Adverse effects of statin therapy: perception vs. the evidence - focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract

Aims: To 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 results: A 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. Conclusion: Long-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

Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel

Aims To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD). Methods and results We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects. Conclusion Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.Peer reviewe

Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management

Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (≥1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal

Successful Pregnancy by in Vitro Fertilization After Mustard Operation for Transposition of the Great Arteries

Scopu

Cardiac Autonomic Responses to Exercise Testing in Patients with Chronic Obstructive Pulmonary Disease

ScopusTr-Dizi

Five year follow-up of patients with high cardiovascular risk in the Turkish population. What are the predictors of highest cardiovascular risk?

Background: Despite the overwhelming evidence from clinical trials showing that preventive measures recommended by recent guidelines significantly reduce mortality, the implementation rate in patients with high cardiovascular risk is still far from optimal. Methods: A total of 5600 patients with a high cardiovascular risk were invited to participate however 3331 (59%) agreed to a five year follow-up in a multicenter, observational study. Primary end-points included death, myocardial infarction, stroke and optimal medication use over 5 years. Results: Primary end-points including cardiovascular mortality were higher in patients with vascular disease (25.3% vs 15.1%, p < 0.001, and 13.5 vs 6.2%, p < 0.001, respectively) and it was doubled in 5 years. Presence of end organ damage further increased the incidence of primary end-point and cardiovascular mortality (30.6% vs 16.2%, p < 0.001 and 18.1% vs 6.8%, p < 0.001, respectively). The optimal preventive treatment (statin, renin-angiotensin system blocker, beta-blocker and antiplatelet) rate was low and did not change significantly in 5 years, although the consistent use of angiotensin-converting enzyme inhibitor seemed to be a protective predictor of cardiovascular mortality. Conclusion: In this high risk Turkish population, mortality and morbidity in the medium to long term were high and the implementation rate of optimal preventive treatment unacceptably low. The highest risk subgroup was identified to be those with previous vascular disease/event and end organ damage requiring aggressive medical treatment. © 2008 World Heart Federation

Lipid lowering drug therapy in patients with coronary heart disease from 24 European countries: findings from the EUROASPIRE IV survey

Objective: Since dyslipidaemia is one of the most important risk factors for coronary heart disease (CHD), lowering of LDL-cholesterol (LDL-C) causes significant reduction in morbidity and mortality, particularly in patients with established CHD. The aim of this survey was to assess how statins were prescribed in CHD patients at discharge after a coronary event from hospitals throughout Europe and how the intake of these drugs was reported by the patients when they were seen more than one year later in relationship with their achieved LDL-C levels. Methods: 6648 CHD patients' data from centres in 24 European countries were gathered using standardized methods. Lipid measurements were performed in one central laboratory. Patients were divided in three groups: high-intensity statin therapy, moderate or low intensity statin therapy and no statin therapy at all. Results: 90.4% CHD patients were on statin therapy at the time of discharge from the hospital which decreased to 86% one year later. Only 37.6% of these patients were prescribed a high-intensity statin at discharge which even decreased to 32.7% later. In only 6 countries (all of them high-income countries) the number of patients on a high-intensity statin therapy increased substantially after the hospital discharge. It is worrying that statin therapy was discontinued in 11.6% and that only 19.3% of all CHD patients achieved target values of LDL-C < 1.8 mmol/L at the time of interview. Conclusions: Too many CHD patients with dyslipidaemia are still inadequately treated and most of these patients on statin therapy are not achieving the treatment targets. Therapeutic control of LDL-C is clearly related to the intensity of lipid lowering drug regimen after the CHD event indicating that a considerable potential still exists throughout Europe to reduce CHD mortality and morbidity rates through more efficient LDL-C lowering