Statin side effects are more troubling than a new paper admits

    12 September 2016

    A review published in the Lancet argues that the negative side effects of statins are widely exaggerated. (The paper, however, has its own flaws — see our expert analysis below).

    The review, led by the Clinical Trial Service Unit at the University of Oxford, looked at data on 10,000 patients who were taking an average of 40mg of statins daily over a period of five years. It was found that within the sample population there were between 50 and 100 cases of negative side effects such as muscle pain or liver damage.

    However, the drugs were found to lower cholesterol levels sufficiently to prevent over 1,000 ‘major cardiovascular events’ such as strokes and heart attacks in patients who had cardiovascular disease, and 500 in people who were merely at risk of the disease due to age or illness, out of the 10,000 patients looked at.

    Another finding of the review is that people who know they are taking statins are more likely to report negative side effects. In randomised blind trials, the incident level was lower.

    The study’s lead author, Professor Rory Collins, said: ‘Our review shows that the numbers of people who avoid heart attacks and strokes by taking statin therapy are very much larger than the numbers who have side effects with it.

    ‘In addition, whereas most of the side effects can be reversed with no residual effects by stopping the statin, the effects of a heart attack or stroke not being prevented are irreversible and can be devastating.

    ‘Consequently, there is a serious cost to public health from making misleading claims about high side effect rates that inappropriately dissuade people from taking statin therapy despite the proven benefits.’

    Instant analysis
    This comprehensive and elegantly written 30-page summary of the evidence appears at first sight to lay the statin controversy to rest once and for all. It does, however, raise several concerns.

    First, the conflicts of interest of the principal author Professor Collins are impressive. The Cholesterol Treatment Trialists’ Collaboration (CTTC) which he heads has not only received millions of pounds in funding from pharmaceutical companies but also refuses to release its data for independent third-party scrutiny.

    The co-authors of the review themselves contributed to the RCTs being reviewed. This is akin to getting architects who designed a building to then assess it for design and structural flaws. The long list of industry links revealed at the end of this paper is also concerning, as we know that trials funded by industry are more likely to reveal positive results.

    The results, though expressed clearly and unambiguously, are also incomplete in places.

    ‘Large-scale evidence from randomised trials shows that each 1 mmol/L reduction in LDL cholesterol with statin therapy produces a proportional reduction of about 25 per cent in the rate of major vascular events (coronary deaths, myocardial infarctions, strokes, and coronary revascularisations) during each year (after the first) that it continues to be taken. Consequently, lowering LDL cholesterol by 2 mmol/L reduces risk by about 45 per cent.’

    In direct terms, ‘lowering LDL cholesterol … for about five years in 10,000 patients would typically prevent major vascular events in about 1,000 (10 per cent) patients at high risk of heart attacks and strokes (eg, secondary prevention) and 500 (five per cent) patients at lower risk (eg, primary prevention)’.

    In other words, 90 per cent of patients with risk factors for cardiovascular disease, and 95 per cent of patients without, will gain no benefit from statin use over five years.

    Of those who gain benefit, the paper omits one very important point: the days of life gained when taking statins. According to a recent paper, an average of 3.4 and 4.1 additional days are gained when statins are taken for primary and secondary prevention respectively. This is hardly impressive.

    Most sceptics will acknowledge the utility of statins in patients who have already had a cardiovascular event like a heart attack (that is, secondary prevention), but for patients who have not had such an event, the evidence is far from compelling: 140 people with a five-year risk of less than 10 per cent need to be treated with statins for five years to prevent one heart attack or stroke. There is also no reduction in overall mortality or serious adverse events. This, of course, did not make its way into the paper.

    The coverage of the potential side effects is at first glance comprehensive, including many side effects that had not been looked at when Professor Collins defended the ‘low side-effect profile’ of statins in the face of criticism last year.

    However, the paper downplays the impact of some of these side effects. The rigour demonstrated when discussing the benefits is sadly not quite so obvious when discussing the risks. References are made to papers with too short a follow-up period in many cases to assess different complications, including cognitive or mood disorders.

    ‘Five years of treatment is expected to cause five cases of myopathy (muscle pain or weakness), 50–100 new cases of diabetes, and 5–10 haemorrhagic strokes, per 10,000 patients treated.

    ‘Absolute excesses of adverse events that are caused by statin therapy are not more than about 100–200 per 10,000 patients (ie, 1–2 per cent) treated for five years, and it is unlikely that large adverse effects on serious adverse events await discovery.’

    When we consider that 90 per cent of high-risk patients and 95 per cent of low-risk patients will not benefit from statins, this incidence of one to two per cent of patients experiencing side effects suddenly looks more profound, especially as diabetes and stroke cost the NHS billions of pounds a year.

    The incidence of myopathy appears low, but even so it can be troublesome and may prevent the kind of healthy physical activity that will itself decrease the risk of cardiac outcomes.

    In summary, this paper presents elegantly expressed and, at first glance, definitive data. We should not forget, however, that in the case of the definitive RCTs quoted, the data is derived from industry-sponsored trials, with no third-party oversight. Some might find this lack of transparency disturbing.

    A comparison between the reputed effectiveness of statins and lifestyle modifications — adopting a Mediterranean diet, for instance — is telling.

    Take-home message: don’t stop any medication without first consulting your physician.
    Research score: 4/5