Evangelos N. Liberopoulos

Effect of multifactorial treatment on non-alcoholic fatty liver disease in metabolic syndrome: a randomised study

ABSTRACT Background: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome (MetS). There is no established treatment for NAFLD. Aim: To evaluate a multifactorial intervention in the treatment of NAFLD. Methods: A prospective, open-label, randomised study in non-diabetic patients (n = 186) with MetS (follow-up: 54 weeks). All patients had both biochemical and ultrasonographic evidence of NAFLD at baseline. Other causes of liver disease were excluded. Patients received lifestyle advice and treatment for hypertension (mainly inhibitors of the renin–angiotensin system), impaired fasting glucose (metformin), obesity (orlistat) and dyslipidaemia [randomly allocated to atorvastatin 20 mg/day (n = 63) or micronised fenofibrate 200 mg/day (n = 62) or both drugs (n = 61)]. Liver ultrasonography was assessed at baseline and at the end of the study. Results: At the end of treatment, 67% of patients on atorvastatin, 42% on fenofibrate and 70% on combination treatment no longer had biochemical plus ultrasonographic evidence of NAFLD ( p < 0.05 vs. baseline for all comparisons). The percentage of patients who no longer had evidence of NAFLD was significantly higher ( p < 0.009) in the atorvastatin and combination groups compared with the fenofibrate group. This effect was independently related to drug treatment, as well as to reductions in high-sensitivity C-reactive protein, waist circumference, body weight, triglycerides, low-density lipoprotein-cholesterol, total cholesterol, systolic blood pressure and glucose. Four patients discontinued treatment because of adverse effects. Conclusions: Multifactorial intervention in MetS patients with both biochemical and ultrasonographic evidence of NAFLD offsets surrogate markers of NAFLD (i.e. elevated aminotransferase plus echogenic liver).

“European Panel on Low Density Lipoprotein (LDL) Subclasses”: A Statement on the Pathophysiology, Atherogenicity and Clinical Significance of LDL Subclasses

Aim of the present Consensus Statement is to provide a comprehensive and up to-date document on the pathophysiology, atherogenicity and clinical significance of low density liproproteins (LDL) subclasses. We sub-divided our statement in 2 sections. section I discusses the pathophysiology, atherogenicity and measurement issues, while section II is focused on the effects of drug and lifestyle modifications. Suggestions for future research in the field are highlighted at the end of section II. Each section includes Conclusions.

Association of Drinking Pattern and Alcohol Beverage Type With the Prevalence of Metabolic Syndrome, Diabetes, Coronary Heart Disease, Stroke, and Peripheral Arterial Disease in a Mediterranean Cohort

The purpose of this study was to investigate the relationship between alcohol consumption and the prevalence of the metabolic syndrome (MetS), type 2 diabetes mellitus (DM), coronary heart disease (CHD), stroke, peripheral arterial disease (PAD), and overall cardiovascular disease (CVD) in a Mediterranean cohort. It consisted of a cross-sectional analysis of a representative sample of Greek adults (n = 4153) classified as never, occasional, mild, moderate, or heavy drinkers. Cases with overt CHD, stroke, or PAD were recorded. In our population, 17% were never, 23% occasional, 27% mild, 24% moderate, and 9% heavy drinkers. Moderate alcohol consumption was associated with a lower trend for the prevalence of the MetS (P = .0001), DM (P < .0001), CHD (P = .0002), PAD (P = .005), and overall CVD (P = .001) but not stroke compared with no alcohol use. Heavy drinking was associated with an increase in the prevalence of all of these disease states. Wine consumption was associated with a slightly better effect than beer or spirits consumption on the prevalence of total CVD, and beer consumption was associated with a better effect than spirits consumption. Alcohol intake was positively related with body weight, high-density lipoprotein cholesterol levels, and hypertension. Moderate alcohol consumption is associated with a lower prevalence of the MetS, DM, PAD, CHD, and overall CVD but not stroke compared with no alcohol use in a Mediterranean population. Heavy drinking was associated with an increase in the prevalence of all of these disease states. Advice on alcohol consumption should probably mainly aim at reducing heavy drinking.

Diagnosis and management of the metabolic syndrome in obesity.

