LDL-c lowering with triple therapy of statin, ezetimibe and bempedoic acid
Combination of bempedoic acid, ezetimibe, and atorvastatin in patients with hypercholesterolemia: A randomized clinical trial
Introduction and methods
Despite proven efficacy of lipid lowering therapies, many patients with hypercholesterolemia fail to achieve treatment goals [1-5]. This has driven the development of new approaches for effective LDL-c lowering. Combination therapy via the addition of non-statin agents to statin therapy is an attractive alternative to up-titrating the statin dose. Bempedoic acid is an ATP citrate lyase inhibitor and inhibits cholesterol synthesis in the liver . Previous studies have shown that bempedoic acid significantly reduces LDL-c, non-HDL-c, total cholesterol, apoB, and hsCRP levels, both alone and in combination with other lipid-lowering therapies [7-12]. However, the efficacy and safety of simultaneous initiation of bempedoic acid, statin and ezetimibe from a baseline of no lipid-lowering therapy has not been studied until now.
This phase 2 double-blind, placebo-controlled, parallel-group study investigated the lipid-lowering effects of triple therapy with bempedoic acid, statin and ezetimibe in 63 patients with hypercholesterolemia (mean age 61.2±11.0 years, 63% women). Participants had fasting LDL-c of 130-189 mg/dL and their clinical status permitted discontinuation of existing lipid-lowering therapy for 12 weeks. After a washout period where all patients discontinued lipid-lowering drugs for a minimum of 5 weeks, patients were randomized 2:1 to receive either triple therapy (one pill each of bempedoic acid 180 mg, ezetimibe 10 mg, and atorvastatin 20 mg once daily, n=43) or matching placebo (n=20) for 6 weeks. The primary endpoint was percent change in LDL-c from baseline to week 6 between triple therapy and placebo. Secondary endpoints included percent change from baseline to week 6 in non-HDL-c, total cholesterol, apoB, hsCRP, triglycerides, and HDL-c levels. Other endpoints were percentage of patients with LDL-c <70 mg/dL at week 6 and percentage of patients with LDL-c lowering ≥50% from baseline at week 6. Treatment-emergent AEs of special interest included metabolic acidosis, hypoglycemia, muscle-related symptoms, hepatic disorders, renal disorders, and neurocognitive/neurologic events.
- Mean LDL-c lowering at week 6 was significantly greater with triple therapy (-63.6%) than with placebo (–3.1%). The difference between groups was -60.5% (95%CI: -68.0% to -53.0%, P<0.001).
- Triple therapy, compared with placebo, also led to significant reductions at week 6 in non-HDL-c (difference between groups: -58.7%; 95%CI -64.9 to -52.6%), total cholesterol (difference: -46.0%; 95%CI -51.6 to -40.4%), apoB (difference: -54.1%; 95%CI -59.7 to -48.6%), hsCRP (difference: -41.9%; 95%CI -60.0 to -21.4%), and triglycerides (difference: -36.3%; 95%CI -49.7 to -22.8%). Triple therapy had no effect on HDL-c levels.
- 90% Of patients in the triple therapy group achieved LDL-c <70 mg/dL at week 6. No patients in the placebo group achieved this target (P<0.001 for between-group comparison). 58.5% Of patients achieved LDL-c <55 mg/dL with triple therapy at week 6, compared with no patients in the placebo group. 95% Of patients experienced LDL-c lowering of ≥50% with triple therapy, compared with no patients in the placebo group (P<0.001 for between-group comparison).
- There was no difference in rates of treatment-emergent AEs between groups. 35% Of patients reported AE’s in both the triple therapy and placebo groups. AEs were predominantly mild or moderate in severity (one severe muscle spasm occurred in a patient in the placebo group). Three AEs of special interest occurred in more than one patient: hepatic enzyme increase (2 [5%] in the triple therapy group, 0 in the placebo group), pain in extremity (2 [5%] in the triple therapy group, 0 in the placebo group), and muscle spasms (1 [2%] in the triple therapy group, 2 [10%] in the placebo group).
This phase 2 randomized clinical trial showed that simultaneous initiation of bempedoic acid, statin and ezetimibe significantly reduces LDL-c by 60.5% in patients with hypercholesteremia, compared with placebo. Treatment goal of LDL-c levels <70 mg/dL was achieved by 90% of patients with triple therapy.
Guideline-directed targets for LDL-c lowering can be hard to achieve in clinical practice due to possible adverse effects, poor adherence, and ceiling effects of drugs at maximally tolerated doses. Maciej Banach (Lodz, Poland) and Peter E. Penson (Liverpool, UK) state in their editorial comment  that using a combination of available therapies is an attractive approach to achieve effective lipid lowering. The study by Rubino et al., provides important knowledge on how multiple lipid-lowering therapies could be used together.
Banach and Penson state that use of a submaximal statin dose is likely to reduce the frequency of side effects. Bempedoic acid is a cholesterol biosynthesis inhibitor that acts on the same pathway as statins. However, bempedoic acid is a prodrug that is converted to its active form in the liver, but not in skeletal muscle. This lowers the potential for muscle-symptoms. Bempedoic acid could therefore be suitable for patients with a dose-limiting statin intolerance. Furthermore, statin therapy -especially at high doses- might be associated with a higher risk of new onset diabetes mellitus (NODM). In contrast, it has been shown that bempedoic acid reduces the risk of NODM. Treatment with a combination of lipid-lowering agents at reduced doses has the potential to reduce treatment-limiting adverse effects compared to high-dose monotherapy. This could not only result in treatment goal achievement, but also in maintaining low LDL-c levels for a long time. In addition, triple therapy in this study led to a substantial reduction in hsCRP. This is interesting since recent studies have provided evidence for a causative role of inflammation in ASCVD residual risk.
Current guidelines advice to start lipid-lowering therapy with a single agent and more drugs can be added later if treatment goals are not met. This approach does not take into account that proportional lipid reduction is predictable. In patients with very high baseline LDL-c, it is unlikely that treatment targets are achieved with monotherapy. This is an argument to initiate lipid-lowering therapy with multiple agents at once in patients at very or extremely high CV risk. Another situation were initiation of treatment with non-statin agents is preferable is in the case of known statin intolerance.
In this study, treatment with triple therapy was compared to placebo. Banach and Penson comment that that it would be interesting and important to study treatment effects of triple therapy in comparison to conventional treatment regiments. They also point out that the study was of short duration. Study endpoints comprised lipid levels after 6 weeks treatment, instead of CV events during a longer follow-up period. However, given the proven efficacy of bempedoic acid, statin and ezetimibe, it would be surprising if the changes in lipid profile did not translate into clinical benefit, according to Banach and Penson. It would also be interesting if combining the three studied agents in one ‘polypill’ would improve compliance. Banach and Penson conclude that -if the studied approach is sustainable in the long term and translates to improved outcomes- the study of Rubino et al. has contributed to a promising approach to achieve lipid targets.