Overview

Have you ever experienced side effects from statins? Or has someone close to you taking statins ever complained about muscle pain, tenderness or weakness that comes out from nowhere?

Navigating cholesterol management can be challenging for people experiencing the side effects of statins. However, a new treatment, bempedoic acid, combined with ezetimibe has now joined the game, serving as a muscle-pain-free alternative for people with statin intolerance. In this article, we will guide you through understanding the new treatment,  addressing your concerns, and providing a comprehensive overview of the new treatment. 

What do statins do?

Globally, statins are most commonly prescribed to help people's cholesterol levels. NICE guidelines recommend those with a 10% or greater risk of having a cardiovascular event in the next 10 years, such as a heart attack or stroke, should be prescribed statins.¹ An easier way of thinking about this is if there were 100 possible versions of your future, and in 10 of them you would develop a cardiovascular disease in the next 10 years. So your GP may recommend taking statins if you’re identified as a high-risker, or have been diagnosed with cardiovascular disease.

Cardiovascular disease is a general term for conditions affecting the heart and/or vessels. It's usually associated with a build-up of fatty deposits (cholesterol) inside vessels in your heart and throughout your body. The excessive amount of cholesterol will increase the risk of blood clogging. If the blood clots travel down and get stuck in the brain, blood flow would be restricted, and this would present with a stroke; towards the heart, a heart attack or towards the limbs, a peripheral arterial disease. 

In England, high cholesterol leads to over 7% of all deaths, and 1 in 6 adults was affected by the condition in 2023.²

Why did my doctor prescribe statins when my cholesterol level is normal?

Did you know that, in the UK, every five minutes, someone is admitted to a hospital due to a heart attack, and almost 2 out of 10 patients may not survive?³

To reduce the risk and prevent future heart and vessel diseases, the NHS suggests that along with lifestyle changes, cholesterol-lowering treatment should be offered to all high-risk groups of people, with statins representing the first line of medical treatment.⁴

How would statins benefit me?

As of March 2023, more than 80% of the patients with recorded cardiovascular disease are currently being treated with cholesterol-lowering treatment, including statins.⁴ The NHS estimates that if 90% of this group of people were treated, almost 14,000 heart attacks, strokes and deaths would be prevented in 3 years.⁵ If this treatment rate was increased to 95%, around 22,000 events would be prevented.⁵

With the treatment of cholesterol-lowering agents, every 1 unit (mmol/L) reduction in bad cholesterol level is associated with a 22% reduction in major cardiovascular events, such as a heart attack, stroke, or death, after 1 year.⁵ With further estimation, a reduction of bad cholesterol by 2-3 units would reduce risk by about half.⁶ Using high-intensity statins is also considered to optimise treatment.⁶ For example,  prescribing  20 mg- 80 mg of atorvastatin daily, via a high-intensity regimen, would lower cholesterol levels by above 40%.⁷

In the UK, around 1 in 250 people have familial hypercholesterolaemia, an inherited condition causing high cholesterol levels from birth. If left untreated, studies have shown that the risk of developing heart disease is up to 13 times higher.⁸ Using high-intensity statins can not only reduce cholesterol levels by half but lower the risk of death from heart disease.³

Statin intolerance

Statin intolerance occurs when a patient is unable to continue to take statins, either because of the development of a side effect or because their blood test shows abnormal readings that may indicate potential health concerns. The most common presentation of statin-related side effects are muscle aches, pains, weakness, cramps, or back pain. The intolerance can be either partial (only some statins at some doses) or complete (all statins at any dose). In most cases, the symptoms are completely reversible shortly after the statin is stopped; however, some rare and serious events can only be dealt with by hospital admissions.

In the UK, it’s estimated that at least 7-8 million adults are currently taking lipid-lowering drugs, such as statins,⁸ and while statins are well-tolerated by most patients, some report muscle pain. Muscle contraction is triggered by the release of calcium within muscle cells, and this release is normally regulated by the ‘gatekeeper’ proteins that are attached to calcium channels. Statins can cause the gatekeeper proteins to detach from their calcium channels, causing calcium to ‘leakage’. Unregulated calcium leaks may cause damage to muscle cells, potentially leading to muscle pain and weakness.⁹

It’s believed that in most people, their muscle cells can tolerate this calcium leak and their body can repair the damage themselves. However, for some people who are more sensitive to statins, the leak of calcium may overwhelm their muscle cells and cause unwanted side effects.

Other potential side-effects 

Research has reported that statins are associated with an increased risk of type 2 diabetes mellitus, in both diagnosed and undiagnosed patients.^10,11 Although the mechanism is not fully known yet, studies have shown that there’s a correlation between statin and increased insulin resistance,¹⁰ which leads to Iess glucose being absorbed from the bloodstream and eventually elevates blood sugar levels. 

How would cholesterol affect my heart health if I don’t take statin?

Sure, statins have side effects, just like every other medicine, even supplements. Although there are risks associated with discomforts and potential medical conditions, cholesterol-lowering treatment is still recommended for most people with or without diabetes, who have high blood cholesterol or a high risk of developing cardiovascular disease. This is because there are greater potential risks if you don’t take them, like having a heart attack or stroke. A UK Study reports patients who don’t adhere to their statin treatment for more than half of the prescribed time are highly associated with increased risks of death rate and cardiovascular diseases.¹²

When encountering drug side effects, it’s always best to talk to your GP about your experience and concerns. Try to write down the symptoms you experience and any lifestyle changes, including diet and exercise. This will allow your doctor to have a better understanding and evaluation. There are multiple alternative treatments available for consideration.

