Bempedoic acid (Nilemdo)

What bempedoic acid is

Bempedoic acid is a prescription-only lipid-lowering drug, approved in the EU since 2020 as Nilemdo and, in combination with ezetimibe, as Nustendi. It belongs to none of the familiar groups such as statins, ezetimibe or PCSK9 inhibitors, but inhibits a different enzyme of cholesterol synthesis.

What is rated is the state of knowledge. For a young drug it is good: one large outcome trial, several randomized trials on LDL lowering and a genetic study that supports the principle of action. In the biohacking scene, bempedoic acid comes up when the topic is lowering LDL or ApoB without a statin; the trials, however, were done in people with high cardiovascular risk, not in healthy people.

How it works

Bempedoic acid is a prodrug. It only becomes active through the enzyme ACSVL1, which occurs in the liver but is absent in skeletal muscle. The active form inhibits ATP citrate lyase, an enzyme that sits upstream of HMG-CoA reductase, the target of statins, in cholesterol synthesis. The liver produces less cholesterol, builds more LDL receptors and removes more LDL from the blood.

The fact that bempedoic acid is not activated in muscle is the basis for the hope of fewer muscle complaints than with statins; the mechanism was shown in cell and animal experiments (Pinkosky 2016). In humans, a genetic study in 654,783 people supports the principle: gene variants that weaken ATP citrate lyase lowered cardiovascular risk per 10 mg/dl less LDL about as much as variants in the statin target gene, odds ratio 0.823 versus 0.836, without increased cancer risk.

What the studies show

CLEAR Outcomes: 13,970 statin-intolerant patients

Nissen 2023 (NEJM) gave 180 mg bempedoic acid daily or placebo to people with established cardiovascular disease or high risk who could not tolerate statins. Major events occurred in 819 versus 927 patients (11.7 versus 13.3 percent). Heart attacks 3.7 versus 4.8 percent, coronary revascularizations 6.2 versus 7.6 percent. There was no significant effect on stroke, cardiovascular death or death from any cause. In absolute terms the groups are separated by 1.6 percentage points; arithmetically that is around 63 people treated for a little over three years per event prevented. This figure was calculated from the event rates and is not in the abstract.

Primary prevention: patients without prior cardiovascular disease

A subanalysis of the same trial (Nissen 2023, JAMA) looked at 4,206 high-risk patients without a previous cardiovascular event, on average 68 years old, 66 percent with diabetes. Major events occurred in 5.3 versus 7.6 percent, hazard ratio 0.70; cardiovascular death 1.8 versus 3.1 percent, death from any cause 3.6 versus 5.2 percent. High-sensitivity CRP fell by 21.5 percent. As a subgroup, the result is less robust than the overall trial.

CLEAR Harmony: added to a statin

Ray 2019 (NEJM) randomized 2,230 patients with cardiovascular disease or familial hypercholesterolemia who were already taking the highest tolerated statin dose, over 52 weeks. LDL fell by 16.5 percent after 12 weeks, 18.1 percentage points more than with placebo. Adverse events overall were equally frequent (78.5 versus 78.7 percent), discontinuations due to side effects were more frequent (10.9 versus 7.1 percent), as was gout (1.2 versus 0.3 percent).

Ference 2019: what the genes say

This Mendelian randomization compared, in 654,783 people, including 105,429 with major cardiovascular events, gene variants in the ACLY gene with variants in the statin target gene HMGCR. Both changed blood lipids in the same pattern and lowered risk per 10 mg/dl less LDL to a similar extent. Neither was associated with increased cancer risk.

Where the data stop

• Healthy people with only slightly elevated LDL. All outcome data come from people with high cardiovascular risk and statin intolerance. There is no study for longevity use in healthy people.
• Mortality. In the overall trial, all-cause mortality, cardiovascular death and stroke did not fall significantly. The more favorable mortality figures come from the subgroup without prior disease.
• A replacement for statins. The trials analyzed here compare bempedoic acid with placebo, not with a statin. How it performs in a head-to-head comparison cannot be read from them; LDL lowering was 18 to 21 percentage points versus placebo.
• Experience over many years. The drug has only been on the market since 2020. The trials provide no data on more than a little over three years of treatment.

Status, approval and legal

Nilemdo was approved in the EU on April 1, 2020, the combination with ezetimibe as Nustendi on March 27, 2020. Bempedoic acid is listed in Annex 1 of the German Prescription Drugs Ordinance (Arzneimittelverschreibungsverordnung) and is therefore prescription-only. According to the European Medicines Agency, Nilemdo is approved in adults with primary hypercholesterolemia or mixed dyslipidemia and in adults with established or high-risk atherosclerotic cardiovascular disease to reduce cardiovascular risk. In CLEAR Outcomes, 180 mg daily was given.

In the US, bempedoic acid has been approved as Nexletol since February 21, 2020; the cardiovascular indication was added in March 2024. Taking it to lower LDL or ApoB as a preventive measure outside these indications is not approved.

Safety

The two clearest signals from CLEAR Outcomes are gout (3.1 versus 2.1 percent) and gallstones (2.2 versus 1.2 percent). In addition, there were small increases in creatinine, uric acid and liver values. In the subgroup without prior disease, gout was 2.6 versus 2.0 percent and gallstones 2.5 versus 1.1 percent.

According to the European Medicines Agency, elevated uric acid and gout are among the most common side effects. Nilemdo must not be used during pregnancy and breastfeeding. Together with simvastatin the risk of side effects increases; simvastatin is then limited to 40 mg per day. If you are being treated for gout or gallstones, this belongs in the medical assessment.

Sources

• Nissen SE et al., N Engl J Med 2023 – CLEAR Outcomes, cardiovascular endpoints in 13,970 statin-intolerant patients
• Nissen SE et al., JAMA 2023 – CLEAR Outcomes, primary prevention in 4,206 high-risk patients
• Ray KK et al., N Engl J Med 2019 – CLEAR Harmony, bempedoic acid added to statins, 2,230 patients
• Ference BA et al., N Engl J Med 2019 – Mendelian randomization on ACLY and cardiovascular disease, 654,783 participants
• Pinkosky SL et al., Nat Commun 2016 – liver-specific activation via ACSVL1, basis for the absent muscle effect
• EMA – Nilemdo, European public assessment report (EPAR)
• FDA, Drugs@FDA – Nexletol (NDA 211616), approval February 21, 2020, extension March 22, 2024
• German Prescription Drugs Ordinance (Arzneimittelverschreibungsverordnung), Annex 1 (bempedoic acid and its esters)