Vasilios G. Athyros

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.

The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study

Background: Little is known about statins in the prevention of dyslipidaemia induced renal function decline. The secondary coronary heart disease (CHD) prevention GREACE study suggested that dose titration with atorvastatin (10–80 mg/day, mean dose 24 mg/day) achieves the national cholesterol educational programme treatment goals and significantly reduces morbidity and mortality, compared with usual care. Aims: To report the effect of statin on renal function compared with untreated dyslipidaemia in both treatment groups. Methods/Results: All patients had plasma creatinine values within the reference range < 115 µmol/litre (13 mg/litre). The on study creatinine clearance (CrCl), as estimated (for up to 48 months) by the Cockroft-Gault formula, was compared within and between treatment groups using analysis of variance to assess differences over time. Patients from both groups not treated with statins (704) showed a 5.2% decrease in CrCl (p < 0.0001). Usual care patients on various statins (97) had a 4.9% increase in CrCl (p  =  0.003). Structured care patients on atorvastatin (783) had a 12% increase in CrCl (p < 0.0001). This effect was more prominent in the lower two quartiles of baseline CrCl and with higher atorvastatin doses. After adjustment for 25 predictors of all CHD related events, multivariate analysis revealed a hazards ratio of 0.84 (confidence interval 0.73 to 0.95; p  =  0.003) with every 5% increase in CrCl. Conclusions: In untreated dyslipidaemic patients with CHD and normal renal function at baseline, CrCl declines over a period of three years. Statin treatment prevents this decline and significantly improves renal function, potentially offsetting an additional factor associated with CHD risk.

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).

The prevalence of the metabolic syndrome using the National Cholesterol Educational Program and International Diabetes Federation definitions

ABSTRACT Objective: The prevalence of metabolic syndrome (MetS), using the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) and International Diabetes Federation (IDF) definitions, was compared in 9669 subjects, representing the Greek population. Results: The age-adjusted prevalence of NCEP ATP III-defined MetS was 24.5% whereas that of IDF-defined MetS was 43.4% (+77%, p < 0.0001). The majority (up to 69%) of older age groups had IDF-defined MetS. The calculated vascular event risk was low (6.1% and 7.2% using the Framingham and PROCAM calculation, respectively) in those with IDF-defined MetS when compared with those with NCEP ATP III MetS (11.3% and 13.7%, respectively) ( p < 0.0001 for both comparisons). Conclusion: MetS could be considered as a ‘normal’ variant if it was present in the majority of the population. Moreover, the vascular risk associated with IDF-defined MetS could be low, raising cost-effectiveness issues. Alternatively, the new IDF definition may realistically reflect the current MetS epidemic. More studies are required to support or refute those interpretations.

Safety and Efficacy of Long-Term Statin- Fibrate Combinations in Patients With Refractory Familial Combined Hyperlipidemia

No monotherapy is able to tackle effectively all atherogenic features of familial combined hyperlipidemia: high low-density lipoprotein (LDL) cholesterol, triglycerides (TG), and plasma fibrinogen, as well as low high-density lipoprotein (HDL) cholesterol. The present study investigated the safety and efficacy of combined pravastotin or simvastatin with gemfibrozil or ciprofibrate treatment on total cholesterol, LDL, TG, plasma fibrinogen, and apoproteins B and A-I in patients with refractory familial combined hyperlipidemia, with or without coronary artery disease. From the initial 420 patients included in the study, 389 (294 men and 95 women, mean age 51 years [range 30 to 65]) completed the study. These patients were followed for a mean period of 29 months (1 year [n = 107], 2 years [n = 102], 3 years [n = 95], and 4 years [n = 85]). Patients given a hypolipidemic diet were randomly assigned to pravastatin + gemfibrozil (n = 135, 20 and 1,200 mg/day, respectively), simvastatin + gemfibrozil (n = 130, 20 and 1,200 mg), or simvastotin + ciprofibrate (n = 124, 20 and 100 mg). Lipid parameters, apoproteins B and A-I, and plasma fibrinogen were assessed every 3 months. Physical and laboratory investigations for adverse effects were performed every month for the first 3 months and every 3 months thereafter. No patient exhibited myopathy or rhabdomyolysis. Five patients (1.3%) were withdrawn from the study because of high transaminases (more than threefold the upper normal limit). Five nonfatal coronary artery disease events were recorded. All 3 combination treatments were more effective in normalizing lipid profile than any monotherapy in the past. Simvastatin + ciprofibrate was more effective than pravastatin + gemfibrozil in reducing LDL, TG, and plasma fibrinogen levels. Simvastatin + gemfibrozil increased HDL levels more than the other 2. The apoprotein B decrease was analogous to the LDL reduction by all combinations, whereas apoprotein A-I was increased more with simvastatin + gemfibrozil. The data suggest that the statin-fibrate combinations used in the study are safe and have a favorable effect on all major coronary artery disease risk factors in patients with refractory familial combined hyperlipidemia with or without coronary artery disease. Early detection of the rare drug-induced reversible hepatotoxicity calls for close monitoring of patients.

