Haralampos J. Milionis

The effect of Mediterranean diet on metabolic syndrome and its components: a meta-analysis of 50 studies and 534,906 individuals.

OBJECTIVES The aim of this study was to meta-analyze epidemiological studies and clinical trials that have assessed the effect of a Mediterranean diet on metabolic syndrome (MS) as well as its components. BACKGROUND The Mediterranean diet has long been associated with low cardiovascular disease risk in adult population. METHODS The authors conducted a systematic review and random effects meta-analysis of epidemiological studies and randomized controlled trials, including English-language publications in PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials until April 30, 2010; 50 original research studies (35 clinical trials, 2 prospective and 13 cross-sectional), with 534,906 participants, were included in the analysis. RESULTS The combined effect of prospective studies and clinical trials showed that adherence to the Mediterranean diet was associated with reduced risk of MS (log hazard ratio: -0.69, 95% confidence interval [CI]: -1.24 to -1.16). Additionally, results from clinical studies (mean difference, 95% CI) revealed the protective role of the Mediterranean diet on components of MS, like waist circumference (-0.42 cm, 95% CI: -0.82 to -0.02), high-density lipoprotein cholesterol (1.17 mg/dl, 95% CI: 0.38 to 1.96), triglycerides (-6.14 mg/dl, 95% CI: -10.35 to -1.93), systolic (-2.35 mm Hg, 95% CI: -3.51 to -1.18) and diastolic blood pressure (-1.58 mm Hg, 95% CI: -2.02 to -1.13), and glucose (-3.89 mg/dl, 95% CI:-5.84 to -1.95), whereas results from epidemiological studies also confirmed those of clinical trials. CONCLUSIONS These results are of considerable public health importance, because this dietary pattern can be easily adopted by all population groups and various cultures and cost-effectively serve for primary and secondary prevention of the MS and its individual components.

A Review of Drug-Induced Hyponatremia

Hyponatremia (defined as a serum sodium level < 134 mmol/L) is the most common electrolyte abnormality in hospitalized patients. Certain drugs (eg, diuretics, antidepressants, and antiepileptics) have been implicated as established causes of either asymptomatic or symptomatic hyponatremia. However, hyponatremia occasionally may develop in the course of treatment with drugs used in everyday clinical practice (eg, newer antihypertensive agents, antibiotics, and proton pump inhibitors). Physicians may not always give proper attention in time to undesirable drug-induced hyponatremia. Effective clinical management can be handled through awareness of the adverse effect of certain pharmaceutical compounds on serum sodium levels. Here, we review clinical information about the incidence of hyponatremia associated with specific drug treatment and discuss the underlying pathophysiologic mechanisms.

Statin Therapy and Outcome After Ischemic Stroke Systematic Review and Meta-Analysis of Observational Studies and Randomized Trials

Background and Purpose— Although experimental data suggest that statin therapy may improve neurological outcome after acute cerebral ischemia, the results from clinical studies are conflicting. We performed a systematic review and meta-analysis investigating the relationship between statin therapy and outcome after ischemic stroke. Methods— The primary analysis investigated statin therapy at stroke onset (prestroke statin use) and good functional outcome (modified Rankin score 0 to 2) and death. Secondary analyses included the following: (1) acute poststroke statin therapy (⩽72 hours after stroke), and (2) thrombolysis-treated patients. Results— The primary analysis included 113 148 subjects (27 studies). Among observational studies, statin treatment at stroke onset was associated with good functional outcome at 90 days (pooled odds ratio [OR], 1.41; 95% confidence interval [CI], 1.29–1.56; P<0.001), but not 1 year (OR, 1.12; 95% CI, 0.9–1.4; P=0.31), and with reduced fatality at 90 days (pooled OR, 0.71; 95% CI, 0.62–0.82; P<0.001) and 1 year (OR, 0.80; 95% CI, 0.67–0.95; P=0.01). In the single randomized controlled trial reporting 90-day functional outcome, statin treatment was associated with good outcome (OR, 1.5; 95% CI, 1.0–2.24; P=0.05). No reduction in fatality was observed on meta-analysis of data from 3 randomized controlled trials (P=0.9). In studies restricted to of thrombolysis-treated patients, an association between statins and increased fatality at 90 days was observed (pooled OR, 1.25; 95% CI, 1.02–1.52; P=0.03, 3 studies, 4339 patients). However, this association was no longer present after adjusting for age and stroke severity in the largest study (adjusted OR, 1.14; 95% CI, 0.90–1.44; 4012 patients). Conclusion— In the largest meta-analysis to date, statin therapy at stroke onset was associated with improved outcome, a finding not observed in studies restricted to thrombolysis-treated patients. Randomized trials of statin therapy in acute ischemic stroke are needed.