The metabolic syndrome is a constellation of interrelated abnormalities that increase the risk for cardiovascular disease and progression to type 2 diabetes. The prevalence of this syndrome is increasing because of the ‘obesity epidemic’. The National Cholesterol Education Program Adult Treatment Panel III defined practical criteria for the diagnosis of the metabolic syndrome and established the basic principles for its management. Also, the International Diabetes Federation recently proposed another definition. The metabolic syndrome is a secondary target for cardiovascular risk reduction. Clinicians should identify individuals with this condition, assess their cardiovascular risk and treat them by an aggressive and multifaceted approach. The most effective therapeutic intervention in patients with the metabolic syndrome should focus on modest weight reduction and regular physical activity. Adoption of a healthier diet and smoking cessation are necessary. Drug therapy may be needed to achieve recommended goals if therapeutic lifestyle changes are not sufficient. Low‐density lipoprotein cholesterol is the primary target of therapy (new aggressive goals should be achieved). Statins are probably the drugs of choice. Fibrates and nicotinic acid are also useful options. Hypertension should be managed aggressively probably starting with an inhibitor of the renin‐angiotensin system or a calcium channel blocker and adding a low dose of a thiazide diuretic if necessary. Aspirin should be administered if the cardiovascular risk is high. In the future acarbose, metformin, meglitinides and thiazolidinediones may be used in patients with the metabolic syndrome to delay the onset of type 2 diabetes and reduce cardiovascular risk. Such an intense and multifactorial approach is likely to reverse the bad prognosis associated with the metabolic syndrome.

How safe is the use of thiazolidinediones in clinical practice

Background: Thiazolidinediones (TZDs) are widely used antidiabetic drugs with proven efficacy regarding mainly surrogate markers of diabetes management. However, efficacy on surrogate markers may not always translate into benefits in clinical outcomes. Thiazolidinediones are usually well tolerated; however, their use may be associated with several adverse effects. The first TZD, troglitazone, was withdrawn from the market owing to serious hepatotoxicity. However, this does not seem to be the case with newer TZDs. Objective: The aim of the present review is to discuss the safety profile of this drug class. Methods: We searched PubMed up to July 2008 using relevant keywords. Conclusions: Common side effects associated with TZDs include edema, weight gain, macular edema and heart failure. Moreover, they may cause hypoglycemia when combined with other antidiabetic drugs as well as decrease hematocrit and hemoglobin levels. Increased bone fracture risk is another TZD-related side effect. Thiazolidinediones tend to increase serum low density lipoprotein cholesterol levels, with rosiglitazone having a more pronounced effect compared with pioglitazone. Moreover, rosiglitazone increases low density lipoprotein particle concentration in contrast to pioglitazone where a decrease is observed. Rosiglitazone has been associated with an increase in myocardial infarction incidence. On the other hand, pioglitazone may reduce cardiovascular events. Overall, TZDs are valuable drugs for diabetes management but physicians should keep in mind that they are associated with several adverse events, the most prominent of which is heart failure.

Effects of Thyroid Dysfunction on Lipid Profile

Thyroid dysfunction has a great impact on lipids as well as a number of other cardiovascular risk factors. Hypothyroidism is relatively common and is associated with an unfavorable effect on lipids. Substitution therapy is beneficial for patients with overt hypothyroidism, improving lipid profile. However, whether subclinical hypothyroidism should be treated or not is a matter of debate. On the other hand, hyperthyroidism can be associated with acquired hypocholesterolemia or unexplained improvement of lipid profile. Overall, thyroid dysfunction should be taken into account when evaluating and treating dyslipidemic patients.

A review of the metabolic effects of sibutramine.

ABSTRACT Background: Obesity is associated with an increased incidence of diabetes, hypertension, dyslipidaemia and coronary artery disease. Current management strategies of obesity include lifestyle interventions and pharmacotherapy. Sibutramine is a drug with established efficacy in weight reduction and maintenance of weight loss. It reduces food intake and attenuates the fall in metabolic rate associated with weight loss. Objective: To review the metabolic effects associated with sibutramine use. Methods: Relevant articles were identified through a Medline search (up to December 2004). Results: Weight loss with sibutramine treatment is associated with improved insulin sensitivity and a fall in glycosylated haemoglobin levels in type 2 diabetic patients. In most trials sibutramine exerted favourable effects on lipids, especially on high density lipoprotein (HDL) cholesterol and triglycerides, as well as on the total:HDL cholesterol ratio. Sibutramine also lowers serum uric acid concentrations. Furthermore, this drug seems to favourably influence adipocytokines; it reduces serum leptin and resistin levels and increases adiponectin levels. Sibutramine also exerts a beneficial effect on hyperandrogenaemia in obese women with polycystic ovary syndrome. Preliminary findings also suggest that weight loss following treatment with sibutramine is useful in patients with non-alcoholic fatty liver disease (NAFLD). Conclusion: Weight loss following sibutramine administration is associated with several favourable metabolic effects.

