Network meta-analysis of LLTs in patients with hypercholesterolemia and high CV risk
Comparative efficacy of non-statin lipid-lowering therapies in patients with hypercholesterolemia at increased cardiovascular risk: a network meta-analysis
Introduction and methods
In the majority of patients with ASCVD and increased cardiovascular risk, treatment with statins alone does not result in a clinically meaningful reduction in LDL-c concentration [1,2]. For these patients, and for patients who cannot tolerate statins, other lipid-lowering agents are available, such as the small interfering RNA inclisiran, the monoclonal antibodies evolocumab and alirocumab, bempedoic acid, and ezetimibe [3-8]. However, it is unclear how the efficacy of these agents compares.
Aim of the study
The aim of this network meta-analysis was to estimate the relative efficacy of inclisiran, evolocumab, alirocumab, bempedoic acid, and ezetimibe in patients with hypercholesterolemia and increased cardiovascular risk receiving maximal tolerated statin therapy.
The researchers conducted a systematic review according to the PRISMA statement. Several databases (MEDLINE, Embase, Cochrane Central Register of Controlled Trials, and Web of Science) were searched for relevant RCTs published through February 2021. Additionally, trial registries were searched for ongoing RCTs. A total of 31 RCTs were selected based on the following predefined criteria: (a) adult patients with hypercholesterolemia, including heterozygous familial hypercholesterolemia, ASCVD and/or high to very high cardiovascular risk, in whom LDL-c concentration was not adequately regulated despite maximal tolerated statin therapy; (b) intervention arm with inclisiran, evolocumab, alirocumab, bempedoic acid, or ezetimibe (at the approved doses); (c) control arm with one of the listed lipid-lowering agents, other lipid-lowering agents, or placebo; and (d) percentage change in LDL-c concentration after 24 (or 12) weeks from baseline as an outcome. Finally, the researchers conducted a Bayesian network meta-analysis of 23 RCTs using random effects models.
The outcome of interest was the percentage change in LDL-c concentration after 24 weeks from baseline. If data were not available after 24 weeks, then data after 12 weeks were used.
- Inclisiran, alirocumab, and evolocumab provided statistically significant greater efficacy when compared with placebo, bempedoic acid, and ezetimibe.
- The efficacy of inclisiran was similar to alirocumab (mean difference: 0.78%; 95%CrI: -8.35 to 9.88) and evolocumab (mean difference: 8.16%; 95%CrI: -1.82 to 18.49).
- There was evidence of statistical heterogeneity across the included RCTs, which roughly corresponded to a variation of 5-10% change in LDL-c concentration after 24 weeks from baseline.
This network meta-analysis of 23 RCTs provides insight into the relative efficacy of the lipid-lowering agents inclisiran, evolocumab, alirocumab, bempedoic acid, and ezetimibe, for which no direct comparative study is available. The results suggest that inclisiran, alirocumab, and evolocumab provide superior efficacy over placebo, bempedoic acid, and ezetimibe in terms of reduction in LDL-c concentration in patients with hypercholesterolemia and increased cardiovascular risk receiving maximal tolerated statin therapy. The efficacy of inclisiran, alirocumab, and evolocumab appears to be similar.