Safety of cholesterol biosynthesis inhibitor in high CV risk patients
Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol
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 . 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.
- 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.
The authors concluded that in the CLEAR Harmony trial, use of bempedoic acid in patients with high CV risk had an acceptable safety profile. Number of deaths was higher in the bempedoic acid group compared to placebo group, but the authors noted that deaths from cancer in general occurred early in the trial, suggesting preexisting cancers and they stated that these findings are likely a chance finding.