Konstantinos Tziomalos

Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis

BACKGROUND Long-term statin treatment reduces the frequency of cardiovascular events, but safety and efficacy in patients with abnormal liver tests is unclear. We assessed whether statin therapy is safe and effective for these patients through post-hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study population. METHODS GREACE was a prospective, intention-to-treat study that randomly assigned by a computer-generated randomisation list 1600 patients with coronary heart disease (aged <75 years, with serum concentrations of LDL cholesterol >2·6 mmol/L and triglycerides <4·5 mmol/L) at the Hippokration University Hospital, Thessaloniki, Greece to receive statin or usual care, which could include statins. The primary outcome of our post-hoc analysis was risk reduction for first recurrent cardiovascular event in patients treated with a statin who had moderately abnormal liver tests (defined as serum alanine aminotransferase or aspartate aminotransferase concentrations of less than three times the upper limit of normal) compared with patients with abnormal liver tests who did not receive a statin. This risk reduction was compared with that for patients treated (or not) with statin and normal liver tests. FINDINGS Of 437 patients with moderately abnormal liver tests at baseline, which were possibly associated with non-alcoholic fatty liver disease, 227 who were treated with a statin (mainly atorvastatin 24 mg per day) had substantial improvement in liver tests (p<0·0001) whereas 210 not treated with a statin had further increases of liver enzyme concentrations. Cardiovascular events occurred in 22 (10%) of 227 patients with abnormal liver tests who received statin (3·2 events per 100 patient-years) and 63 (30%) of 210 patients with abnormal liver tests who did not receive statin (10·0 events per 100 patient-years; 68% relative risk reduction, p<0·0001). This cardiovascular disease benefit was greater (p=0·0074) than it was in patients with normal liver tests (90 [14%] events in 653 patients receiving a statin [4·6 per 100 patient-years] vs 117 [23%] in 510 patients not receiving a statin [7·6 per 100 patient-years]; 39% relative risk reduction, p<0·0001). Seven (<1%) of 880 participants who received a statin discontinued statin treatment because of liver-related adverse effects (transaminase concentrations more than three-times the upper limit of normal). INTERPRETATION Statin treatment is safe and can improve liver tests and reduce cardiovascular morbidity in patients with mild-to-moderately abnormal liver tests that are potentially attributable to non-alcoholic fatty liver disease. FUNDING None.

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).

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.

Atherosclerosis and osteoporosis: age-dependent degenerative processes or related entities?

Osteoporosis and atherosclerosis, two multifactorial and degenerative entities, are major public health problems. These diseases accompany the aging process and share common risk factors. Furthermore, several common pathophysiological factors have been suggested. These include similar molecular pathways involving bone and vascular mineralization, estrogen deficiency, parathyroid hormone, homocysteine, lipid oxidation products, inflammatory process, as well as vitamin D and K. Moreover, the use of statins, biphosphonates, beta-blockers and experimental dual-purpose therapies based on the biological linkage of the above entities may simultaneously benefit bone loss and vascular disease. This review considers a potential link between osteoporosis and atherosclerosis beyond aging. These common factors may lead to appropriate treatment strategies.

Endothelial dysfunction in metabolic syndrome: Prevalence, pathogenesis and management

The metabolic syndrome (MetS) is characterized by the presence of central obesity, impaired glucose metabolism, dyslipidemia and hypertension. Several studies showed that MetS is associated with increased risk for type 2 diabetes mellitus (T2DM) and vascular events. All components of MetS have adverse effects on the endothelium. Endothelial dysfunction plays a role in the pathogenesis of atherosclerosis and might also increase the risk for insulin resistance and T2DM. We review the prevalence and pathogenesis of endothelial dysfunction in MetS. We also discuss the potential effects of lifestyle measures and pharmacological interventions on endothelial function in these patients. It remains to be established whether improving endothelial function in MetS will reduce the risk for T2DM and vascular events.

