Statins users ‘are genetically predisposed to suffering muscle aches and pains’

Many people prescribed the cholesterol-lowering pills stop taking them because of the side effect putting them at higher risk of developing diseases of the heart and blood vessels.

Now a study led by the University of Dundee found there was a common variant in a gene that predisposes people to developing muscle aches, regardless of whether they are taking statins.

But there were a genetic sub-group of people who have a higher risk of muscle aches caused by the pills.

The findings could allow doctors to screen people for this gene so they can be given alternatives while those genetically predisposed to muscle aches could be warned about the possibility of developing symptoms and be closely monitored.

It is estimated between seven and 29 per cent of those prescribed statins complain of muscle aches.

Those who cannot tolerate statins are offered alternative treatments include ezetimibe and a new class of drugs called PCSK9-inhibitors.

Professor Colin Palmer said: “We found that there are people in the general population who carry a genetic factor that predisposes them to muscle aches.

“If these people are put on statins, they might discontinue their medication in the erroneous belief that it is the statin that is making their muscles ache.

“At the same time, we observed that there is a genetic sub-group of patients who are susceptible to statin-specific muscle ache, although at this stage we don’t understand the mechanism responsible for this effect.”

Previous research found a genetic variant of the LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B member 5) gene was associated with lower levels of enzymes called creatine phosphokinase (CK) and lactate dehydrogenase (LDH).

These enzymes are released from injured muscle tissue. Raised CK levels are often taken as clinical confirmation of adverse muscle-based reactions to statin therapy.

This suggested the LILRB5 variant could be involved in muscle-related symptoms so the scientists hypothesised the variant would reduce the risk of muscle-based symptoms, while the more common form of the gene, seen in 60 per cent of the Caucasian population, might increase risk.

The study looked at the association between the LILRB5 variant and statin intolerance.

They selected statin users who had stopped taking statins and divided them into those who had raised CK levels, defined as general statin intolerance, and those intolerant to the lowest approved dose of a statin before switching or discontinuing therapy defined as low dose intolerance).

This was done because some patients do not necessarily show the expected raised CK levels, but do experience muscle aches.

Among 11,912 Scottish statin users taking part in the Genetics of Diabetes Audit and Research, Tayside Scotland (GoDARTS) study it was found the likelihood of statin intolerance was increased in patients who carried two identical copies of the common form of the LILRB5 gene.

In particular there was a two-fold increased risk of general statin intolerance and a 1.4-fold increased risk of low dose intolerance after taking into account important factors that could affect the results, such as the patients’ use of other medications, type of statin and its dosage, diabetes status, age and sex.

A study of 661 Swedes and Britons with a more severe type of intolerance, statin-induced myopathy, or muscle disease, and another of 8,749 patients from 26 countries who developed muscle aches after taking the statin rosuvastatin confirmed the results.

A meta-analysis of these and of a third in which no significant effect could be seen, showed patients with two copies of the common form of the gene had 1.3-fold increased risk of suffering adverse effects associated with statin intolerance compared to those without identical copies.

In the international clinical trial, the researchers could determine how many patients receiving statin therapy developed muscle aches, as opposed to those who were given placebo.

Statins were not associated with an increased risk, while the common form of the LILRB5 gene was clearly associated with an overall increased risk of muscle aches.

However, true statin-specific muscle aches could only be observed in patients who had one or both copies of the variant form of the gene, which would normally have protected them from muscle aches that were not caused by statins.

Professor Palmer added: “This means that it would be possible to test prospective statin users for key genetic variants, including LILRB5, to prevent people being put on statins if they are likely to have an adverse reaction to them.

“Adverse reactions are the driving reason for therapy cessation, which puts the patient at an increased risk of a cardiovascular event.

“This is the first time a genetic variant thought to be involved in the repair and regeneration of muscles has been found to be associated with this side effect.”

First author Postdoctoral Research Assistant Dr Moneeza Siddiqui added further research was planned to confirm exactly how the genetic variant is involved in the repair of muscles.

She said: “All we know as facts are that the immune system is involved in the repair and regeneration of muscles, that our gene (LILRB5) is involved in the immune system, and, more specifically, that people with two identical copies of the genetic variant have lower expression of a key factor, called Foxp3, that enables the mechanism by which the immune system repairs muscle cells.

“So, we have a strong hypothesis for the involvement of our gene in the process of muscle repair and recovery.”The study was published in the European Heart Journal.