Effect of orlistat, micronised fenofibrate and their combination on metabolic parameters in overweight and obese patients with the metabolic syndrome: the FenOrli study

ABSTRACT Background: Obesity is becoming increasingly common worldwide and is strongly associated with the metabolic syndrome (MetS). MetS is considered to be a cluster of risk factors that increase the risk of vascular events. Objective: In an open-label randomised study (the FenOrli study) we assessed the effect of orlistat and fenofibrate treatment, alone or in combination on reversing the diagnosis of the MetS (primary end-point) as well as on anthropometric and metabolic parameters (secondary end-points) in overweight and obese patients with MetS but no diabetes. Methods: Overweight and obese patients (N = 89, body mass index (BMI) > 28 kg/m2) with MetS [as defined by the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III criteria] participated in the study. Patients were prescribed a low-calorie low-fat diet and were randomly allocated to receive orlistat 120 mg three times a day (tid) (O group), micronised fenofibrate 200 mg/day (F group), or orlistat 120 mg tid plus micronised fenofibrate 200 mg/day (OF group). Body weight, BMI, waist circumference, blood pressure, serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL‐C), high-density lipoprotein cholesterol (HDL‐C), non-HDL‐C, triglyceride, creatinine (SCr) and uric acid (SUA) levels, as well as homeostasis model assessment (HOMA) index and liver enzyme activities were measured at baseline and after 3 months of treatment. Results: Of the 89 patients enrolled, three (one in each group) dropped out during the study due to side effects. After the 3‐month treatment period, 43.5% of patients in the O group, 47.6% in the F group and 50% in the OF group no longer met the MetS diagnostic criteria (primary end-point, p < 0.0001 vs. baseline in all treatment groups). No significant difference in the primary end-point was observed between the three treatment groups. Significant reductions in body weight, BMI, waist circumference, blood pressure, TC, LDL‐C, non-HDL‐C, triglyceride and SUA levels, as well as gamma-glutamyl transpeptidase activity and HOMA index were observed in all treatment groups. In the OF group a greater decrease in TC (–26%) and LDL‐C (–30%) was observed compared with that in the O and F groups ( p < 0.01) and a more pronounced reduction of triglycerides (–37%) compared with that in the O group ( p < 0.05). SUA levels and alkaline phosphatase activity decreased more in the F and OF groups compared with the O group ( p < 0.05). Moreover, SCr significantly increased and estimated creatinine clearance decreased in the F and OF groups but they were not significantly altered in the O group ( p < 0.01 for the comparison between O and either F or OF groups). Glucose (in groups O and OF), as well as insulin levels and HOMA index (in all groups), were significantly reduced after treatment ( p < 0.05 vs. baseline). Conclusion: The combination of orlistat and micronised fenofibrate appears to be safe and may further improve metabolic parameters in overweight and obese patients with MetS compared with each monotherapy.

Novel roles of vitamin D in disease: What is new in 2011?

Vitamin D is a steroid molecule, mainly produced in the skin that regulates the expression of a large number of genes. Until recently its main known role was to control bone metabolism and calcium and phosphorus homeostasis. During the last 2 decades it has been realized that vitamin D deficiency, which is really common worldwide, could be a new risk factor for many chronic diseases, such as the metabolic syndrome and its components, the whole spectrum of cardiovascular diseases, several auto-immune conditions, and many types of cancer as well as all-cause mortality. Except for the great number of epidemiological studies that support the above presumptions, vitamin D receptors (VDRs) have been identified in many tissues and cells. The effect of vitamin D supplementation remains controversial and the need for more persuasive study outcomes is intense.

Preventing Type 2 Diabetes in High Risk Patients: An Overview of Lifestyle and Pharmacological Measures

BACKGROUND Type 2 diabetes mellitus (T2DM) is a common disease that is associated with an increased risk of vascular complications. The incidence of T2DM is also increasing. It follows that T2DM prevention is important. METHODS Relevant articles (review articles, randomised studies and large cohort and case-control studies) were identified through a Medline search (up to March 2005). RESULTS The first trials on T2DM prevention were based on lifestyle intervention. The results of these studies were impressive since they demonstrated that even a small reduction in weight could significantly reduce the incidence of T2DM. However, the main disadvantage of lifestyle measures is that they are difficult to achieve and sustain. Therefore, pharmacological interventions have also been evaluated. The results of trials using metformin, orlistat, nateglinide, acarbose, thiazolidinediones, hormone replacement therapy, statins or fibrates are either encouraging or require more extensive evaluation. In addition, studies using antihypertensive drugs (mainly angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists) showed that these drugs could also reduce the progression to T2DM in high risk individuals. CONCLUSIONS T2DM has major quality of life and cost implications. Therefore, more research is needed to establish safe and cost effective ways to prevent this modern epidemic.