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......................................................................................................................................................................... 8.1.3 Other effects of statins Although reduction of LDL-C levels is the major effect of statins, a number of other, potentially important effects have been suggested (pleiotropic effects of statins).204,205 Among such effects that are potentially relevant for the prevention of CVD are the antiinflammatory and antioxidant effects of statin treatment. These effects have been shown in vitro and in experimental systems, but their clinical relevance remains unproven.18,206

8.1.3.1 Effect on cardiovascular morbidity and mortality. A large number of meta-analyses have been performed to analyse the effects of statins in populations and in subgroups.3436,38,51,207214 In the Cholesterol Treatment Trialists (CTT) meta-analysis of individual participant data (IPD) from >170 000 participants in 26 RCTs of a statin vs. control or a more vs. less intensive statin regimen,34 for each 1 mmol/L reduction in LDL-C, statin/more statin reduced major vascular events (MI, CAD death, or any stroke or coronary revascularization) by 22%, major coronary events by 23%, CAD death by 20%, total stroke by 17%, and total mortality by 10% over 5 years. The proportional effects (per mmol/L reduction in LDL-C) on major vascular events were similar in all subgroups examined, so the absolute risk reduction was proportional to the absolute baseline risk. The relative benefits were half as large in the first year as compared with subsequent years. There was no increased risk for any non-CV cause of death, including cancer, in those allocated statins. The absolute benefit from statin treatment was lower in people in primary prevention, who are typically at lower risk.36,38,214,215 In the CTT meta-analysis of treatment in people with a low-risk of vascular disease,36 the relative risk reduction of major vascular events per mmol/L reduction in LDL-C was at least as large in low-risk individuals (i.e. in primary prevention). In those without a history of vascular disease, statin therapy reduced the risk of all-cause mortality by 9% per mmol/L reduction in LDL cholesterol. Similar results were reported in a Cochrane review in 2013.213 The West of Scotland Coronary Prevention Study (WOSCOPS) data were recently reanalysed, and demonstrated that even people without DM and a 10 year predicted ASCVD risk of <7.5% benefit from statin treatment. There was also a legacy effect with a mortality benefit of 18% in all-cause death over 20 years.216 Statins are effective for the prevention of ASCVD in the elderly, including those aged >75 years.217 Statins are not effective in a few specific groups, notably those with heart failure (HF) or patients receiving haemodialysis.214,218222 Current available evidence from meta-analyses suggests that the clinical benefit of statin treatment is largely a class effect, driven by the absolute LDL-C reduction; therefore, the type of statin used should reflect the treatment goals for a given patient.

The following scheme may be proposed. • Evaluate the total CV risk of the individual. • Determine the treatment goals (depending on current risk). • Involve the patient in decisions on CV risk management. • Choose a statin regimen and, where necessary, additional treatments (e.g. ezetimibe or PCSK9 inhibitors) that can meet the treatment goals (per cent and absolute value). • Response to statin treatment is variable, therefore uptitration of the statin dose may be required before additional LDL-lowering treatments are started. These are general criteria for the choice of drug. Factors such as the clinical condition of the patient, concomitant medications, drug tolerability, local treatment tradition, and drug cost will play major roles in determining the final choice of drug and dose.

Furthermore, the effects of statins on a number of other clinical conditions have been evaluated. For cancer, a meta-analysis of IPD from randomized trials has shown that statins do not have any significant effect on cancer, at least over a period of 5 years.223 Other conditions, such as dementia,224 hepatic steatosis,225 venous thromboembolism,226 atrial fibrillation,227,228 and polycystic ovary syndrome229 have also been studied, and no effect of statins on these conditions has been reliably demonstrated. The suggested effect on Alzheimer’s disease was recently reviewed in a Cochrane analysis reporting no conclusive effect from statins.230 Furthermore, neurocognitive functions were extensively investigated in the Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects (EBBINGHAUS) study231 and no excess risk was observed among patients on a statin regimen randomized to a PCSK9 mAb.

8.1.4 Adverse effects and interactions of statins Statins differ in their absorption, bioavailability, plasma protein binding, excretion, and lipophilicity. Evening administration is usually recommended. Lovastatin and simvastatin are prodrugs, whereas the other available statins are administered in their active form. Their bioavailability is relatively low, owing to a first-pass effect in the liver, and many statins undergo significant hepatic metabolism via cytochrome P450 (CYP) isoenzymes, except pravastatin, rosuvastatin, and pitavastatin. These enzymes are expressed mainly in the liver and gut wall. Although statins are generally very well tolerated, they do have some specific adverse effects on muscle, glucose haemostasis, and haemorrhagic stroke. However, there is also widespread misinformation about potential adverse effects, as reviewed recently.232,233

8.1.4.1 Adverse effects on muscle. Myopathy is the most clinically relevant adverse effect of statins. Among the risk factors for myopathy, it is particularly important that interaction with concomitant drug therapy is considered (see below). Rhabdomyolysis is the most severe form of statin-induced muscle damage, characterized by severe muscular pain, muscle necrosis, and myoglobinuria potentially leading to renal failure and death. In rhabdomyolysis, creatine kinase (CK) levels are elevated by >_10 times, and often >_40 times, the upper limit of normal (ULN).234 The frequency of rhabdomyolysis has been estimated to represent 13 cases/100 000 patient-years.235 Patients taking statin therapy frequently report muscle symptoms [so-called ‘statin-associated muscle symptoms’ (SAMS)], and in nonrandomized, observational studies, statins are associated with muscular pain and tenderness (myalgia) without CK elevation or major functional loss, with the reported frequency of SAMS in such studies varying between 1015% among statin-treated individuals.236238 However, in part because individuals in observational studies are not blind to the treatment they are receiving, such studies are unreliable when used to assess the adverse effects of statins.233 In contrast, in blinded randomized trials of statins vs. placebo there is no, or only a Downloaded from academic.oup.com/eurheartj/article/41/1/111/5556353 by guest on 07 October 2026