular prevention.      

Cutaneous allergy to insulin: Could statins and ACE inhibitors play a role? A case report

Insulin allergy is rare. Both statins and angiotensin converting enzyme (ACE) inhibitors may cause local urticarial skin reactions and have been implicated to precipitate local reactions to insulin. We describe a case of a localised urticarial allergic reaction related to insulin use in a patient co-prescribed an ACE inhibitor and statin.     

Short- and long-term effect of simvastatin therapy on the heterogeneity of cardiac repolarization in diabetic patients

The interlead variability of QT interval in the 12-lead electrocardiogram, QT dispersion (QTd), has been shown to reflect dispersion of ventricular refractoriness and may provide a measure of arrhythmogenic potential in diabetic patients. QTd and heart rate corrected QTd (QTcd) were also proposed to be accurate predictors of cardiac death in patients with diabetes. In recent years, experimental and clinical evidence demonstrates that statins exert antiarrhythmic properties. Therefore, in the present study, we have examined whether simvastatin treatment has any effect on the QTd and QTcd in patients with diabetes mellitus. Sixty type 2 diabetic patients without known coronary artery disease and low-density lipoprotein cholesterol >100mg/dl and 30 age and sex-matched non-diabetic controls were included in a prospective study. Out of 60 diabetic patients, 30 were treated with simvastatin 40 mg/day for 1 year and the remaining 30 subjects were served as diabetic controls. No lipid lowering therapy was administered to the diabetic and the non-diabetic controls. QTd and QTcd of treated diabetics and the non-diabetic controls were measured at baseline, 6, 12 weeks and at 1 year. QTd and QTcd of the diabetic controls were obtained at baseline, 6 and 12 weeks. Both QTd and QTcd were significantly greater in patients with the diabetes than in the non-diabetic controls at baseline (52+/-13 ms vs. 41+/-12 ms, p<0.001 and 62+/-17 ms vs. 42+/-11 ms, p<0.001, respectively). Simvastatin therapy significantly decreased both QTd and QTcd at the end of first year compared to baseline (51+/-15 ms vs. 33+/-11 ms, p<0.001 and 60+/-18 ms vs. 38+/-12 ms, p<0.001, respectively). No significant change were found in QTd and QTcd in the non-diabetic (p=0.29 and p=0.87 by ANOVA, respectively) and in the diabetic controls (p=0.72 and p=0.57, by ANOVA, respectively). This study suggests for the first time that simvastatin treatment in diabetic patients with hyperlipidemia is associated with an improvement in the heterogeneity of cardiac repolarization. This may be one of the mechanisms for the reduction in clinical events reported in the survival studies with statins. Further prospective randomized studies are warranted to confirm our findings.     

他汀类药物的抗心律失常作用研究进展

近年来研究显示,他汀类药物不仅能降低血脂水平,而且有独立于降脂作用之外的其他有益作用,称之为他汀的多效性,其中抗心律失常作用更是热点之一,其具体机制尚不明确。现将他汀类药物的抗心律失常作用及其机制予以综述。     

A nutraceutical based approach to reduce cholesterolaemia in patients previously intolerant of more than a statin: a pilot study

This study was aimed at evaluating the tolerability of a nutraceutical combination with anticholesterolaemic action in patients intolerant of statin treatment. A total of 32 hypercholesterolaemic patients, all intolerant to at least two statin treatments, were enrolled in the ambulatory service. None of the enrolled patients was diabetic or undergoing secondary prevention of cardiovascular disease. Patients consumed one yoghurt with 2 g of added phytosterols each morning (Pro-Activ, Unilever, Milan, Italy) and one tablet of a registered combined nutraceutical (Armolipid Plus, Rottapharm, Monza, Italy). We tested the efficacy of the treatment after 4 and 6 months. One tablet of Armolipid Plus contains: berberine 500 mg, monacolin 3 mg, and policosanol 10 mg. After 3 months of treatment the patients showed a significant decrease in total cholesterol, low-density lipoprotein cholesterol and triglycerides, and a significant increase in the plasma level of high-density lipoprotein cholesterol. These results were maintained after 6 months of treatment without a significant change in the mean values.     

Lipid-lowering drugs and essential omega-6 and omega-3 fatty acids in patients with coronary heart disease

BACKGROUND AND AIM: There are only little data about the effects of lipid-lowering drugs (LLDs) on the metabolism of essential n-6 and n-3 fatty acids in patients with established coronary heart disease (CHD). METHODS AND RESULTS: Male patients with CHD and high cholesterol levels (>6.2 mmol/L) were randomized (double-blind protocol) to receive either simvastatin 20mg (S) or fenofibrate 200mg daily (F) for 3 months. Dietary habits and plasma fatty acids were not different in the two groups at baseline. After treatment, there were significant changes in both the groups for the main n-6 fatty acids, with an increase in arachidonate (from 6.5+/-1.7% of total fatty acids to 7.5+/-2.1, p<0.001 in S and from 6.2+/-1.4 to 6.8+/-1.4, p<0.005 in F) and a decrease in linoleate (from 26.9+/-3.9 to 24.2+/-3.6, p<0.001, and from 27.8+/-3.4 to 26.1+/-4.2, p<0.05, in S and F, respectively). In addition, there was a decrease in two major n-3 fatty acids (alpha-linolenate and docosahexanoate, both p<0.05), but only in F. CONCLUSIONS: For the first time in a double-blind randomized study in CHD patients, we report that LLDs significantly alter the metabolism of essential fatty acids that are critically important for the pathogenesis and prevention of CHD. Further studies are urgently needed to examine the effects of higher dosages of statins (as currently proposed to reduce more cholesterol) on these essential fatty acids in the clinical setting and the crucial questions of whether specific dietary intervention (combining low intake of n-6 fatty acids and high intake of n-3 fatty acids) may improve the effectiveness of these drugs.