Bempedoic acid (Nexletol)

Bempedoic acid lowers LDL through the same metabolic pathway as a statin but acts one step earlier. Statins inhibit HMG-CoA reductase, bempedoic acid inhibits ATP citrate lyase, which sits further upstream in cholesterol synthesis. The result is the same: the liver cell puts more LDL receptors on its surface and pulls more LDL out of the blood.

The actual trick lies elsewhere. Bempedoic acid is a prodrug and first has to be activated by an enzyme called ACSVL1. That enzyme sits in the liver and is absent from skeletal muscle. So the active drug never even forms in muscle.

This information is for research and educational purposes only. No medical advice.

Statin-associated muscle complaints are the most common reason people stop a cholesterol agent. That is exactly where the design of bempedoic acid starts: no activating enzyme in muscle, so no active drug in muscle, so theoretically no muscle burden. The registration trials confirmed this, with muscle complaint rates sitting at placebo level.

As monotherapy it lowers LDL by roughly 20 to 25 percent, meaning less than a mid-range statin. Combined with ezetimibe another 20 percent or so is added, which is why the two also exist as a fixed combination.

CLEAR Outcomes (NEJM 2023) is the decisive trial, because it is the only one that tested hard endpoints. Almost 14,000 patients with statin intolerance and cardiovascular risk received bempedoic acid or placebo. The combined endpoint of heart attack, stroke, revascularisation and cardiovascular death fell by 13 percent. That is a real but moderate effect and matches the moderate LDL reduction.

CLEAR Harmony (NEJM 2019) tested safety over 52 weeks in over 2,200 patients and showed an LDL reduction of around 18 percent on top of statin therapy. CLEAR Wisdom (JAMA 2019) confirmed roughly 17 percent additional reduction at maximally tolerated statin dose. CLEAR Serenity (J Am Heart Assoc 2019) specifically examined statin-intolerant patients and arrived at around 21 percent.

The trials are consistent with each other, which speaks for the substance. What is missing is long-term data across many years of the kind that exists for statins.

• Raised uric acid: the most relevant side effect. Anyone prone to gout or already running high values should keep an eye on it. Gout attacks occurred more often than under placebo in the trials.
• Tendon rupture: a slightly elevated risk is documented. For anyone training hard this matters more than for the average patient and deserves an honest mention.
• Liver values: small rises possible.
• Kidney values: a slight creatinine rise is described, usually without disease significance.

Store dry, at room temperature and protected from light. Keep out of reach of children.