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Zafrir B.,Lady Davis Carmel Medical Center | Jain M.,University of California at San Diego
Cardiovascular Drugs and Therapy | Year: 2014

Lipid-lowering therapies constitute an essential part in the treatment and prevention of cardiovascular diseases and are consistently shown to reduce adverse cardiovascular outcomes in wide-scale populations. Recently, there is increased awareness of the possibility that lipid-lowering drugs may affect glucose control and insulin resistance. This phenomenon is reported in all classes of lipid-modifying agents, with differential effects of distinct drugs. Since the prevalence of metabolic syndrome and diabetes is rising, and lipid-modifying therapies are widely used to reduce the cardiovascular burden in these populations, it is of importance to examine the relationship between lipid-lowering drugs, glycemic control and incident diabetes. In the current review we discuss the evidence, ranging from experimental studies to randomized controlled clinical trials and meta-analyses, of how lipid-modifying therapies affect glycemic control and insulin sensitivity. Cumulative data suggest that both statins and niacin are associated with increased risk of impaired glucose control and development of new-onset diabetes, as opposed to bile-acid sequestrants which display concomitant moderate lipid and glucose lowering effects, and fibrates (particularly the pan-PPAR agonist bezafibrate) which may produce beneficial effects on glucose metabolism and insulin sensitivity. Ezetimibe is implied to ameliorate metabolic markers such as hepatic steatosis and insulin resistance, with yet little support from clinical trials, while fish oils which in experimental studies produce favorable effects on insulin sensitivity, although studied extensively, continue to show inconclusive effects on glucose homeostasis in patients with diabetes. Suggested mechanisms of how lipid-modifying agents affect glucose control and their clinical implications in this context, are summarized. © 2014 Springer Science+Business Media New York.

Preis M.,Dartmouth Hitchcock Medical Center | Preis M.,Lady Davis Carmel Medical Center | Lowrey C.H.,Dartmouth Hitchcock Medical Center
American Journal of Hematology | Year: 2014

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder that is often suspected in a patient presenting with non-immune hemolytic anemia associated with pancytopenia or venous thrombosis. This disorder is a consequence of acquired somatic mutations in the phosphatidylinositol glycan class A (PIG-A) gene in the hematopoietic stem cells (HSC) of patients. The presence of these mutations leads to production of blood cells with decreased glycosyl phosphatidylinositol-anchored cell surface proteins, making red blood cells derived from the clone more sensitive to complement mediated hemolysis. The diagnosis of PNH may be difficult in some cases due a low proportion of PNH cells in the blood and occasionally due to difficulties in selecting the most appropriate diagnostic studies. The latest generation of tests allow for detection of very small populations of PNH cells, for following the natural course and response to therapy of the disease, and for helping to decide when to initiate therapy with monoclonal antibody targeting the terminal complement protein C5 (Eculizumab), anticoagulation, and in some cases allogeneic HSC transplant. In this article, we review the different diagnostic tests available to clinicians for PNH diagnosis. © 2013 Wiley Periodicals, Inc.

Cooper T.J.,University of Stavanger | Guazzi M.,University of Milan | Al-Mohammad A.,Sheffield Teaching Hospital | Amir O.,Lady Davis Carmel Medical Center | And 3 more authors.
European Journal of Heart Failure | Year: 2013

Aims: Heart failure (HF) is a major clinical problem and, despite advances in both pharmacological and device therapy, the mortality remains high and quality of life poor. Over the last decade there has been growing interest in using phosphodiesterase-5 (PDE-5) inhibitors in HF associated with group 2 pulmonary hypertension (PH), with benefits reported on pulmonary haemodynamic and functional status in single-centre trialsMethodsThe Sildenafil in Heart Failure (SilHF) trial is a randomized, placebo-controlled multinational trial designed to assess efficacy and tolerability of PDE-5 inhibition with sildenafil (target dose 40 mg three times per day) in 210 patients with HF, New York Heart Association (NYHA) functional class II or III, and evidence of group 2 PH. The co-primary endpoints are patient global assessment and the 6 min walk test. Secondary endpoints include NYHA functional class and the quality of life tools Euro QoL 5D and the Kansas City questionnaire. Patients will be followed up for 6 months.PerspectiveThe authors hypothesize that PDE-5 inhibition can improve exercise capacity and symptoms with acceptable tolerability in patients with HF and group 2 PH © 2012 The Author.

Cannon C.P.,Harvard University | Blazing M.A.,Duke Clinical Research Institute DCRI | Giugliano R.P.,Harvard University | McCagg A.,Harvard University | And 14 more authors.
New England Journal of Medicine | Year: 2015

BACKGROUND: Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known. METHODS: We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke. The median follow-up was 6 years. RESULTS: The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P = 0.016). Rates of pre-specified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups. CONCLUSIONS: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit. Copyright © 2015 Massachusetts Medical Society.

Adir Y.,Lady Davis Carmel Medical Center | Harari S.,U.O. di Pneumologia e UTIR
Current Opinion in Pulmonary Medicine | Year: 2014

PURPOSE OF REVIEW: Severe pulmonary hypertension worsens the prognosis of patients with chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF). With the aim of better understanding the pathogenesis of this event and identifying the possible targets for therapeutic intervention, a great deal of clinical and translational research is now focused on this relevant field of medicine. RECENT FINDINGS: Some studies that were published last year have helped to better define the clinical and physiological profiles of patients with COPD or IPF and severe pulmonary hypertension. The importance of pulmonary rehabilitation was confirmed, particularly in patients with pulmonary hypertension associated with IPF. Information on the use of drugs approved for the treatment of pulmonary arterial hypertension is still very limited, because of some limitations and selection biases in the studies' design. New strategies (i.e. the use of fasudil or sepiapterin in pulmonary hypertension associated with IPF) have been evaluated in animal models. SUMMARY: Pulmonary hypertension in COPD or IPF may range from mild to severe. When pulmonary hypertension is more advanced, it can drive a poor outcome. Therefore, future studies should focus on this subset. © 2014 Wolters Kluwer Health | Lippincott Williams &Wilkins.

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