Quantitative evaluation of statin effectiveness versus intolerance and strategies for management of intolerance
Graphical abstract
Introduction
Statins are the most widely prescribed cholesterol-lowering drugs. There has been considerable controversy about the true incidence of side-effects of statins and how much these impair their therapeutic effectiveness [[1], [2], [3], [4], [5], [6], [7], [8], [9], [10]]. On the one hand, randomised controlled clinical trials report very low rates of even the most well authenticated side effects, such as myopathy [1,4,7], but on the other, in uncontrolled observational studies, muscle symptoms are reported in as many as 10–20% of statin recipients [[2], [3], [4], [5], [6], [7]]. Recently, there has been considerable disquiet about type 2 diabetes mellitus (T2DM) developing on statin treatment [8,9]. This has led to reluctance amongst certain physicians to prescribe statins, and spilling over into the lay press and social media has created considerable difficulty in persuading patients to take statins and to persevere with them [[11], [12], [13], [14]]. Quantitative comparisons between likely benefit and the possibility of adverse events due to statin treatment may improve the situation.
The benefit of statin therapy in terms of prevented atherosclerotic cardiovascular disease (ASCVD) events depends on the absolute ASCVD risk before statin treatment and the extent to which low density lipoprotein (LDL) cholesterol concentration is reduced, which is in turn dependent on its initial concentration [[15], [16], [17]]. The degree of LDL reduction depends not only on its level before statin treatment but also on the potency and dose of the particular statin chosen.
Estimates of the erosion of statin benefit attributable to side effects have thus far mainly been semi-quantitative [3,4,6,9,10]. They have often been subject to bias by inclusion of many people close to the treatment thresholds where benefit is limited: the full range of ASCVD risk and LDL cholesterol for which statins are used has not been adequately taken into account. Unless both CVD risk and LDL cholesterol are considered, the benefit to harm ratio may be underestimated. Here we calculate the balance between benefit and harms of receiving statin therapy, taking into account pre-treatment absolute ASCVD risk and LDL cholesterol and the extent of LDL cholesterol lowering achievable with various statins as monotherapy and in combination with the most commonly prescribed alternative, ezetimibe, to determine the most evidence-based approach to clinical management.
Section snippets
Data derivation
The incidence of statin side-effects and ASCVD events was obtained from reports in PubMed in which this was recorded in both controls and actively treated patients. We sought to identify randomised controlled trials (RCT) and observational studies in which controls were obtained from a similar demographic background. Three meta-analyses provided RCT data: the Cholesterol Treatment Trialists’ (CTT) Collaboration [18], Naci et al. [19] and Khan et al. [20] These provide summary data on 170,000
Adverse events
Our literature search provided consistent evidence in both randomised and non-randomised controlled investigations for three major groups of adverse events: myopathy, raised liver transaminases and type 2 diabetes mellitus (T2DM).
Myopathy
Table 1 shows the HR for clinically relevant increased CK in statin-treated patients. The CTT Collaboration [4] reported from meta-analyses that the excess incidence of myopathy (defined as muscle pain or weakness combined with large increases in serum CK activity,
Discussion
It has been suggested by some that the incidence of even minor statin side effects outweighs their benefit [2,3,[9], [10], [11], [12], [13], [14]]. Our analysis does not reveal any treatment category defined within major clinical guidelines in which the HR for adverse events, minor or major, is equivalent to the HR for reduced ASCVD risk. The overall NNH for statins even at their highest dose, as we have shown, is unlikely to be less than 75, which is to say that no more than 1.33% of patients
CRediT authorship contribution statement
Handrean Soran: Conceptualization, Writing - review & editing, Funding acquisition. Michael France: Writing - review & editing. Safwaan Adam: Software, Validation. Zohaib Iqbal: Software, Validation. Jan H. Ho: Software, Validation. Paul N. Durrington: Conceptualization, Formal analysis, Data curation, Writing - original draft.
Declaration of competing interest
HS and PND have served as consultants to pharmaceutical companies marketing lipid-lowering drugs, and have received travel expenses, payment for speaking at meetings and funding for research from some of these companies. MF, SA, ZI and JHH has no conflict of interest to declare.
Acknowledgements
The authors acknowledge support from Lipid Disease Fund, Manchester Comprehensive Local Research Network, and The National Institute for Health Research/Wellcome Trust Clinical Research Facility, United Kingdom.
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