Statins in older adults

Statin use in people over 65 years of age is high.

A meta-analysis of older patients included in randomised trials found good evidence that statins reduce vascular events and mortality in people with existing coronary heart disease.

In older adults, exposure to higher doses of statins or higher potency statins does not increase their effectiveness, but does increase the risk of adverse effects such as myopathy and cognitive impairment.

Increasing age is a risk factor for adverse events with statins. Older patients may be less resilient to these effects.

Older patients may have more comorbidities and be taking more concomitant drugs than the study populations in statin trials. Applying the evidence for statins to older individuals therefore requires frequent review and consideration of the therapeutic goals and potential benefits and harms.

Statins (hydroxymethylglutaryl coenzyme A reductase inhibitors) are the most commonly used cholesterol-lowering drugs. They are being taken by more than 40% of Australians over 65 years of age.¹ Although the prevalence of statin use increases with age, the balance between evidence of their benefits and the risk of adverse effects such as myopathy or impaired cognition may change. In extreme old age, preserving function and avoiding frailty and injury in the short term may become more important than longer term goals such as preventing future cardiovascular events or even extending life.

Older people have an increased risk of cardiovascular disease. However, epidemiological studies suggest that the relative risk for coronary heart disease associated with high cholesterol decreases with age.² In addition, in old age, there is an inverse relationship between high cholesterol and the risk of stroke³ and there are conflicting data on the relationship between high cholesterol and non-cardiovascular mortality.

Cardiovascular events

Statins are most beneficial for preventing cardiovascular events in patients who already have coronary heart disease. A meta-analysis of patients with existing disease (aged 65–82 years) found that all-cause mortality was significantly lower with statins than with placebo (15.6% vs 18.7%) over five years.⁴ This equates to a number needed to treat of 28 over five years to save one life. Approximately 25% of patients in the trials were female. Frail older patients may have been excluded because of comorbidity or organ dysfunction.

The role of statins in primary prevention of cardiovascular disease in older people is unclear. Their effects seem to increase over five years, with only minimal benefits over placebo seen in the first year.⁵ It is therefore important to consider the patient's probable lifespan when deciding whether to start or continue a statin.

Studies of secondary prevention in patients with cerebrovascular disease suggest that statins are associated with a decrease in recurrent ischaemic stroke but an increase in haemorrhagic stroke.⁵

Other clinical outcomes

There are very limited data assessing the impact of statins on other outcomes such as frailty, physical and cognitive function and institutionalisation. Epidemiological data suggest that statins are not associated with an increase in the risk of developing frailty.⁶ This is a condition of increased vulnerability to external stressors and an independent risk factor for adverse clinical outcomes. Symptoms and signs of frailty include complaints of fatigue, unintentional weight loss and low grip strength. We recently investigated the relationship between statins and institutionalisation and mortality, according to frailty in community-dwelling men aged 70 years and over. There was no association between statin use and institutionalisation or death in older men. Statins did not appear to improve mortality or delay institutionalisation.⁷

Observational studies report conflicting results on the association of statins and muscle mass, strength and function. Results of randomised trials on the effects of statins on cognition are conflicting.⁸ In patients with dementia, statins do not significantly affect cognitive decline, global function, behaviour or activities of daily living.⁹ A recent pilot study of statin withdrawal showed that statin reduction is associated with improvements in cognitive function in patients with Alzheimer's disease. Moreover, rechallenge with statins was associated with a decline in cognition function.¹⁰

Statin dose

Meta-analyses suggest that 80% of the lipid-lowering effect of statins occurs at half the maximal statin dose.¹¹ In older patients, the efficacy of statins for secondary prevention of acute myocardial infarction and death appears to be a class effect, with no difference observed between high or low potency statins.¹² Surrogate markers, such as low density lipoprotein cholesterol, should be interpreted with care in older people. Epidemiological data indicate that lowering low density lipoprotein cholesterol has a smaller impact on the relative risk of coronary heart disease as age increases.¹¹

Adverse effects appear to vary between types and doses of statins. The risk of common events such as myopathy and liver enzyme elevations increases with statin potency and exposure. The degree of statin exposure (area under the concentration–time curve) depends on dose, drug interactions and patient factors including genetic polymorphisms. With ageing, there is a decrease in body size, particularly in muscle mass, and in hepatic and renal function, so the same dose will result in a greater degree of exposure in older patients.

Muscle symptoms

The most common adverse effects that limit treatment with statins are muscle symptoms. These include myalgia, myositis and rhabdomyolysis (Table 1). The risks of muscle symptoms are related to the dose of the statin.

