Safety of cholesterol biosynthesis inhibitor in high CV risk patients

Introduction and methods

Statin use alone is often insufficient to lower LDL-c to goal levels in patients with increased CV risk [1,2]. Therefore, additional therapies are needed that are safe and effective in lowering LDL-c on top of standard-of-care medical therapies.

Bempedoic acid has been shown to lower LDL-c by inhibiting ATP citrate lyase, a key enzyme in the cholesterol biosynthesis pathway upstream of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the target for statins. Bempedoic acid inhibits production of cholesterol in the liver, but not in muscles [3]. Results of 12 weeks treatment with bempedoic acid have been shown previously [4-8]. Now, patients were followed for 1 year.

The CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) Harmony trial, was a randomized, double-blind, placebo-controlled, parallel-group, phase 3 trial of bempedoic acid, in which safety, side-effect profile and efficacy was assessed over a 1-year intervention period (conducted from Jan 2016-Feb 2018). Patients with ASCVD or heterozygous FH were included, who were taking maximally tolerated statins alone or in combination with other lipid-lowering therapies, in addition they had LDL-c levels ≥70 mg/dL (1.8 mmol/L). Patients were assigned in a 2:1 ratio to receive bempedoic acid (n=1488) or placebo (n=742). Primary endpoint was safety.

Main results

• Any adverse events were reported in 1167 patients (78.5%) receiving bempedoic acid and in 584 (78.7%) receiving placebo, with the majority of events being graded as mild to moderate.
• Incidence of serious adverse events was similar in the two groups (14.5% in the bempedoic acid group and 14.0% in the placebo group). Percentage of patients who discontinued the trial drug due to an adverse event was higher in the bempedoic acid group than in the placebo group (162 patients [10.9%] vs. 53 [7.1%] (P=0.005).
• Death was reported in 13 patients (0.9%) in the bempedoic acid group and in 2 (0.3%) in the placebo group. In the bempedoic acid group, 5 death were attributable to cancer (3 cases were diagnosed within 90 days after start of the trial) and 6 were due to CV causes.
• Major adverse cardiac events occurred in 68 patients (4.6%) in the bempedoic acid group and in 42 (5.7%) in the placebo group. Hospitalization for heart failure was observed in 9 patients (0.6%) in the bempedoic acid group vs. 1 patient (0.1%) in the placebo group.
• Number of muscle disorders in the bempedoic acid group was 195 (13.1%) vs. 75 (10.1%) in the placebo group (P=0.05), and gout occurred more in the bempedoic acid group than in the placebo group (18 patients [1.2%] vs. 2 [0.3%] (P=0.03).
• Incidence of new-onset diabetes or worsening of diabetes was lower in the bempedoic acid group than in the placebo group (49 patients [3.3%] vs. 40 [5.4%], P=0.02).
• Incidence of elevations in aminotransferase and the creatine kinase level was relatively low in the two groups (7 patients [0.5%] in the bempedoic acid group and 1 [0.1%] in the placebo group for both markers). Uric acid levels were increased in the bempedoic acid group vs. decreased in the placebo group (P<0.001) and a difference was observed in change in creatinine levels between bempedoic acid group (0.02 mg/dL) vs. placebo group (-0.02 mg/dL) (P<0.001). Number of patients with decrease in eGFR was 8 (0.5%) in the bempedoic acid group and 0 in the placebo group.
• There was no difference in adverse events when stratified for intensity of background statin therapy.

Conclusion

References

Find this article online at NEJM