New treatment

There are approximately 9% of those who would benefit from statins are unable to take them, primarily due to muscle-related symptoms.¹³ Luckily, there are some alternative LDL cholesterol–lowering therapies, such as ezetimibe, proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitors, and the latest “bempedoic acid”.

Bempedoic acid is a new treatment for high cholesterol, along with ezetimibe and diet control. According to NICE (the National Guidance), it can be used when statins can not be tolerated or when ezetimibe is not working well enough on its own.¹⁴

Why is this new treatment needed?

Ezetimibe is used alone normally when statins can’t be tolerated. Due to its modest effect in lowering cholesterol levels and the risk of cardiovascular events, ezetimibe is more commonly used as a combined therapy with other cholesterol-lowering treatments.¹⁵

PCSK9 inhibitors, a highly effective agent at lowering the LDL cholesterol level, currently only exist in injection form, and are expensive. Due to these characteristics, NICE has strict criteria for who can take them.¹⁶ The responses from patients and clinical experts show that the uptake of PCSK9 inhibitors is between 65% and 72% lower than expected, possibly due to insufficient cholesterol management navigation for eligible patients.¹⁷ 

Research has noted that bempedoic acid is an inexpensive, oral preparation that is easy to use and suitable for people who cannot tolerate statins. This new treatment option for managing cholesterol has now been recommended by NICE.¹⁷

Bempedoic acid, in combination with ezetimibe, along with diet control are prescribed:¹⁴

• To people who are unable to take statins
• When ezetimibe alone does not lower their cholesterol level enough 

How does bempedoic acid work differently?

Like statins, bempedoic acid lowers cholesterol in the blood by reducing the production of cholesterol in the liver. Statins block an enzyme known as HMG-CoA reductase. While the liver is a major site of cholesterol production, HMG-CoA reductase activity occurs throughout the whole body, for example, muscle tissues.¹⁸

Bempedoic acid works similarly by slowing down a different enzyme in the cholesterol production pathway, known as ATP citrate lyase. Unlike statins, bempedoic acid only works in the liver so it is much less likely to cause side effects affecting the muscles and blood sugar levels.¹⁸

How does it lower the risk of heart disease?

In clinical trials, bempedoic acid on its own has been shown to reduce LDL cholesterol by between 17-28% after 12 weeks.¹⁹ When combined with ezetimibe, the concomitant treatment can give up to 38% reduction in LDL cholesterol, equivalent to the efficacy of medium-intensity statins.²⁰ Additionally, there is no statistical evidence of elevated sugar levels and muscle-related side effects associated with bempedoic acid.^19,20

Study shows that the reduction in cholesterol levels from bempedoic acid corresponded to a 13% lower risk of major adverse cardiovascular events, which represents collective data of death from cardiovascular causes, nonfatal heart attack, nonfatal stroke, and coronary revascularization.¹⁹ For patients who cannot tolerate statins, bempedoic acid would be an efficient alternative to protect patients’ heart and vessel health. Although the sole use of bempedoic acid doesn’t sound as effective as statins, don’t forget that according to UK guidelines, NICE recommends the combined treatment with both bempedoic acid and ezetimibe for statin-intolerant patients.¹⁴

Bempedoic acid has been proven to be safe and effective in clinical trials. However, there is currently no direct data to support the benefit of reducing the risk of death from cardiovascular causes. Like other developments in any medicine, this benefit requires long-term studies to support the evidence.

Does it cause side effects?

Like all medicines, bempedoic acid can cause side effects too, but not everybody will experience them. 

The most common side effect that has been reported is an increase in blood uric acid levels, leading to an increased risk of gout, a type of arthritis that causes pain and swelling in your joints due to excessive uric acid accumulation.²¹

Other side effects reported include:²¹

• Pain in the extremities (shoulders, legs and arms)
• Anaemia
• Constipation (when taken with ezetimibe)

How do you take bempedoic acid?

There are currently two medicines available, both of which come as a tablet and can be taken with or without food:²²

• Bempedoic acid 180mg: once a day 
• Bempedoic acid 180mg + ezetimibe 10mg: once a day

If you’re taking statins

Your doctor should be aware of drug interactions if you are taking statins, such as Simvastatin and Pravastatin, since bempedoic acid might increase the potency of statins leading to an increased risk of muscle side effects.²²

Summary

Statins, commonly prescribed cholesterol-lowering agents, although rare, still can cause muscle-related side effects. Bempedoic acid, normally combined with ezetimibe, serves as an effective alternative for people who cannot tolerate statins but wish to control their cardiovascular risks. This cost-effective medicine showcases its benefit in effectively lowering cholesterol levels, with no muscle-related side-effects, and no increasing blood sugar levels recorded. More long-term and large-scale studies are expected to demonstrate further benefits. It’s also important to talk to your GP and/or pharmacists if you experience these side effects. If there are any signs of serious allergic reactions or severe intolerable side effects, immediate medical attention will be required.