No abstract

Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7–29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.

Abstract-Statin monotherapy is generally well tolerated, with a low frequency of adverse events. The most important adverse effects associated with statins are myopathy and an asymptomatic increase in hepatic transaminases, both of which occur infrequently. Because statins are prescribed on a long-term basis, however, possible interactions with other drugs deserve particular attention, as many patients will typically receive pharmacological therapy for concomitant conditions during the course of statin treatment.

The beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on coronary events have generally been attributed to their hypocholesterolaemic properties. However, as mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are necessary for cell proliferation and other important cell functions, effects other than cholesterol reduction may explain the pharmacological properties of statins. In the present review, we discuss the current knowledge on the nonlipid-related effects of statins, with a special emphasis on their potential benefits in different diseases, such as atherosclerosis and cancer. The mechanism(s) responsible for their favourable properties are also reviewed.

AimsTo objectively appraise evidence for possible adverse effects of long-term statin therapy on glucose homeostasis, cognitive, renal and hepatic function, and risk for haemorrhagic stroke or cataract.Methods and resultsA literature search covering 2000–2017 was performed. The Panel critically appraised the data and agreed by consensus on the categorization of reported adverse effects. Randomized controlled trials (RCTs) and genetic studies show that statin therapy is associated with a modest increase in the risk of new-onset diabetes mellitus (about one per thousand patient-years), generally defined by laboratory findings (glycated haemoglobin ≥6.5); this risk is significantly higher in the metabolic syndrome or prediabetes. Statin treatment does not adversely affect cognitive function, even at very low levels of low-density lipoprotein cholesterol and is not associated with clinically significant deterioration of renal function, or development of cataract. Transient increases in liver enzymes occur in 0.5–2% of patients taking statins but are not clinically relevant; idiosyncratic liver injury due to statins is very rare and causality difficult to prove. The evidence base does not support an increased risk of haemorrhagic stroke in individuals without cerebrovascular disease; a small increase in risk was suggested by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels study in subjects with prior stroke but has not been confirmed in the substantive evidence base of RCTs, cohort studies and case–control studies.ConclusionLong-term statin treatment is remarkably safe with a low risk of clinically relevant adverse effects as defined above; statin-associated muscle symptoms were discussed in a previous Consensus Statement. Importantly, the established cardiovascular benefits of statin therapy far outweigh the risk of adverse effects.

Intraplaque release of inflammatory cytokines from macrophages is implicated in atherogenesis by inducing the proliferation and migration of media smooth muscle cells (SMCs). PCSK9 is present and released by SMCs within the atherosclerotic plaque but its function is still unknown. In the present study, we tested the hypothesis that PCSK9 could elicit a pro-inflammatory effect on macrophages. THP-1-derived macrophages and human primary macrophages were exposed to different concentrations (0.250 ÷ 2.5 µg/ml) of human recombinant PCSK9 (hPCSK9). After 24 h incubation with 2.5 µg/ml PCSK9, a significant induction of IL-1β, IL-6, TNF-α, CXCL2, and MCP1 mRNA, were observed in both cell types. Co-culture of THP-1 macrophages with HepG2 overexpressing hPCSK9 also showed the induction of TNF-α (2.4 ± 0.5 fold) and IL-1β (8.6 ± 1.8 fold) mRNA in macrophages. The effect of hPCSK9 on TNF-α mRNA in murine LDLR−/− bone marrow macrophages (BMM) was significantly impaired as compared to wild-type BMM (4.3 ± 1.6 fold vs 31.1 ± 6.1 fold for LDLR−/− and LDLR+/+, respectively). Finally, a positive correlation between PCSK9 and TNF-α plasma levels of healthy adult subjects (males 533, females 537) was observed (B = 8.73, 95%CI 7.54 ÷ 9.93, p < 0.001). Taken together, the present study provides evidence of a pro-inflammatory action of PCSK9 on macrophages, mainly dependent by the LDLR.

Gender-specific medicine is the study of how diseases differ between men and women in terms of prevention, clinical signs, therapeutic approach, prognosis, psychological and social impact. It is a neglected dimension of medicine. In this review we like to point out some major issues in five enormous fields of medicine: cardiovascular diseases (CVDs), pharmacology, oncology, liver diseases and osteoporosis.CVDs have been studied in the last decades mainly in men, but they are the first cause of mortality and disability in women. Risk factors for CVD have different impacts in men and women; clinical manifestations of CVD and the influence of drugs on CVD have lot of gender differences. Sex-related differences in pharmacokinetics and pharmacodynamics are also emerging. These differences have obvious relevance to the efficacy and side effect profiles of various medications in the two sexes. This evidence should be considered for drug development as well as before starting any therapy. Gender disparity in cancer incidence, aggressiveness and prognosis has been observed for a variety of cancers and, even if partially known, is underestimated in clinical practice for the treatment of the major types of cancer. It is necessary to systematize and encode all the known data for each type of tumor on gender differences, to identify where this variable has to be considered for the purposes of the prognosis, the choice of treatment and possible toxicity. Clinical data suggest that men and women exhibit differences regarding the epidemiology and the progression of certain liver diseases , i.e., autoimmune conditions, genetic hemochromatosis, non-alcoholic steatohepatitis and chronic hepatitis C. Numerous hypotheses have been formulated to justify this sex imbalance including sex hormones, reproductive and genetic factors. Nevertheless, none of these hypothesis has thus far gathered enough convincing evidence and in most cases the evidence is conflicting. Osteoporosis is an important public health problem both in women and men. On the whole, far more epidemiologic, diagnostic and therapeutic studies have been carried out in women than in men. In clinical practice, if this disease remains underestimated in women, patients ' and physicians ' awareness is even lower for male osteoporosis, for which diagnostic and therapeutic strategies are at present less defined.In conclusion this review emphasizes the urgency of basic science and clinical research to increase our understanding of the gender differences of diseases.

No abstract