Michael S. Kostapanos

Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis.

CONTEXT Considerable controversy exists regarding the association of omega-3 polyunsaturated fatty acids (PUFAs) and major cardiovascular end points. OBJECTIVE To assess the role of omega-3 supplementation on major cardiovascular outcomes. DATA SOURCES MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials through August 2012. STUDY SELECTION Randomized clinical trials evaluating the effect of omega-3 on all-cause mortality, cardiac death, sudden death, myocardial infarction, and stroke. DATA EXTRACTION Descriptive and quantitative information was extracted; absolute and relative risk (RR) estimates were synthesized under a random-effects model. Heterogeneity was assessed using the Q statistic and I2. Subgroup analyses were performed for the presence of blinding, the prevention settings, and patients with implantable cardioverter-defibrillators, and meta-regression analyses were performed for the omega-3 dose. A statistical significance threshold of .0063 was assumed after adjustment for multiple comparisons. DATA SYNTHESIS Of the 3635 citations retrieved, 20 studies of 68,680 patients were included, reporting 7044 deaths, 3993 cardiac deaths, 1150 sudden deaths, 1837 myocardial infarctions, and 1490 strokes. No statistically significant association was observed with all-cause mortality (RR, 0.96; 95% CI, 0.91 to 1.02; risk reduction [RD] -0.004, 95% CI, -0.01 to 0.02), cardiac death (RR, 0.91; 95% CI, 0.85 to 0.98; RD, -0.01; 95% CI, -0.02 to 0.00), sudden death (RR, 0.87; 95% CI, 0.75 to 1.01; RD, -0.003; 95% CI, -0.012 to 0.006), myocardial infarction (RR, 0.89; 95% CI, 0.76 to 1.04; RD, -0.002; 95% CI, -0.007 to 0.002), and stroke (RR, 1.05; 95% CI, 0.93 to 1.18; RD, 0.001; 95% CI, -0.002 to 0.004) when all supplement studies were considered. CONCLUSION Overall, omega-3 PUFA supplementation was not associated with a lower risk of all-cause mortality, cardiac death, sudden death, myocardial infarction, or stroke based on relative and absolute measures of association.

Differential Effect of Hypolipidemic Drugs on Lipoprotein-Associated Phospholipase A2

Objective— Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a predictor for incident atherosclerotic disease. We investigated the effect of 3 hypolipidemic drugs that exert their action through different mechanisms on plasma and lipoprotein-associated Lp-PLA2 activity and mass. Methods and Results— In 50 patients with Type IIA dyslipidemia were administered rosuvastatin (10 mg daily), whereas in 50 Type IIA dyslipidemic patients exhibiting intolerance to previous statin therapy were administered ezetimibe as monotherapy (10 mg daily). Fifty patients with Type IV dyslipidemia were given micronised fenofibrate (200 mg daily). Low- and high-density lipoprotein (LDL and HDL, respectively) subclass analysis was performed electrophoretically, whereas lipoprotein subfractions were isolated by ultracentrifugation. Ezetimibe reduced plasma Lp-PLA2 activity and mass attributable to the reduction in plasma levels of all LDL subfractions. Rosuvastatin reduced enzyme activity and mass because of the decrease in plasma levels of all LDL subfractions and especially the Lp-PLA2 on dense LDL subfraction (LDL-5). Fenofibrate preferentially reduced the Lp-PLA2 activity and mass associated with the VLDL+IDL and LDL-5 subfractions. Among studied drugs only fenofibrate increased HDL-associated Lp-PLA2 (HDL-Lp-PLA2) activity and mass attributable to a preferential increase in Lp-PLA2 associated with the HDL-3c subfraction. Conclusion— Ezetimibe, rosuvastatin, and fenofibrate reduce Lp-PLA2 activity and mass associated with the atherogenic apoB-lipoproteins. Furthermore, fenofibrate improves the enzyme specific activity on apoB-lipoproteins and induces the HDL-Lp-PLA2. The clinical implications of these effects remain to be established.

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.

Treating to target patients with primary hyperlipidaemia:comparison of the effects of ATOrvastatin and ROSuvastatin (the ATOROS study)

ABSTRACT Objectives: In a 24-week, open-label, randomized, parallel-group study, we compared the efficacy and metabolic effects, beyond low density lipoprotein cholesterol (LDL-C)-lowering, of atorvastatin (ATV) and rosuvastatin (RSV) in cardiovascular diseasefree subjects with primary hyperlipidaemia, treated to an LDL-C target (130 mg/dL). Methods: After a 6‐week dietary lead-in period, patients were randomized to RSV 10 mg/day ( n = 60) or ATV 20 mg/day ( n = 60). After 6 weeks on treatment the dose of the statin was increased (to RSV 20 mg/day or ATV 40 mg/day) if the treatment goal was not achieved. A control group of healthy volunteers ( n = 60) was also included for the validation of baseline serum and urinary laboratory parameters. The primary outcome was the percentage of patients reaching the LDL‐C goal; secondary outcomes were changes in lipid and non-lipid metabolic parameters. Results: A total of 45 patients (75.0%) in the RSV-treated group and 43 (71.7%) in the ATV-treated group achieved the treatment target at the initial dose. Both regimens were generally well tolerated and there were no withdrawals due to treatment-related serious adverse events. Similar significant reductions in total cholesterol, LDL‐C, apolipoprotein (apo) B, triglycerides, apoB/apoA1 ratio, fibrinogen and high-sensitivity C‐reactive protein levels were seen. RSV had a significant high density lipoprotein cholesterol (HDL‐C)-raising effect and showed a trend towards increasing apoA1 levels. Glycaemic control and renal function parameters were not influenced by statin therapy. ATV, but not RSV, showed a significant hypouricaemic effect. Conclusions: RSV and ATV were equally efficacious in achieving LDL‐C treatment goals in patients with primary hyperlipidaemia at the initial dose and following dose titration. RSV seems to have a significantly higher HDL‐C-raising effect, while ATV lowers serum uric acid levels.

