Aletho News

A new cholesterol drug for ‘statin intolerant’ people

But what is the evidence?

By Maryanne Demasi, PhD and Robert DuBroff, MD (Cardiologist, New Mexico) | June 5, 2023

For years, researchers have tried to convince patients that statins don’t cause muscle aches and pains. They’d say that people in trials who took statins experienced muscle aches at the same rate as people on placebo, and that if they did experience muscle pain, it was “rare.”

But now, researchers have had a change of heart. Statins do cause muscle aches in about 20% of people, a problem known as ‘statin intolerance.’ Why the change of heart?

Well, there’s a new drug for people with statin intolerance, one that lowers cholesterol like a statin, but without the muscle aches.

The drug is called bempedoic acid.  It acts on the same cholesterol biosynthesis pathway as statins and reduces the amount of cholesterol made by the liver.

The drug is being touted as “revolutionary.” Recently, Stephen Nicholls, cardiologist, and co-investigator on a major trial of the drug said:

“This drug provides another option for lowering cholesterol and is particularly important for patients that cannot tolerate statins. That’s a real problem in clinical practice which limits our ability to effectively lower cholesterol in many patients.’’

Bempedoic acid on trial

Almost 14,000 participants across 32 countries took part in a clinical trial of bempedoic acid and the study was published in the New England Journal of Medicine.

All the trial participants had statin intolerance — half were given placebo and the other half were given 180 mg bempedoic acid daily, and followed for a median duration of 3.3 years.

The drug lowered LDL-cholesterol by about 20%, as well as a marker of inflammation called C-Reactive Protein (CRP) – but did that translate into less major cardiovascular events?

The primary outcome analysed was a composite of four outcomes: heart attack, stroke, revascularisation, and cardiovascular death.

After taking bempedoic acid daily for an average of 3.3 years, the relative risk reduction of the composite outcome was 13% and the absolute risk reduction was 1.6%.

However, in terms of individual categories within the composite endpoint, bempedoic acid had no significant effect on fatal or non- fatal stroke, death from cardiovascular causes, and death from any cause.

The small risk reduction of a cardiovascular event (1.6%) must be weighed up against the increased risk of gout (1%), gall stones (1%) and other drug interactions.

Is the push to lower cholesterol futile?

In 1996, Nobel laureates Brown and Goldstein wrote an editorial in Science titled, “Heart attacks: gone with the century?”

The authors surmised that “proof of the cholesterol hypothesis, discovery of effective drugs, and better definition of genetic susceptibility factors – may well end coronary disease as a major public health problem early in the next century”.

But over a quarter of a century later, drugs to lower cholesterol have made virtually no impact on ending heart disease.

As we published in the journal, Preventative Medicine, over the past 10 years cholesterol levels have been falling, while the number of Americans dying of heart disease has been steadily climbing.

If high cholesterol was “causal” in heart disease, as the prescribing guidelines suggest, then we’d expect to see an opposite trend.

Our most recent meta-analysis of 21 statin trials was unable to find a consistent relationship between lowering LDL-cholesterol and death, heart attack or stroke, following statin therapy.

And despite the widespread use of cholesterol-lowering statins in Europe, observational studies indicate that there has been no accompanying decline in coronary heart disease deaths.

A review of 29 major randomised controlled trials of cholesterol reduction published between 2004 and 2018, found that only two reported a mortality benefit while nearly two-thirds reported no cardiovascular benefit at all.

Further, other types of cholesterol lowering medications like niacin, fibrates and cholesteryl ester transfer protein (CETP) inhibitors, which do ‘everything right’ by lowering LDL, raising HDL (the good cholesterol) and reducing triglycerides, have failed to save lives or reduce cardiovascular events in randomised clinical trials.

This should underscore the limitation of targeting LDL-cholesterol, a surrogate marker. By concentrating almost exclusively on lowering cholesterol, we have diverted our attention from more important drivers of atherosclerosis like metabolic syndrome and insulin resistance.

The simplicity of just taking a statin pill has also fuelled patients’ complacency about being ‘protected’ from heart disease, at the expense of engaging in more protective lifestyle interventions like regular exercise and eating a nutritionally complete diet.

In the field of science, the accumulation of contradictory evidence should lead to a rejection or modification of the prevailing hypothesis – yet the cholesterol hypothesis lives on.

It leads us to the inescapable conclusion that cholesterol-lowering medications are not the miracle drugs we had hoped for.

*NB: Bempedoic acid (oral pill 180mg) has been approved in the US, Canada, UK, and Europe – but not in Australia (possibly in 2yrs). 

Bempedoic acid may also be prescribed in combination with another non-statin drug called ezetimibe for additional LDL-C lowering.

June 7, 2023 - Posted by aletho | Science and Pseudo-Science, Timeless or most popular