Comparison of four definitions of the metabolic syndrome in a Greek (Mediterranean) population

Abstract Background: There is a need to evaluate the prevalence of metabolic syndrome (MetS) diagnosed by the new Joint Interim Societies (JIS) MetS definition. The JIS definition was compared with three previous definitions to assess their ability to predict cardiovascular disease (CVD) risk. Methods: A cross-sectional analysis of a representative sample of Greek adults (n  = 9669) was performed to estimate the prevalence of MetS and CVD using the JIS vs. the three older definitions of MetS: the National Cholesterol Education Program-Adult Treatment Panel-III (NCEP-ATP-III), the International Diabetes Federation (IDF) and the American Heart Association/National Heart Lung and Blood Institute (AHA/NHLBI) definitions. Results: The age-adjusted MetS prevalence was 45.7%, 43.4%, 24.5% and 26.3% (ANOVA p  < 0.001) with the JIS, IDF, NCEP and AHA/NHLBI definitions. The prevalence of CVD was 11.4% in the whole study population and 17.6%, 18.3%, 23.3%, 22.6% and in subjects with MetS according to the JIS, IDF, NCEP and AHA/NHLBI definitions (ANOVA p  < 0.001). The prevalence of CVD was only 10.4% (i.e., lower than in the whole study population) in subjects with MetS according to the JIS but not according to the NCEP-ATP-III and AHA/NHLBI definitions (p  < 0.001 vs. subjects with MetS as defined by NCEP-ATP-III or AHA/NHLBI). Conclusions: When diagnosed according to the new JIS definition, the prevalence of MetS was high in a Greek Mediterranean cohort (nearly half of the adult population). The NCEP-ATP-III and AHA/NHLBI definitions were more predictive of CVD risk than the new JIS definition. These findings, though limited by the cross sectional analysis, may have implications regarding the choice of the definition to diagnose MetS.

Insulin resistance and endocrine characteristics of the different phenotypes of polycystic ovary syndrome: a prospective study

BACKGROUND Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by oligo- or anovulation (ANOV), biochemical or clinical manifestations of hyperandrogenemia (HA) and PCOs. Four phenotypes of PCOS exist [phenotype 1 (ANOV + HA + PCO), phenotype 2 (ANOV + HA), phenotype 3 (HA + PCO) and phenotype 4 (ANOV + PCO)] but the differences between them are not well studied. We compared markers of insulin resistance (IR) and endocrine characteristics between the different PCOS phenotypes. METHODS We prospectively studied 1212 consecutive women with PCOS and 254 BMI-matched healthy women. RESULTS Phenotypes 1-4 were present in 48.2, 30.7, 9.7 and 11.4% of patients, respectively. BMI did not differ between the four phenotypes and controls. Both normal weight and overweight/obese women with phenotypes 1 and 2 were more insulin resistant than controls. Overweight/obese, but not normal weight, women with phenotype 4 were more insulin resistant than controls, while IR in women with phenotype 3 did not differ from controls regardless of obesity. In normal weight subjects, women with phenotypes 1 and 2 were more insulin resistant than women with phenotype 4. In overweight/obese subjects, women with phenotype 1 were more insulin resistant than women with phenotypes 2 and 3 and women with phenotype 4 were more insulin resistant than those with phenotype 3. Circulating androgens were higher in normal weight and overweight/obese PCOS patients with phenotypes 1-3 compared with those with phenotype 4, and higher in normal weight PCOS patients with phenotype 1 than in those with phenotype 2. CONCLUSIONS Phenotype 1 is associated with more IR and more pronounced HA than phenotype 2. Phenotypes 2 and 4 with obesity, are also characterized by IR. In contrast, phenotype 3 is not associated with IR.

