Metabolic medicine consultant Dr Anthony Wierzbicki offers an update on non-statin lipid lowerers plus how to manage patients who are intolerant of an initial statin
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Statins are first-line therapy for almost all hyperlipidaemias – with the exception being severe hypertriglyceridaemias, where TGs are greater than 8mmol/l.
Unfortunately a proportion of patients are unable to tolerate these drugs and yet still require a lipid lowerer to achieve the desired targets for secondary prevention.
The perceived incidence of statin side-effects differs between clinical trials where levels approach that of placebo (but where many of the patients were statin-experienced) to clinical practice.
However, options exist beyond statin therapy to reduce LDL-cholesterol and are worth trying in cases of statin intolerance. It is worth pointing out that the prescribing advice in this article is basically the same if another lipid-lowerer has to be added to a statin to achieve a lipid target.
Practical implications in primary care
In a patient with presumed statin intolerance, the first action is to confirm the diagnosis – so question patients about their symptoms.
Statin-induced myalgia is usually generalised, exercise exacerbated and more common in older patients, African and Afro-Caribbean patients (especially those with raised baseline creatine kinase), patients with hypothyroidism and patients with impaired renal function.
Statins may also exacerbate underlying disorders with a muscular component, such as polymyalgia rheumatica.
An asymptomatic rise in creatine kinase to five times the upper limit of normal – around 1000iu/l – is the threshold for discontinuing statin therapy.
If myalgia symptoms are present then a rise to three times ULN – 600iu/l – is suspicious of statin-induced myopathy with inflammation (myositis).
Liver function tests
A rise in transaminases (not gamma-glutamyl transferase) to three times ULN – around 150iu/l – is the threshold to discontinue statin therapy.
Persistently abnormal LFTs exacerbated by statins may indicate an underlying hepatic disorder.
Common causes include:
• non-alcoholic fatty liver
• alcohol-related liver disease
• diabetic hepatic steatosis
• hepatitis virus infection
• alpha-1 antitrypsin heterozygote
• coeliac disease
Try another statin
There is an evidence base for low-dose statin therapy even in primary prevention as 10mg pravastatin reduced events by 32% over five and 10 years in the 8000 patients in the MEGA trial in Japan.1
Other options include the use of a stronger statin with a longer half life at lower frequencies. So atorvastatin can be used at 10mg alternate days or rosuvastatin can be used at 5mg once per week and still achieve a 20% LDL reduction.
But lower dose or less frequent statin therapy will often be inadequate especially in secondary prevention where guidelines are increasingly recommending a total cholesterol of less than 4mmol/l and/or a LDL of less than 2mmol/l. So other therapies need to be added to the statin.
Primary LDL reduction action
Ezetimibe is a specific cholesterol absorption inhibitor and can deliver an 18 to 23% reduction in LDL when added to any other lipid-lowering medication.2
It is generally well tolerated but a few patients can get gastrointestinal symptoms on initiation and a very small number get myalgia – especially if already on a statin.
The drug has a controversial evidence base as monotherapy trials have failed to show a reduction in surrogate measures of atherosclerosis – as measured by carotid intima-media thickness – while statin plus ezetimibe combination therapy trials have been underpowered for CVD events, controversial in their design and disappointing in their results to date.
Bile acid sequestrants are non-absorbed drugs that bind bile acids in the gut. Older ionic bile acid sequestrants are effective in lowering cholesterol by 20-25% and have an evidence base for reducing cardiovascular events – although not mortality. But they are poorly tolerated, with 30-40% of patients developing gastrointestinal symptoms. The drugs are also bulky, inconvenient and poorly accepted with patients saying they taste of grit.
Newer non-ionic bile acid sequestrants such as colesevelam are available as capsules and deliver similar LDL reductions with a gastrointestinal side-effect rate of 10%. Unlike older types of these drugs it does not neutralise ezetimibe by binding it. But there is no specific evidence base for colesevelam – as opposed to other bile acid sequestrants – and it is relatively expensive.
Secondary LDL reduction action
Other lipid-lowering drugs are capable of lowering LDL as a part of their action though this effect is not a primary action of these compounds.
Fibrates are PPAR-alpha-agonists that reduce triglycerides and raise HDL by 10 to 15% but some – fenofibrate and bezafibrate – can reduce LDL by 6% to 15%. The fibrates main side-effects are gastrointestinal but they can cause myalgia. The evidence base for fibrates is strongest in patients with features of the metabolic syndrome or with diabetes. But meta-analyses of all fibrate trials suggest they can reduce non-fatal – but not fatal – myocardial infarcts by 20%.
Niacin has a complex and unclear mechanism of action. It increases HDL
by up to 25% and also decreases triglycerides, LDL and lipoprotein (a) levels by about 20% at higher doses. Multiple studies have shown benefits with niacin in monotherapy, in combination with fibrates or statins in reducing progression of atherosclerosis.3 As long ago as 1975 it was shown that niacin monotherapy can reduce cardiovascular events and eventually mortality.4
It has a lower rate of liver side-effects and the lowest rate of muscle side-effects compared with the systemic lipid-lowering drugs. But its use is limited by flushing (and itching), which is not totally suppressible with aspirin. The modern formulations show lower rates of flushing but this occurs in 70% of patients on about five occasions and about 30% have to discontinue due to flushing. The newest variant – laropiprant – contains niacin co-formulated with a PGD1 receptor antagonist, which in early trials reduced recurrent flushing to about 10% of the population. These new formulations are being tested on top of statin therapy in cardiovascular disease in ongoing trials.
The recent HALTS (ARBITER-6) trial has compared the effects on carotid IMT progression of statin-ezetimibe with statin-niacin. This study was stopped early, but was short and relatively small. The results suggested greater benefits in patients with more effective lipid control and the niacin arm was superior to the ezetimibe arm.
Most patients respond well if switched to an intermittent statin plus another lipid-lowering drug. Risks of myopathy are greater with statin-fibrate combinations – and very high if the combination contains gemfibrozil. That risk is mildly raised with the combination of niacin and statin. It may be necessary to use alternating day drug regimes to minimise this.
In severe hypercholesterolaemia with multiple lipid drug intolerances, combination therapies are often required.
But note that the lipid-lowering therapy may be uncovering an underlying latent disease – such as autoimmune muscle disease, a primary muscle disorder or a mitochondrial myopathy. Patients with severe lipid-lowering drug intolerance require further investigation as a diagnosis may be made of the primary cause.
Dr Anthony Wierzbicki is consultant in metabolic medicine/chemical pathology at St Thomas Hospital, London
Competing interests: Dr Wierzbicki has received honoraria for research or lecturing from MSD, Schering Plough, Genzyme and AbbottKey points Ezetimibe CPD questions
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