Scientists uncover the hidden reason some patients cannot tolerate statins

For tens of millions of people worldwide, statins represent a daily defence against heart disease. Yet roughly one in ten of those who take the cholesterol-lowering medication experience a mysterious and often debilitating side effect — one that leads many to abandon a treatment that could save their lives.

Now, scientists believe they may have found at least part of the answer.

Calcium gate at the centre of new findings

Research conducted by Columbia University and the University of Rochester in the United States has identified a potential mechanism behind the problem: a tiny calcium gate inside muscle cells that statins may force open.

The resulting calcium leak appears to damage muscle tissue, offering a new explanation for at least some cases of what is clinically known as statin-associated muscle symptoms, or SAMS.

"I've had patients who've been prescribed statins, and they refused to take them because of the side effects," said lead author Andrew Marks, a cardiologist at the Columbia University Vagelos College of Physicians and Surgeons.

How statins work — and where they go wrong

Statins function by blocking an enzyme essential to the biosynthesis of cholesterol in the liver. This reduces levels of so-called "bad" LDL cholesterol in the bloodstream, helping to guard against cardiovascular diseases such as atherosclerosis — the build-up of fatty deposits in blood vessels — which ranks among the leading causes of death in the United States.

However, statins also interact with "off-target" molecules, among them a protein called ryanodine receptor 1 (RyR1).

Shaped like a mushroom, RyR1 is a channel, or gate, located on the sarcoplasmic reticulum — a web-like structure that envelops muscle fibres.

It functions rather like a bouncer at a club, opening and closing to regulate the flow of calcium ions into muscles, a process that is fundamental to muscle contractions.

Using mice as research models, the scientists observed the precise manner in which statins bind to RyR1, employing an imaging technique known as cryo-electron microscopy (cryo-EM).

The method involves flash-freezing biological samples before subjecting them to electron beams; the resulting deflection patterns reveal minute structures, enabling researchers to produce highly detailed three-dimensional images of proteins and their constituent molecules.

When the gate stays open

Cholesterol-lowering drugs such as simvastatin may keep these RyR1 gates open, allowing calcium ions to flood into muscle cells.

That influx can either cause direct damage to the muscle tissue or activate enzymes that break it down. The consequence for statin users may be persistent pain, weakness, tenderness, and cramps.

The problem is compounded in individuals who carry RyR1 mutations, who may additionally suffer episodes of malignant hyperthermia — a severe overheating reaction triggered by medication — or diaphragm weakness that impairs lung function and leads to respiratory disorders.

In rare but potentially life-threatening cases, statin side effects can escalate to rhabdomyolysis, a serious condition in which muscle tissue ruptures and its contents leak into the bloodstream, ultimately causing kidney failure.

An equally severe outcome, autoimmune-mediated necrotising myositis, may also rarely develop — a condition in which the immune system turns on its own tissue and destroys muscle.

Scale of the problem

Approximately 40 million adults in the United States alone take statins, and around ten per cent of those patients experience SAMS.

"It's the most common reason patients quit statins, and it's a very real problem that needs a solution," said Marks.

The researchers acknowledge that the leaky calcium gate mechanism may not account for every case of SAMS. Even so, the identification of this pathway could help clinicians recognise patients who are at elevated risk of statin intolerance before symptoms arise.

Two potential routes forward

The study highlights two promising therapeutic avenues. The first involves redesigning statins so that they no longer bind to RyR1 while still effectively inhibiting cholesterol production in the liver.

The second approach centres on an experimental class of drug called Rycal, currently used to treat patients with rare muscle diseases.

When statin-intolerant mice were treated with Rycal, researchers were able to close the leaky RyR1 calcium gates and prevent simvastatin-induced muscle weakness.

"It is unlikely that this explanation applies to everyone who experiences muscular side effects with statins," Marks explained. "But even if it explains a small subset, that's a lot of people we could help if we can resolve the issue."

The research was published in the Journal of Clinical Investigation.