Elsevier

Atherosclerosis

Volume 306, August 2020, Pages 33-40
Atherosclerosis

Quantitative evaluation of statin effectiveness versus intolerance and strategies for management of intolerance

https://doi.org/10.1016/j.atherosclerosis.2020.06.023Get rights and content

Highlights

  • From published controlled studies of statins, more than 75 patients need treatment with statin therapy for 10 years to experience a minor reversible side effect attributable to the statin.

  • The number of patients needing statin treatment to prevent one atherosclerotic cardiovascular disease (ASCVD) event over 10 years is between 3 and 61 depending on ASCVD risk and pre-treatment LDL cholesterol.

  • Statin adverse events of equivalent severity to ASCVD occurr with a frequency of <0.133% over 10 years eroding statin benefit minimally.

  • The most severe complication of SI is discontinuation of effective cholesterol-lowering treatment in patients who might otherwise benefit.

  • When statin intolerance (SI) is encountered, re-challenge is recommended with a statin with the potential to reach the appropriate therapeutic target.

Abstract

Background and aims

There is disquiet about statin effectiveness and side effects in both the medical and lay media.

Methods

We searched the literature for reports on the incidence of statin intolerance (SI) in which control rates of similar events were also recorded. The number of people who must receive treatment (NNT) to prevent one atherosclerotic cardiovascular disease (ASCVD) event at 5–50% 10-year risk and LDL cholesterol 2–7 mmol/l was compared with the number of those who would experience harm attributable to statin (NNH). Using a similar method, the effectiveness of various strategies to overcome SI in preventing CVD was then compared.

Results

Observational studies with non-randomised control groups report higher rates of statin adverse events than randomised trials. Overall, at least 75 patients must be treated for one to experience a side effect. In contrast, the NNT to prevent one ASCVD event with statins as monotherapy or in combination with other cholesterol-lowering medications to achieve at least 50% decrease in LDL cholesterol and <1.8 mmol/l was between 3 and 61, depending on risk and LDL cholesterol. NNH for adverse events of severity equivalent to ASCVD was >750 (<0.1333%).

When SI is encountered, the most effective current management for most patients in terms of ASCVD reduction is to rechallenge with low dose potent statin and then up-titrate until the cholesterol target has been achieved with, if necessary, the addition of ezetimibe 10 mg daily.

Conclusions

The most severe complication of SI is discontinuation of effective cholesterol-lowering treatment in patients who, by virtue of their CVD risk and cholesterol level, might otherwise benefit.

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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