Efficacy and safety of inclisiran versus PCSK9 inhibitor versus statin plus ezetimibe therapy in hyperlipidemia: a systematic review and network meta-analysis

Abstract

Objective: Hyperlipidemia plays a crucial role in increasing the risk of cardiovascular diseases such as atherosclerosis. Recent studies have established that inclisiran positively influences lipid regulation. Nevertheless, its effectiveness in comparison to conventional treatments is still questionable. Hence, a methodical assessment of its effectiveness and safety is required. This research evaluates the efficacy and safety of inclisiran, PCSK9 inhibitors, and the combination of statins with ezetimibe in the treatment of hyperlipidemia via a network meta-analysis of randomized controlled trials (RCTs).

Methods: We performed an extensive search of English-language publications in the PubMed, Medline, Embase, and Cochrane Library databases until April 2024. We conducted a web-based meta-analysis and reported in accordance with the guidelines. We selected the percentage change in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), triglycerides (TG), and high-density lipoprotein cholesterol (HDL-C) as efficacy evaluation metrics and the incidence of adverse events as safety evaluation metrics for analysis and comparison.

Result: We incorporated 33 studies involving 23,375 patients, evaluating three interventions regarding their effects on LDL-C, TC, TG, HDL-C, and adverse events. All treatments improved metrics over placebo. Inclisiran significantly reduced LDL-C compared to statins (mean - 15.21, 95% CI [-25.19, -5.23]) but showed no significant difference from statin + ezetimibe. Surface under the cumulative ranking curve (SUCRA) rankings placed inclisiran highest for LDL-C reduction (26.2%). The combination of statin and ezetimibe was the most efficacious for triglyceride reduction (mean 17.2, 95% CI [10.22, 24.19]; mean 15.61, 95% CI [16.87, 24.35]). The safety profiles were comparable across treatments.

Conclusion: Inclisiran with its superior LDL-C reduction and low frequency of administration, appears promising for hyperlipidemia treatment, particularly for patients with adherence issues or side effects from other medications.

Systematic review registration: CRD42024550852.

Keywords: A systematic review; Ezetimibe; Hyperlipidemia; Inclisiran; Network meta-analysis; PCSK9 inhibitor; Statin.

Fig. 1

PRISMA flow diagram for search and selection of eligible studies included in the network meta-analysis

Fig. 2

Network of eligible comparisons for all treatments included in the analyses. Note (A) LDL-C, (B) HDL-C, (C) TC, (D) TG, (E) safety

Fig. 3

The forest plot comparing various intervention measures in improving LDL-C and TG. (A) A: Ezetimibe, B: Ezetimibe + statin, C: statin D: Placebo, E: PCSK9 inhibitor, F: PCSK9 inhibitor + Ezetimibe, G: Inclisiran. (B)A: Ezetimibe, B: Ezetimibe + statin, C: statin D: Placebo, E: PCSK9 inhibitor, F: Inclisiran

Fig. 4

SUCRA for various intervention measures in improving LDL-C, HDL-C, TC and TG (A)A: Ezetimibe, B:Ezetimibe + statin, C: statin D: Placebo, E: PCSK9 inhibitor, F: PCSK9 inhibitor + Ezetimibe, G: Inclisiran (B, C, D)A: Ezetimibe, B:Ezetimibe + statin, C:statin D: Placebo, E: PCSK9 inhibitor, F: Inclisiran

Fig. 5

The forest plot (A) and SUCRA (B) for various intervention measures in safety (A, B)A: Ezetimibe, B:Ezetimibe + statin, C:statin D: Placebo, E: PCSK9 inhibitor, F: PCSK9 inhibitor + Ezetimibe, G: Inclisiran

Fig. 6

Risk of bias graph

Fig. 7

Risk of bias summar