New drug 'effective' for those with intolerable stat...

"A breakthrough drug can slash levels of bad cholesterol by half without the side effects of statins," the Daily Mail reports.

Statins are a class of drug used to reduce high cholesterol levels, they are often given to people thought to be at risk of heart disease or stroke.

A complaint from some people who take statins is that they seem to trigger muscle pains and spasms. In some cases, these side effects are so troublesome that a person stops taking the drug all together.

This study included almost 500 people who previously had muscle problems when they tried several types of statin.

They were randomised to take either low-dose atorvastatin or inactive placebo, and were unaware of which drug they were taking. The researchers found just under half reported muscle problems when taking the statin only.

These people were then randomised to take two alternative non-statin drugs – oral ezetimibe or the new injected drug evolocumab. Overall, researchers found the latter was better at reducing cholesterol.

One practical consideration regarding evolocumab is its cost. The drug is expensive: a year's supply is reported to cost £4,450.

The National Institute for Health and Care Excellence (NICE) is reported to be making a final decision about whether evolocumab should be offered on the NHS and, if so, in what circumstances.

People should continue to take their statins as prescribed, but anyone with unexplained muscle aches and pains should report these to their doctor. Lowering the dose or trying a different type of statin may help relieve these symptoms.

Where did the story come from?

The study was carried out by researchers from the University of Amsterdam School of Medicine at Mount Sinai in the US and various other institutions worldwide.

Funding was provided by Amgen, which produces the cholesterol-lowering medication evolocumab, sold under the tradename Repatha™.

According to the researchers, Amgen was "involved in the design and conduct of the study, selected the investigators, monitored the trial, and collected and managed the trial data. The sponsor participated in the decision to publish the study and committed to publication of the results prior to unblinding the trial."

The study was published in the peer-reviewed journal JAMA on an open-access basis, so you can read it for free online.

There is also an accompanying editorial (also free) written by independent experts, which provides a useful second opinion about the implications of the research.

The Daily Mail's reporting of the study is accurate, but its claim that, "Breakthrough treatment could get NHS green light by end of the month" is possibly overoptimistic.

In contrast, The Daily's Telegraph reporting of the study is somewhat confusing and misleading.

The Telegraph said: "Statins really do cause painful muscle cramps, scientists have found, vindicating hundreds of thousands of people who have repeatedly claimed to have suffered debilitating side effects" which seems to imply that doctors don't recognise these types of side effects. This is simply not the case: these are known side effects that are highlighted in the product literature.

It remains a puzzle as to why people taking statins experience these types of side effects – as yet, no plausible biological explanation has been found.

What kind of research was this?

This randomised controlled trial was conducted in two phases. Researchers aimed to see whether statins do cause muscle symptoms and then compare the fat (lipid) lowering ability of two alternative non-statin medications.

Statins are well established to be effective drugs for lowering cholesterol, but muscle-related adverse effects such as pain and weakness have often been reported. This risk is recognised by the medical profession.

Subsequently, people who have experienced muscle-related effects need to look for alternative treatments. Approaches may include using very low-dose statins, giving statins intermittently, or alternatively giving non-statin treatments.

Non-statin options include ezetimibe, which limits the absorption of cholesterol, and a new group of drugs called proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. Evolocumab (given by injection) is a PCSK9 inhibitor that has recently been approved by medical regulators for use in the UK.

A randomised controlled trial is the best way of looking at the safety and effectiveness of treatments.

What did the research involve?

The trial was conducted in two phases. The first phase compared atorvastatin – usually the first-choice statin medication – with inactive placebo, looking at muscle-related side effects. The second phase compared the non-statin drugs ezetimibe and evolocumab for their cholesterol-lowering effects.

The trial specifically included people previously unable to tolerate a normal statin dose because of muscle pains.

They went through a four-week washout period in which they took no medication. They were then randomised to either inactive placebo or a "re-challenge" with atorvastatin (20mg) for 10 weeks.

During this time neither participants nor researchers knew which drug they were taking. The drugs were then stopped and they had another two-week washout period before they were switched to the alternative drug (placebo or atorvastatin).

After phase one, those who had experienced muscle-related effects using atorvastatin were eligible to enter phase two – the 24-week trial of oral ezetimibe versus injected evolocumab.

This trial was also double blind, and involved people either taking a dummy tablet or having a dummy injection, depending on which treatment they were assigned to.

In phase one the main study endpoint was therefore the incidence of muscle-related side effects. The main study endpoint at phase two was changes in low-density lipoprotein (LDL) – "bad" – cholesterol, though any side effects were also reported.

What were the basic results?

A total of 492 people entered phase one of the study, most of whom had been intolerant of at least three different statins in the past. Overall, 42.6% of these people experienced muscle-related side effects with atorvastatin, but not placebo.

Somewhat oddly, around a quarter reported muscle-related side effects while using the placebo but not atorvastatin. The remainder either had symptoms with both or neither.

A person had a significantly higher risk of developing muscle-related side effects while taking atorvastatin than placebo.

The main results relate to the effectiveness of the two alternatives. A total of 218 people entered phase two.

Overall, evolocumab lowered LDL cholesterol significantly more than ezetimibe – an absolute difference of 37%.

There was no significant difference in the muscle-related symptoms of these two drugs, which were reported by 29% of people taking ezetimibe and 21% of people taking evolocumab.

How did the researchers interpret the results?

The researchers concluded: "Among patients with statin intolerance related to muscle-related adverse effects, the use of evolocumab compared with ezetimibe resulted in a significantly greater reduction in LDL-C levels after 24 weeks."

Conclusion

The main results of this study relate to the lipid-lowering effects of two alternative non-statin medications. However, it highlights the muscle-related adverse effects that can occur with statins.

The study is carefully designed and has many strengths, including:

a washout period between drugs to remove any residual effects
double-blind design throughout so people didn't know what they were taking
sufficient duration for each phase of the study (10 and 24 weeks) to allow effects to develop
a good sample size – the researchers calculated beforehand how many people would need to be recruited to enable them to reliably detect differences between the groups

There are some points to keep in mind, however.

This study isn't able to inform us of the overall incidence of muscle aches and pains when people take statins. A specific sample of people was recruited to the study, and they had already reported muscle problems when taking several statins previously.

It can then tell us that when these people took low-dose atorvastatin and placebo in a double-blinded manner, just under a half of them experienced these problems when taking the statin only. This suggests that these were effects definitely related to the statin.

However, that's not to say the remaining half had previously imagined these effects – they could have had effects with other statins or with higher doses than the 20mg taken here.

The muscle-related side effects of statins are already well known. Product literature notes side effects of muscle aches, pains and weakness, and the potential risk of developing the serious condition rhabdomyolysis. This is where muscle fibres are broken down and released into the bloodstream, which can damage the kidneys. Doctors are advised to use statins with caution in people with a history of muscle weakness or rhabdomyolysis.

Statins are highly effective and relatively safe drugs, and are the medication of first choice for lowering cholesterol. Ezetimibe is currently only recommended by the regulatory body NICE for people who cannot take a statin.

Evolocumab has only recently been licensed for the treatment of people who cannot take statins, or in combination with a statin if a statin alone is ineffective at reducing cholesterol.

NICE issued draft guidance at the end of last year that did not recommend this drug if other lipid-lowering treatments could be taken. However, the final version of the guidance, which may say something different, is expected some time this year.

People should continue to take their statins as prescribed, but anyone with unexplained muscle aches and pains should report these to their doctor.

Often, lowering the dose or switching to an alternative type of statin can help prevent side effects. Lifestyle changes such as eating a healthy diet and taking regular exercise can also help lower your cholesterol.