Safety and Efficacy of Achieving Very Low LDL Cholesterol Concentrations with PCSK9 Inhibitors

Abstract

Background: The advent of newer pharmacological agents, particularly proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors, in combination with conventional lipid-lowering treatments, has allowed for the significant lowering of low-density lipoprotein cholesterol (LDL-C). However, it is unclear if very low LDL-C levels achieved with the use of PCSK-9 inhibitors are associated with increased adverse events that may outweigh potential benefits. Methods: A systematic search of PubMed, Medline, and Cochrane databases was conducted from their inception to 21 February 2025, for randomized controlled trials (RCTs) reporting clinical outcomes with intensive lipid-lowering treatment with PCSK-9 inhibitors leading to very low (<40 mg/dL) LDL-C levels vs. a control group with higher LDL-C levels. The outcomes of interest included the incidence of major adverse cardiovascular events (MACEs), neurocognitive disorders, diabetes mellitus, muscle disorders, any adverse events, events leading to drug discontinuation, cataract, hepatobiliary disorders, and cancer. Random effects meta-analysis models were used to calculate the pooled incidence and odds ratio (OR) with 95% confidence intervals (Cis). Results: A total of six RCTs with 52,951 patients (11,209 very low LDL-C, and 41,742 control) met the inclusion criteria. Compared with patients in the control arm, very low LDL-C was associated with a reduction in MACEs (OR = 0.76, 95% CI: 0.64, 0.89; p < 0.01; I² = 44.8%). The incidence of most safety outcomes including neurocognitive disorders, diabetes mellitus, muscle disorders, any adverse events, events leading to drug discontinuation, cataract, hepatobiliary disorders, and cancer were comparable between the very low LDL-C and control groups. Conclusions: Very low LDL-C values following intensive lipid-lowering with PCSK-9 inhibitors are associated with a major reduction in cardiovascular events without any significant increase in serious side effects.

Keywords: PCSK9 inhibitors; adverse events; major adverse cardiovascular events; very low LDL.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram of study selection.

Figure 2

Forest plot of studies with odds ratios for (A) MACEs; (B): neurocognitive disorders; (C): diabetes mellitus; (D): muscle disorders in the very low low-density lipoprotein cholesterol group vs. control group. Forest plot of studies with odds ratios for (E): any adverse events; (F): adverse events leading to drug discontinuation; (G): cataract; (H): hepatobiliary, (I): cancer in the very low low-density lipoprotein cholesterol group vs. control group. Legend: Odds ratio for individual studies are indicated by squares and 95% CIs by horizontal lines. Overall totals and their 95% CIs are represented by diamonds, in which the diamond’s center denotes the point estimate, and the width denotes the 95% CI. The size of the squares and the diamonds are proportional to the statistical information conveyed.

Figure 2

Forest plot of studies with odds ratios for (A) MACEs; (B): neurocognitive disorders; (C): diabetes mellitus; (D): muscle disorders in the very low low-density lipoprotein cholesterol group vs. control group. Forest plot of studies with odds ratios for (E): any adverse events; (F): adverse events leading to drug discontinuation; (G): cataract; (H): hepatobiliary, (I): cancer in the very low low-density lipoprotein cholesterol group vs. control group. Legend: Odds ratio for individual studies are indicated by squares and 95% CIs by horizontal lines. Overall totals and their 95% CIs are represented by diamonds, in which the diamond’s center denotes the point estimate, and the width denotes the 95% CI. The size of the squares and the diamonds are proportional to the statistical information conveyed.