Lipoprotein (a) and stroke

Strokes are one of the most common causes of mortality and long term severe disability. There is evidence that lipoprotein (a) (Lp(a)) is a predictor of many forms of vascular disease, including premature coronary artery disease. Several studies have also evaluated the association between Lp(a) and ischaemic (thrombotic) stroke. Several cross sectional (and a few prospective) studies provide contradictory findings regarding Lp(a) as a predictor of ischaemic stroke. Several factors might contribute to the existing confusion—for example, small sample sizes, different ethnic groups, the influence of oestrogens in women participating in the studies, plasma storage before Lp(a) determination, statistical errors, and selection bias. This review focuses on the Lp(a) related mechanisms that might contribute to the pathogenesis of ischaemic stroke. The association between Lp(a) and other cardiovascular risk factors is discussed. Therapeutic interventions that can lower the circulating concentrations of Lp(a) and thus possibly reduce the risk of stroke are also considered.

Components of the Metabolic Syndrome and Risk for First-Ever Acute Ischemic Nonembolic Stroke in Elderly Subjects

Background and Purpose— Metabolic syndrome (MetSyn) represents a constellation of lipid and nonlipid risk factors for cardiovascular disease and is a recognized target for increased behavioral therapy. Objective— The association between acute ischemic/nonembolic stroke and the MetSyn in elderly individuals was assessed in a population-based case-control study in the prefecture of Ioannina, Greece. Study Population— A total of 163 patients aged older than 70 years admitted with first-ever-in-a-lifetime acute ischemic/nonembolic stroke and 166 controls were included. Results— The prevalence of MetSyn (defined according to NCEP/ATP III criteria) was high in stroke patients (46.0% versus 15.7%, P<0.001). Compared with controls as a group (with and without MetSyn), stroke patients with the MetSyn showed higher concentrations of triglycerides, lipoprotein(a), uric acid, and fibrinogen, and lower high-density lipoprotein (HDL) cholesterol and apolipoprotein A-I levels. In logistic regression analysis, crude and adjusted odd ratios (ORs) for MetSyn were 5.33 (95% confidence interval [CI], 2.91 to 9.79; P<0.0001) and 2.59 (95% CI, 1.24 to 5.42; P=0.012), respectively. The analysis of interaction between MetSyn and its individual components revealed significant associations with abdominal obesity (adjusted OR, 2.74; 95% CI, 1.15 to 6.50; P=0.02), hypertension (OR, 2.03; 95% CI, 0.91 to 4.49; P=0.08), high fasting glucose levels (OR, 2.95; 95% CI, 1.19 to 7.35; P=0.02), high triglyceride (OR, 5.55; 95% CI, 2.71 to 11.37; P<0.0001]), and low HDL cholesterol (OR, 5.42; 95% CI, 2.85 to 10.30; P<0.0001). Notably, in stroke patients with the MetSyn the inverse relationship between HDL cholesterol levels and ischemic stroke was negated (OR, 1.04; 95% CI, 1.02 to 1.05; P<0.0001). Conclusions— MetSyn is associated with an increased risk for acute ischemic/nonembolic stroke in elderly subjects with significant contributions from its individual components. In the presence of MetSyn, HDL cholesterol loses its protective role against ischemic stroke.