The use of sibutramine in the management of obesity and related disorders: An update

Aims: To review the major trials that evaluated the efficacy and safety of the use of sibutramine for weight loss and the impact of this agent on obesity-related disorders. Methods and results: The most important articles on sibutramine up to January 2009 were located by a PubMed and Medline search. Sibutramine reduces food intake and body weight more than placebo and has positive effects on the lipid profile (mainly triglycerides and high density lipoprotein cholesterol), glycemic control and inflammatory markers in studies for up to one year. Preliminary studies showed that sibutramine may also improve other obesity-associated disorders such as polycystic ovary syndrome, left ventricular hypertrophy, binge eating disorder and adolescent obesity. The high discontinuation rates and some safety issues mainly due to the increase in blood pressure and pulse rate have to be considered. Additionally, it has not yet been established that treatment with sibutramine will reduce cardiovascular events and total mortality. Conclusions: Sibutramine, in conjunction with lifestyle measures, is a useful drug for reducing body weight and improving associated cardiometabolic risk factors and obesity-related disorders. Studies of longer duration are required to determine the precise indications of the drug, to evaluate safety issues and to assess its efficacy on cardiovascular mortality.

Angiotensin II reactivation and aldosterone escape phenomena in renin-angiotensin-aldosterone system blockade: is oral renin inhibition the solution?

This editorial considers the use of the first selective oral renin inhibitor, aliskiren, in reducing angiotensin (Ang) II reactivation or aldosterone (ALDO) escape during renin–angiotensin–aldosterone system (RAAS) inhibition. RAAS blockade with angiotensin converting enzyme inhibitors (ACEIs) and/or angiotensin receptor AT1 blockers (ARBs) is very useful for the treatment of arterial hypertension, chronic heart failure (CHF), atherosclerosis and diabetes. ‘Ang II reactivation’ and ‘ALDO escape’ or ‘breakthrough’ have been observed during either ACEI or ARB treatment, and may attenuate the clinical benefit of RAAS blockade. Renin and Ang I accumulate during ACE inhibition, and might overcome the ability of an ACEI to effectively suppress ACE activity. There is also data suggesting that 30 – 40% of Ang II formation in the healthy human during RAAS activation is formed via renin-dependent, but ACE-independent, pathways. Moreover, ACE gene polymorphisms contribute to the modulation and adequacy of the neurohormonal response to long-term ACE inhibition, at least in patients with CHF (up to 45% of CHF patients have elevated Ang II levels despite the long-term use of an ACEI) or diabetes. The reactivated Ang II promotes ALDO secretion and sodium reabsorption. ALDO breakthrough also occurs during long-term ARB therapy, mainly by an AT2-dependent mechanism. This was related to target-organ damage in animal models. Oral renin inhibition with aliskiren has showed excellent efficacy and safety in the treatment of hypertension. Aliskiren can be co-administered with ACEIs, ARBs or hydrochlorothiazide. Furthermore, there is evidence suggesting that aliskiren reduces Ang II reactivation in ACE inhibition and ALDO escape during treatment with an ACEI or an ARB, at least to the degree that this is associated with the RAAS. For RAAS-independent ALDO production, the combination of aliskiren with eplerenone might prove useful.

Epidemiological Survey for the Prevalence of Overweight and Abdominal Obesity in Greek Adolescents

This study was designed to provide estimates of overweight (OW), obesity (OB), and abdominal OB (AO) in a representative sample of adolescents throughout the whole of Greece. A total of 14,456 adolescents aged 13–19 years (6,677 boys and 7,779 girls) had direct measurements (height, weight, waist circumference (WC)) taken at school during 2003. The overall prevalence of OW including OB in the population studied was 29.4% in boys and 16.7% in girls. OB prevalence was also higher in boys than in girls (6.1% vs. 2.7%), whereas prevalence of AO was higher in girls than in boys (21.7% vs. 13.5%). Rates of OW, OB, and AO were significantly more prevalent in the Greek than in the foreign male population (immigrants). OW% in adolescent girls was independently associated with smoking and alcohol consumption. The prevalence of OW and OB in Greek adolescents is high, particularly in boys, comparable with that reported for most Mediterranean European countries. AO, mainly in adolescent girls, also appears high. Preventive and treatment strategies are urgently needed to combat this OB epidemic in Greece.