High blood pressure. Causes, symptoms, treatments

Divergent effects of lithium and sodium valproate on brain-derived neurotrophic factor (BDNF) production in human astrocytoma cells at therapeutic concentrations.

2017-05-03

Reciprocal relationships between endothelial dysfunction and insulin resistance suggest that therapies improving endothelial dysfunction will simultaneously improve insulin sensitivity and other metabolic parameters. However, previous studies with some statins either did not alter insulin sensitivity or promoted insulin resistance despite significant improvements in endothelial dysfunction and decreases in circulating pro-inflammatory markers. This may be due to pleiotropic or off-target effects of some statins to cause insulin resistance by diverse mechanisms unrelated to endothelial dysfunction. Indeed, there is evidence of other differential metabolic actions of distinct statins including effects on hydroxymethylglutaryl-CoA reductase inhibition, isoprotenoid synthesis, calcium release, glucose transport, insulin secretion, and/or insulin resistance. Pravastatin increases expression of adiponectin mRNA, enhances adiponectin secretion, increases plasma levels of adiponectin, and enhances insulin sensitivity in mice and humans. Clinical studies including large scale randomized controlled trials demonstrate potential differences between individual statins, with pravastatin promoting risk reduction for new onset of diabetes. Conversely, other statins including atorvastatin, rosuvastatin, and simvastatin all promote significant increase in this risk. Given the frequent concordance of metabolic diseases including diabetes, obesity, and metabolic syndrome with cardiovascular diseases associated with hyperlipidemia, it is important to understand the potential metabolic risks and benefits of therapies with distinct statins. In this review, we discuss these differential effects of statins on metabolic homeostasis and insulin sensitivity.

Itraconazole produced modest increases in rosuvastatin plasma concentrations, which are unlikely to be of clinical relevance. The results support previous in vitro metabolism findings that CYP3A4 plays a minor role in the limited metabolism of rosuvastatin.

Most patients (81.3%) were at high risk for CVD. The most frequently used statin was atorvastatin (42.8%), followed by simvastatin (27.6%) and rosuvastatin (22.8%). Only 35.5% patients achieved low density lipoprotein-cholesterol treatment target. Patients treated with more potent statins had better results. A total of 22.3% of patients had high density lipoprotein-cholesterol below 1.0 mmol/L (~40 mg/dL) for men and below 1.2 (~45 mg/dL) for women and 46.4% had triglycerides above 1.7 mmol/L (~150 mg/dL) but there were no significant differences between statins in improving these parameters. Most of the patients on more potent statins were not advised by their cardiologists to change the type or dosage of statin, which was more common in patients on less potent statins.

The increased incidence of diabetes with rosuvastatin treatment in Justification for the Use of Statins in Primary Prevention: an intervention Trial Evaluating Rosuvastatin (JUPITER) reignited attention on the link between statin therapy and diabetes. The JUPITER findings are supported by two recent meta-analyses of large-scale placebo-controlled and standard care-controlled trials, which, respectively, observed a 9% [odds ratio 1.09; 95% confidence interval (CI) 1.02-1.17] and 13% (risk ratio 1.13; 95% CI 1.03-1.23) increased risk for incident diabetes associated with statin therapy. However, the underlying mechanisms for this association remain unclear. Experimental evidence supports a paradigm implicating inhibition of β-cell glucose transporters, delayed ATP production, pro-inflammatory and oxidative β-cell effects of plasma-derived cholesterol, inhibition of calcium channel-dependent insulin secretion, and β-cell apoptosis.

Dyslipidemia is a risk factor for premature cardiovascular morbidity and mortality in renal transplant recipients (RTRs). Pharmacotherapy with mTOR inhibitors aggravates dyslipidemia, thus necessitating lipid-lowering therapy with fluvastatin, pravastatin, or atorvastatin. These agents may not sufficiently lower lipid levels, and therefore, a more potent agent like rosuvastatin maybe needed.

The potent statin improves baPWV and carotid stiffness β, in addition to CIMT (surrogate markers of coronary artery disease), in postmenopausal women with low-risk dyslipidemia. Further studies to clarify the common mechanisms underlying the link between cholesterol-lowering therapy and atherosclerosis in postmenopausal women are required.

Rosuvastatin is a new statin with a great number of pharmacological benefits related to the capacity of modifying favorably the lipid profile but also for the selective binding with 3-hydroxy-3-methylglutaryl coenzyme A reductase, relative hydrophilic properties and selectivity for hepatic cells. Rosuvastatin demonstrated to be more efficacious in reducing LDL cholesterol levels than other statins and to be capable of increasing HDL cholesterol levels. It is well tolerated in a wide range of dosages maintaining its effectiveness. Many trials are ongoing with the aim to evaluate not only the efficacy of rosuvastatin in terms of surrogate endpoints but also in terms of cardiovascular morbidity and mortality. The usefulness of rosuvastatin will be evaluated also in selective patient populations affected by advanced renal disease or chronic heart failure. Two relevant research projects have been started recently, the GALAXY Programme, designed for evaluating the efficacy of rosuvastatin in atherosclerosis and ischemic heart disease and the GISSI-HF trial planned with the aim of testing the efficacy of this statin on morbidity and mortality in chronic heart failure and investigating the pharmacological effects on the pathophysiological mechanisms of heart failure.