Anna I. Kakafika

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.

Prevalence of atherosclerotic vascular disease among subjects with the metabolic syndrome with or without diabetes mellitus: the METS-GREECE Multicentre Study

SUMMARY Aims: To estimate the prevalence of vascular disease (coronary heart disease/stroke/peripheral arterial disease) in individuals with the metabolic syndrome (MetSyn) with or without diabetes mellitus (DM) when compared with subjects without the MetSyn. Patients and methods: A cross-sectional analysis of a representative sample of Greek adults (n = 4153), men and women (49% and 51%, respectively), living in urban, semi-urban and rural areas (54%, 25% and 21%, respectively). The National Cholesterol Education Program – Adult Treatment Panel III definition of the MetSyn was used. Results: The age-adjusted prevalence of the MetSyn was 23.6% [95% confidence interval (CI) = 22.4%–25.1%]; this was similar in men and women. The fully adjusted prevalence of vascular disease in those with the MetSyn (n = 984) was 29.4%, significantly higher than in those without (n = 3169, 9.6%, p < 0.0001), while subjects without both the MetSyn and DM had the lowest vascular disease prevalence (n = 3035, 8.9%). Subjects with the MetSyn but no DM (n = 674) had a vascular disease prevalence of 24.1% ( p < 0.0001 vs. those without the MetSyn), which was similar to that in subjects with DM without the MetSyn (n = 134, 25.4%), but lower than in those with both the MetSyn and DM (n = 310, 40.7%, p < 0.0001 vs. all). In comparison to those without the MetSyn [odds ratio (OR) = 1], the ORs of prevalent vascular disease, after multivariate analysis for age, sex and components of the MetSyn, and antiatherosclerotic drugs were: all MetSyn = 1.94 (95% CI = 1.35–2.47), with both MetSyn and DM = 3.04 (95% CI = 1.98–4.11) and with MetSyn but no DM = 1.48 (95% CI = 1.12–1.92). Conclusions: The prevalence of vascular disease was markedly increased in the presence of the MetSyn. Those with both the MetSyn and DM had the highest prevalence of vascular disease, followed by those with the MetSyn without DM. Probably MetSyn without DM should be considered as a coronary heart disease-risk equivalent in future guidelines. This initiative would reset treatment targets and potentially provide additional benefit in patients with the MetSyn.

Do we need to consider inflammatory markers when we treat atherosclerotic disease

This review considers the value of monitoring inflammatory markers as a guide to selecting appropriate drugs in patients at high risk of cardiovascular disease (CVD). Clinical and experimental studies investigated inflammation in patients with acute coronary syndromes (ACS), stable coronary artery disease (CAD) and diabetes mellitus (DM) or metabolic syndrome (MetS), non-alcoholic fatty liver disease (NAFLD) or systemic autoimmune diseases (SAD). Evidence suggests that in these high risk groups inflammation plays a role in the extent and severity of atherosclerosis. Simple inflammatory markers (e.g. C-reactive protein and fibrinogen) can be monitored cost effectively and may influence the selection of drugs that can normalize both traditional CVD risk factors and inflammation. However, this concept requires proof in appropriately designed trials that include clinically relevant end points.

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.

Effectiveness of Ezetimibe Alone or in Combination With Twice a Week Atorvastatin (10 mg) for Statin Intolerant High-Risk Patients

This study was undertaken to investigate the effect of ezetimibe (10 mg/day) alone or in combination with atorvastatin (10 mg twice a week) on hypercholesterolemia in 56 high-risk patients intolerant to daily statin use. Ezetimibe monotherapy was well tolerated (2 withdrawals) and induced a mean reduction in low-density lipoprotein (LDL) cholesterol of 20% (p <0.05) at the third month. However, of the 54 patients still taking ezetimibe, only 5 (9%) were at their LDL cholesterol targets. Atorvastatin 10 mg twice a week was then added to ezetimibe and was well tolerated (3 withdrawals). This combination reduced LDL cholesterol (in a treatment-based analysis) by 37% compared with baseline (p <0.001), with 43 (84%) patients reaching their LDL cholesterol goals. When patients (n = 34, 25 men) with baseline serum creatinine values in the upper 2 tertiles were analyzed separately, there was a significant (p = 0.041) decrease in serum creatinine levels after 6 months of treatment. In conclusion, the combination of ezetimibe plus atorvastatin 10 mg twice a week might be a therapeutic option for high-risk patients intolerant to daily statin monotherapy.