CHADS2, CHA2DS2-VASc, and long-term stroke outcome in patients without atrial fibrillation

Objective: CHADS2 and CHA2DS2-VASc scores are used to assess stroke risk in patients with atrial fibrillation (AF). We investigated whether these scores are associated with stroke outcome in non-AF stroke patients. Methods: Consecutive patients with acute first-ever ischemic stroke but without AF were classified into subgroups according to prestroke CHADS2 and CHA2DS2-VASc scores and followed up for 5 years. The end points were death, stroke recurrence, and a composite of major cardiovascular events. Results: Among 1,756 patients (aged 67.2 ± 12.3 years, 68.2% males), there were 258 (14.7%), 617 (35.3%), and 878 (50.0%) patients with low, intermediate, and high CHADS2 score, respectively. The corresponding figures for CHA2DS2-VASc subgroups were 110 (6.3%), 255 (14.5%), and 1,391 (79.2%). There were significant differences between CHADS2 subgroups in 5-year mortality (log-rank test = 74.5, p < 0.0001), stroke recurrence (log-rank test = 12.3, p = 0.002), and cardiovascular events (log-rank test = 19.4, p < 0.001). Similarly, there were significant differences between CHA2DS2-VASc subgroups in 5-year mortality (log-rank test = 74.5, p < 0.0001), stroke recurrence (log-rank test = 10.6, p = 0.005), and cardiovascular events (log-rank test = 16.4, p < 0.001). Compared with the low-risk group, patients in intermediate- and high-risk CHADS2 subgroups had higher 5-year mortality (hazard ratio [HR]: 2.22 [95% confidence interval {CI}: 1.78–2.77] and 3.66 [95% CI: 2.38–5.62], respectively), stroke recurrence (HR: 1.74 [95% CI: 1.09–2.79] and 1.71 [95% CI: 1.08–2.71], respectively), and cardiovascular events (HR: 1.78 [95% CI: 1.23–2.57] and 1.86 [95% CI: 1.30–2.67], respectively). Compared with the low-risk group, patients in the high-risk CHA2DS2-VASc subgroup also had higher 5-year mortality (HR: 3.56, 95% CI: 1.89–6.70), stroke recurrence (HR: 2.93, 95% CI: 1.30–6.61), and cardiovascular events (HR: 2.71, 95% CI: 1.49–4.95). Conclusions: Prestroke CHADS2 and CHA2DS2-VASc scores predict long-term stroke outcomes in non-AF patients with acute ischemic stroke. These scores may provide a simple way of stroke prognostic risk stratification among non-AF stroke patients.

Association of interleukin-6 (IL-6)-174G/C gene polymorphism with cardiovascular disease in patients with rheumatoid arthritis: The role of obesity and smoking

BACKGROUND Cardiovascular morbidity and mortality are increased in rheumatoid arthritis (RA). Interleukin-6 (IL-6) is high in RA and, together with smoking and obesity, an important contributor to the development of cardiovascular disease (CVD). The present study examined the potential association of IL-6-174 G/C polymorphism, together with obesity and smoking, with the presence of CVD in RA patients. METHODS AND RESULTS DNA samples were collected from 383 RA patients (who also had extensive clinical and laboratory evaluations). IL-6-174 G/C was identified using real time PCR and melting curve analysis. Serum IL-6 levels were measured in a subgroup of 135 RA patients to examine the functionality of the polymorphism. Carriers of the IL6-174C-allele demonstrated increased prevalence of CVD (26.2% vs. 17.0%, p=0.041). There was a significant association with CVD, even after adjustment for traditional CVD risk factors (OR=1.92, 95%CI: 1.03 to 3.58, p=0.041). IL-6 levels were significantly increased in C-allele carriers [14.02 (3.21-38.81) vs. 4.48 (2.25-16.5), p=0.028]. No significant interactions were observed between adiposity and IL6-174G/C genotypes. There was only a trend for an interaction between ever smoking and IL6 C-allele carriers on CVD. CONCLUSION The IL-6-174C-allele may associate with CVD in RA patients and possibly exerts its effect via increased inflammation. This finding, if confirmed in future studies, may be used as a part of a genetic screening tool for RA patients at high CVD risk.