A Comparison of the Aldosterone‐blocking Agents Eplerenone and Spironolactone

Improved understanding of the adverse pharmacological properties of aldosterone has prompted investigation of the clinical benefits of blocking aldosterone at the receptor level. This article reviews the pharmacology, clinical efficacy, and tolerability of the two available blocking agents, spironolactone and eplerenone. A Medline search identified clinical studies assessing spironolactone and eplerenone. Priority was given to large, well‐controlled, clinical trials and comparative studies. Pharmacological differences between spironolactone and eplerenone include lower affinity of eplerenone for progesterone, androgen, and glucocorticoid receptors; more consistently demonstrated nongenomic properties for eplerenone; and the presence of long‐acting metabolites for spironolactone. Both agents effectively treat hypertension and heart failure but comparisons are complicated by the deficiency of head‐to‐head trials and differences between patient populations. There are differences in the tolerability profiles; spironolactone is associated with dose‐dependent sexual side effects. Both agents produce dose‐dependent increases in potassium concentrations, although the effect with spironolactone appears to be greater when both agents are administered at recommended doses. Choice of a specific agent should be based on individual patient issues, such as the nature of heart failure and patient concerns about adverse events. Copyright

The prevalence of the metabolic syndrome in Greece : The Mets-Greece Multicentre Study

Background:  The Third Report (ATP III) of the National Cholesterol Education Program Expert Panel (NCEP) highlighted the importance of identifying and treating patients with the metabolic syndrome (MetS) to prevent cardiovascular disease (CVD) and progression to diabetes mellitus. Limited information is available about the prevalence of MetS, as defined by the NCEP ATP III, in Europe, especially in Greece.

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.

Glucagon-like peptide-1-based therapies and cardiovascular disease: looking beyond glycaemic control

Type 2 diabetes mellitus is a well‐established risk factor for cardiovascular disease (CVD). New therapeutic approaches have been developed recently based on the incretin phenomenon, such as the degradation‐resistant incretin mimetic exenatide and the glucagon‐like peptide‐1 (GLP‐1) analogue liraglutide, as well as the dipeptidyl dipeptidase (DPP)‐4 inhibitors, such as sitagliptin, vildagliptin, saxagliptin, which increase the circulating bioactive GLP‐1. GLP‐1 exerts its glucose‐regulatory action via stimulation of insulin secretion and glucagon suppression by a glucose‐dependent way, as well as by weight loss via inhibition of gastric emptying and reduction of appetite and food intake. These actions are mediated through GLP‐1 receptors (GLP‐1Rs), although GLP‐1R‐independent pathways have been reported. Except for the pancreatic islets, GLP‐1Rs are also present in several other tissues including central and peripheral nervous systems, gastrointestinal tract, heart and vasculature, suggesting a pleiotropic activity of GLP‐1. Indeed, accumulating data from both animal and human studies suggest a beneficial effect of GLP‐1 and its metabolites on myocardium, endothelium and vasculature, as well as potential anti‐inflammatory and antiatherogenic actions. Growing lines of evidence have also confirmed these actions for exenatide and to a lesser extent for liraglutide and DPP‐4 inhibitors compared with placebo or standard diabetes therapies. This suggests a potential cardioprotective effect beyond glucose control and weight loss. Whether these agents actually decrease CVD outcomes remains to be confirmed by large randomized placebo‐controlled trials. This review discusses the role of GLP‐1 on the cardiovascular system and addresses the impact of GLP‐1‐based therapies on CVD outcomes.

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.