Do Statins Beneficially or Adversely Affect Glucose Homeostasis

The effect of statin treatment on glucose metabolism and the risk of diabetes remains an issue of controversy. Since statins are drugs commonly prescribed for the prevention of cardiovascular disease even in patients with prediabetes or diabetes, it is of great importance to identify the role of statin treatment on glucose homeostasis. In this review, we have scrutinized available data with regard to the effect of every drug of the class on glycemic outcomes. Experimental data describing mechanisms through which these drugs potentially modify the metabolism of carbohydrates have been described. In order to identify statins which may be preferentially used to improve parameters of glycemic control, studies comparing different agents of this class as to their effect on glucose homeostasis have been discussed. According to experimental studies statin lipophilicity as well as the potential to inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase should be regarded as prognostic factors of an adverse impact of statin treatment on carbohydrate metabolism. On the other hand, the hypotriglyceridemic capacity, the endothelial-dependent increase in pancreatic islet blood flow, the anti-inflammatory properties along with the capacity of statins to alter circulating levels of several adipokines known to affect glucose homeostasis, including adiponectin, leptin, visfatin and resistin, may beneficially alter glycemic status. In clinical trials, a beneficial, neutral or adverse impact on glycemic control of different populations has been ascribed to various statins. From all drugs of the class pravastatin seems to beneficially affect glucose metabolism and decrease the risk of diabetes. Controversial findings have come to the fore with regard to other statins commonly prescribed in the clinical setting, including rosuvastatin, atorvastatin and simvastatin. More data are needed to clarify the exact role of lovastatin, fluvastatin and the newest statin pitavastatin on carbohydrate metabolism. Comparison trials suggest a potential preferable effect of the hydrophilic statins pravastatin, rosuvastatin and pitavastatin as compared to lipophilic components of the class, including atorvastatin and simvastatin.

Comparison of the effects of simvastatin vs. rosuvastatin vs. simvastatin/ezetimibe on parameters of insulin resistance.

Background:  Statin treatment may be associated with adverse effects on glucose metabolism. Whether this is a class effect is not known. In contrast, ezetimibe monotherapy may beneficially affect insulin sensitivity.

The effects of orlistat and fenofibrate, alone or in combination, on high-density lipoprotein subfractions and pre-beta1-HDL levels in obese patients with metabolic syndrome.

Objective:  We assessed the effect of orlistat and fenofibrate, alone or in combination, on plasma high‐density lipoprotein (HDL) subfractions and plasma pre‐beta1‐HDL levels in overweight and obese subjects with metabolic syndrome (MetS).

Rosuvastatin treatment is associated with an increase in insulin resistance in hyperlipidaemic patients with impaired fasting glucose

Aim of the study:  The increase in physician‐reported diabetes following rosuvastatin treatment in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin study has raised concerns whether this statin exerts a detrimental effect on glucose metabolism. We assessed the effect of rosuvastatin treatment across dose range on glucose homeostasis in hyperlipidaemic patients with impaired fasting glucose (IFG), who are at high risk to develop diabetes mellitus.

Current role of fenofibrate in the prevention and management of non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a common health problem with a high mortality burden due to its liver- and vascular-specific complications. It is associated with obesity, high-fat diet as well as with type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS). Impaired hepatic fatty acid (FA) turnover together with insulin resistance are key players in NAFLD pathogenesis. Peroxisome proliferator-activated receptors (PPARs) are involved in lipid and glucose metabolic pathways. The novel concept is that the activation of the PPARα subunit may protect from liver steatosis. Fenofibrate, by activating PPARα, effectively improves the atherogenic lipid profile associated with T2DM and MetS. Experimental evidence suggested various protective effects of the drug against liver steatosis. Namely, fenofibrate-related PPARα activation may enhance the expression of genes promoting hepatic FA β-oxidation. Furthermore, fenofibrate reduces hepatic insulin resistance. It also inhibits the expression of inflammatory mediators involved in non-alcoholic steatohepatitis pathogenesis. These include tumor necrosis factor-α, intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Consequently, fenofibrate can limit hepatic macrophage infiltration. Other liver-protective effects include decreased oxidative stress and improved liver microvasculature function. Experimental studies showed that fenofibrate can limit liver steatosis associated with high-fat diet, T2DM and obesity-related insulin resistance. Few studies showed that these benefits are also relevant even in the clinical setting. However, these have certain limitations. Namely, these were uncontrolled, their sample size was small, fenofibrate was used as a part of multifactorial approach, while histological data were absent. In this context, there is a need for large prospective studies, including proper control groups and full assessment of liver histology.