New drug development for hypercholesterolemia

The study shows that bempedoic acid, when added to statin therapy, reduces LDLc levels further. Bempedoic acid is an inhibitor of ATP citrate lyase, an important enzyme of cholesterol and fatty acid synthesis.

A group of 2300 patients with either established cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia (HeFH) were followed for about 12 months.  Baseline LDLc was 103 mg/dL.  Mean LDLc reduction with bempedoic acid was about 20 mg/dL.

These results are meaningful as it is well-established that the lower the LDLc the lower the ASCVD outcomes.  No increased adverse events were seen with the ATP Citrate lyase inhibitor compared to placebo.

GT

Also see:

Lipids

CVD

Statins


N E J M

CLEAR Harmony

March 2019


Background

Short-term studies have shown that bempedoic acid, an inhibitor of ATP citrate lyase, reduces levels of LDLc.

Data are limited regarding the safety and efficacy of bempedoic acid treatment in long-term studies involving patients with hypercholesterolemia who are receiving guideline-recommended statin therapy.

METHODS

We conducted a randomized, controlled trial involving patients with ASCVD, heterozygous familial hypercholesterolemia, or both.

Patients had to have an LDLc level of at least 70 mg/dL while they were receiving maximally tolerated statin therapy with or without additional lipid-lowering therapy.

  • Maximally tolerated statin therapy was defined as the highest intensity statin regimen that a patient was able to maintain, as determined by the investigator.

Patients were randomly assigned in a 2:1 ratio to receive bempedoic acid or placebo.

  • Primary endpoint was safety

  • Principal secondary endpoint (principal efficacy end point) was the percentage change in the LDLc level at week 12 of 52 weeks.

RESULTS

The trial involved 2230 patients, of whom 1488 were assigned to receive bempedoic acid and 742 to receive placebo.

The mean (±SD) LDLc level at baseline was 103.2±29.4 mg/dL.

The incidence of adverse events (1167 of 1487 patients [78.5%] in the bempedoic acid group and 584 of 742 [78.7%] in the placebo group) and serious adverse events (216 patients [14.5%] and 104 [14.0%], respectively) did not differ substantially between the two groups during the intervention period.

  • But the incidence of adverse events leading to discontinuation of the regimen was higher in the bempedoic acid group than in the placebo group (10.9% vs. 7.1%),

  • as was the incidence of gout (1.2% vs. 0.3%).

At week 12, bempedoic acid reduced the mean LDLc level by 19.2 mg/dL, representing a change of −16.5% from baseline (difference vs. placebo in change from baseline, –18.1 % points; p<0.001).

Safety and efficacy findings were consistent, regardless of the intensity of background statin therapy.

CONCLUSIONS

In this 52-week trial, bempedoic acid added to maximally tolerated statin therapy did not lead to a higher incidence of overall adverse events than placebo, but led to significantly lower LDLc levels.