Effect of Fenofibrate on Serum Inflammatory Markers in Patients With High Triglyceride Values

Background: Atherosclerosis is the leading cause of death in developed countries. Although the mechanisms that underlie this process are not well defined, it has been proposed that atherosclerosis is mainly an inflammatory disease. In this context, a number of inflammatory markers have been studied for their ability to predict future cardiovascular events in asymptomatic individuals or patients with established atherosclerotic disease. Methods and Results: The aim of our study was to evaluate the effect of micronized fenofibrate on serum inflammatory markers, such as C-reactive protein, fibrinogen, and plasma platelet-activating factor acetylhydrolase (PAF-AH) in patients with high triglyceride values. An analysis of baseline values revealed that hypertriglyceridemic patients (n = 58) exhibit an atherogenic phenotype, characterized not only by elevated lipid values but also by high concentrations of serum inflammatory markers. Along with the improvement in serum lipid profile (reduction in triglycerides and total cholesterol, low-density lipoprotein, and nonhigh-density lipoprotein-cholesterol, with a concomitant increase in high-density lipoprotein-cholesterol levels), fenofibrate administration significantly reduced the values of serum inflammatory markers by 34%, 9.5%, and 24.8% for C-reactive protein, fibrinogen, and plasma PAF-AH, respectively. However, with the exception of PAF-AH, these reductions in inflammatory markers were not correlated with the changes in lipid values. Conclusions: In addition to its well-known hypolipidemic effects, fenofibrate may also possess significant anti-inflammatory properties that can contribute its antiatherogenic effect.

Effect of a plant stanol ester-containing spread, placebo spread, or Mediterranean diet on estimated cardiovascular risk and lipid, inflammatory and haemostatic factors

BACKGROUND AND AIMS Mediterranean diet is associated with a reduced risk for cardiovascular disease (CVD). Use of plant stanols decreases low density lipoprotein cholesterol (LDL-C) concentrations. We compared the effects of the Mediterranean diet and plant stanol esters on vascular risk factors and estimated CVD (eCVD) risk. METHODS AND RESULTS In this prospective, randomized, placebo-controlled study, 150 mildly hypercholesterolaemic subjects were randomized to Mediterranean diet, a spread containing plant stanol esters (2 g/day) or a placebo spread. Vascular risk factors were assessed every month for 4 months and the eCVD risk was calculated using the PROspective- Cardiovascular-Munster (PROCAM), Framingham, and Reynolds risk engines. Placebo had no significant effect on risk factors or eCVD risk. Mediterranean diet gradually induced a significant reduction in total cholesterol (TC), LDL-C, triglycerides, high sensitivity C-reactive protein (hsCRP), blood pressure and eCVD risk (24-32%). The plant stanol ester spread reduced (by 1 month) TC (-14%), LDL-C (-16%), hsCRP (-17%), and estimated CVD risk (26-30%). eCVD risk reduction was sustained at 4th months when the gradual Mediterranean diet eCVD risk reduction became comparable to that of the stanol group. CONCLUSIONS Plant stanol esters yielded an early, by 1st treatment month, reduction of eCVD risk that resulted from a TC, LDL-C, and hsCRP decrease. eCVD risk reduction on the Mediterranean diet resulted from a change in several CVD risk factors and equaled that of plant stanol at 4 months. The consumption of plant stanol esters by moderately hypercholesterolaemic patients may be a useful option to reduce CVD risk in those who do not adopt a Mediterranean diet.

Comparative Effects of Atorvastatin, Simvastatin, and Fenofibrate on Serum Homocysteine Levels in Patients with Primary Hyperlipidemia

Hyperhomocysteinemia is regarded as an independent risk factor for cardiovascular disease. Lipid‐lowering agents, such as fibrates, can modify homocysteine levels. However, less is known about the effect of statin therapy on homocysteine. The authors compared the effects of atorvastatin (40 mg/day), simvastatin (40 mg/day), and micronized fenofibrate (200 mg/day) on the serum concentrations of total homocysteine, vitamin B12, and folic acid in patients with primary hyperlipidemia. A total of 128 patients with primary hyperlipidemia (total cholesterol > 240 mg/dL and triglycerides < 350 mg/dL) were assigned to atorvastatin, simvastatin, or fenofibrate. Serum lipid and metabolic parameters were measured at baseline and at 6 and 12 weeks of treatment. Homocysteine correlated positively with serum creatinine and uric acid levels and inversely with serum folic acid levels. All treatment modalities reduced total, low‐density lipoprotein (LDL) cholesterol, and triglyceride concentrations. High‐density lipoprotein (HDL) cholesterol levels significantly increased only in the fenofibrate‐treated patients (47.9 ± 12.5 vs. 50.7 ± 12.6 vs. 51.2 ± 12.8 mg/dL, p 0.01). Atorvastatin and fenofibrate treatment resulted in a significant reduction of serum uric acid levels (5.3 ± 1.6 vs. 4.9 ± 1.4 vs. 4.8 ± 1.4 mg/dL, p < 0.0001 for atorvastatin; 5.6 ± 1.6 vs. 4.3 ± 1.4 vs. 4.4 ± 1.4 mg/dL, p < 0.0001 for fenofibrate). Homocysteine levels were significantly increased only by fenofibrate (10.3 ± 3.3 vs. 14.1 ± 3.8 vs. 14.2 ± 3.6 μU/L, p < 0.001) but did not change from baseline following statin treatment. Neither statins nor fenofibrate had any effect on serum vitamin B12 and folic acid levels. In contrast to fenofibrate, therapeutic dosages of atorvastatin and simvastatin have a neutral effect on serum homocysteine levels, which is in favor of their “cardioprotective” properties.