Rosuvastatin-Associated Adverse Effects and Drug-Drug Interactions in the Clinical Setting of Dyslipidemia

HMG-CoA reductase inhibitors (statins) are the mainstay in the pharmacologic management of dyslipidemia. Since they are widely prescribed, their safety remains an issue of concern. Rosuvastatin has been proven to be efficacious in improving serum lipid profiles. Recently published data from the JUPITER study confirmed the efficacy of this statin in primary prevention for older patients with multiple risk factors and evidence of inflammation.Rosuvastatin exhibits high hydrophilicity and hepatoselectivity, as well as low systemic bioavailability, while undergoing minimal metabolism via the cytochrome P450 system. Therefore, rosuvastatin has an interesting pharmacokinetic profile that is different from that of other statins. However, it remains to be established whether this may translate into a better safety profile and fewer drug-drug interactions for this statin compared with others. Herein, we review evidence with regard to the safety of this statin as well as its interactions with agents commonly prescribed in the clinical setting.As with other statins, rosuvastatin treatment is associated with relatively low rates of severe myopathy, rhabdomyolysis, and renal failure. Asymptomatic liver enzyme elevations occur with rosuvastatin at a similarly low incidence as with other statins. Rosuvastatin treatment has also been associated with adverse effects related to the gastrointestinal tract and central nervous system, which are also commonly observed with many other drugs. Proteinuria induced by rosuvastatin is likely to be associated with a statin-provoked inhibition of low-molecular-weight protein reabsorption by the renal tubules. Higher doses of rosuvastatin have been associated with cases of renal failure. Also, the co-administration of rosuvastatin with drugs that increase rosuvastatin blood levels may be deleterious for the kidney. Furthermore, rhabdomyolysis, considered a class effect of statins, is known to involve renal damage. Concerns have been raised by findings from the JUPITER study suggesting that rosuvastatin may slightly increase the incidence of physician-reported diabetes mellitus, as well as the levels of glycated hemoglobin in older patients with multiple risk factors and low-grade inflammation. Clinical trials proposed no increase in the incidence of neoplasias with rosuvastatin treatment compared with placebo.Drugs that antagonize organic anion transporter protein 1B1-mediated hepatic uptake of rosuvastatin are more likely to interact with this statin. Clinicians should be cautious when rosuvastatin is co-administered with vitamin K antagonists, cyclosporine (ciclosporin), gemfibrozil, and antiretroviral agents since a potential pharmacokinetic interaction with those drugs may increase the risk of toxicity. On the other hand, rosuvastatin combination treatment with fenofibrate, ezetimibe, omega-3-fatty acids, antifungal azoles, rifampin (rifampicin), or clopidogrel seems to be safe, as there is no evidence to support any pharmacokinetic or pharmacodynamic interaction of rosuvastatin with any of these drugs.Rosuvastatin therefore appears to be relatively safe and well tolerated, sharing the adverse effects that are considered class effects of statins. Practitioners of all medical practices should be alert when rosuvastatin is prescribed concomitantly with agents that may increase the risk of rosuvastatin-associated toxicity.

An overview of the extra-lipid effects of rosuvastatin.

Statins, in addition to their beneficial lipid modulation effects, exert a variety of several so-called “pleiotropic” actions that may result in clinical benefits. Rosuvastatin, the last agent of the class to be introduced, has proved remarkably potent in reducing low-density lipoprotein cholesterol levels. At present, no large-scale primary or secondary prevention clinical trials document either its long-term safety or its effectiveness in preventing cardiovascular events. A substantial number of experimental and clinical studies have indicate favorable effects of rosuvastatin on endothelial function, oxidized low-density lipoprotein, inflammation, plaque stability, vascular remodeling, hemostasis, cardiac muscle, and components of the nervous system. Available data regarding the effects of rosuvastatin on renal function and urine protein excretion do not seem to raise any safety concerns. Whether the established “pleiotropy” and/or lipid-lowering efficacy of rosuvastatin may translate into reduced morbidity and mortality remains to be shown in ongoing clinical outcome trials.

Medication-induced hypophosphatemia: a review

Hypophosphatemia (serum phosphorus concentration <2.5 mg/dl, 0.8 mmol/l), although rare in the general population, is commonly observed in hospitalized patients and may be associated with drug therapy. In fact, hypophosphatemia frequently develops in the course of treatment with drugs used in every-day clinical practice including diuretics and bisphosphonates. Proper diagnostic approach of patients with low serum phosphorus concentrations should involve a detailed medical history with special attention to the recent use of medications. The clinical manifestations of drug-induced hypophosphatemia are usually mild but might also be severe and potentially life-threatening. This review aims at a thorough understanding of the underlying pathophysiological mechanisms and risk factors of drug therapy-related hypophosphatemia thus allowing prevention and effective intervention strategies.