The risk of muscle damage with statins increases with age over 70 years, and with age-associated factors such as multiple medicines use, comorbidity and sarcopenia (low skeletal muscle mass and function) (Table 2).

Statin myopathy is likely to have a greater impact in older people, with limited musculoskeletal reserve, than in younger people, who generally have more muscle mass and strength and better mobility.

Liver enzyme increases

Elevated hepatic transaminases occur in 0.5–2% of patients treated with statins and are dose-dependent. Their clinical significance is uncertain and progression to liver failure is very rare. The transaminases may normalise if the statin dose is reduced and elevation does not always recur if the patient resumes the statin.¹³ The effect of ageing on the risk of hepatic damage with statins is not known. In old age the risk of drug-induced liver injury appears to increase for some drugs, such as non-steroidal anti-inflammatory drugs, and decrease for others such as paracetamol. While drug-induced liver injury is commonly defined as moderate with an increase in liver enzymes over 2.5 times the upper limit of normal and severe at 5 times the upper limit of normal, these thresholds may be lower in older people because of their 30% decrease in liver mass.

Other adverse effects

The commonest adverse effects observed with statins are gastrointestinal, such as abdominal pain, constipation and nausea. A rare but serious adverse event is reversible peripheral neuropathy.

An increased risk of diabetes with statins was recently reported. Diabetes has also been found to be more common in older patients and those taking higher dose and higher potency statins.¹⁴

Studies have reported reversible cognitive impairment with statin use, both in patients with previously intact cognition and in those with pre-existing cognitive impairment.^15–17 This prompted the US Food and Drug Administration to change the prescribing information for statins* and has been noted by the Australian Therapeutic Goods Administration†.

A recent randomised controlled trial in younger patients suggested that compared to placebo, those prescribed statins were more likely to report a loss of energy and worsening exertional fatigue over six months of treatment.¹⁸ This effect may have considerable impact on older patients with less functional reserve.

Gemfibrozil is the drug most commonly associated with statin-induced myopathy. When taken concomitantly it inhibits the hepatic uptake of statins (via the organic anion transporter polypeptide 1B1) and their biotransformation by glucuronidases. There is a smaller increase in the risk of myopathy with co-administration of other fibrates and statins because this pharmacokinetic interaction does not occur. The metabolism of atorvastatin and simvastatin is inhibited by cytochrome P450 3A4 inhibitors (for example macrolide antibiotics, amiodarone), increasing the risk of adverse effects (see Drug interactions: Fatal rhabdomyolysis following voriconazole and simvastatin, Aust Prescr 2012;35:88-9).

When healthcare professionals and patients agree that there is no clinical benefit of treatment or the risks are greater than any potential benefit, treatment should be stopped. Withdrawal or deprescribing of statins should be considered when:

• the potential benefits are no longer clinically relevant. In patients with severe physical or cognitive impairments, or those in their last year of life, therapeutic aims often change from preventative to palliative and reducing the risk of vascular events or mortality may not be relevant.
• patients have serious adverse effects such as myositis, rhabdomyolysis or severe hepatic failure
• patients have symptoms or signs consistent with adverse effects in a temporal pattern consistent with statin exposure, such as myalgia, moderate or severe elevation of hepatic enzymes, cognitive impairment or fatigue
• patients need medicines that interact with statins (increasing the risk of toxicity).

Good opportunities to discuss withdrawal of statins include comprehensive health assessments by general practitioners or specialists, assessments on admission to or discharge from hospital or on entry to residential aged-care facilities, and after medication reviews by accredited pharmacists.

Evidence supports statin use for secondary prevention of coronary heart disease in older adults. However, this age group has an increased risk of adverse events from statins, particularly myopathy. The effect of these drugs on frailty, disability and institutionalisation is not well established. They are likely to decrease the risk of these outcomes by preventing vascular events, but to increase the risk by causing myopathy.

Randomised trials in older people (frail and robust) with clinically relevant endpoints are required to inform therapy in this large and growing patient population. Management of older adults relies on extrapolation of the available evidence and frequent reassessment as the patient's physiology, pathology, function and priorities change over time.

* PressAnnouncements/ucm293623.htm [cited 2013 May 3]

† www.tga.gov.au/safety/alerts-medicinesstatins-120302.htm [cited 2013 May 3]

Conflict of interest: none declared

Acknowledgement: Danijela Gnjidic is supported by a National Health and Medical Research Council Early Career Fellowship.

The following statements are either true or false.

1. Statins are associated with a decrease in haemorrhagic stroke in secondary prevention studies of people with cerebrovascular disease.
2. Macrolides increase the risk of adverse effects with atorvastatin and simvastatin.

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