Effect of Lipid-Lowering Therapies on Coronary Plaque Burden: A Meta-Analysis of High-Intensity Statin and PCSK-9 Inhibitor Therapies.

Background: Atheromatous plaques are the hallmark of atherosclerotic cardiovascular disease (ASCVD) and major adverse cardiac events. Low-density-lipoprotein-cholesterol (LDL-C) affects atheroma progression significantly. High-intensity statin therapy (HIST) is commonly used as lipid-lowering therapy to reduce atheroma burden. With the increasing use of Proprotein Convertase Subtilisin/Kexin type 9 (PCSK-9) inhibitors, a comprehensive analysis on PAV regression through HIST and additional PCSK-9 therapy is needed.

Objectives: We aimed to assess the effects of lipid-lowering therapies on LDL-C level reductions and investigate the driving forces of associated changes in PAV.

Methods: We performed a meta-analysis on existing randomized controlled trials utilizing HIST monotherapy or HIST plus PCSK-9 inhibitors and compared the extent of LDL-C level and percent atheroma volume (PAV) changes assessed by serial intravascular ultrasound (IVUS). We further analyzed subgroups with follow-up LDL-C levels greater than and less than 70 mg/dl. Random-effects models with Hartung-Knapp adjustments for smaller sample sizes enabled more conservative estimations. Treatment effect (TE) sizes were reported as standardized mean difference (SMD) in mg/dl for LDL-C and percentage points for PAV with corresponding 95% confidence intervals (CI). P-values <0.05 were regarded as statistically significant.

Results: Nine eligible RCTs with a total of 6353 patients were included. These reflected a total of four therapeutic strategies, ranging from moderate intensity statin therapy only to HIST plus PCSK9-inibitor therapy. For LDL-C, the SMD for LDL-C of all included studies was -66.16 mg/dl (TE -2.36, 95% CI -80.8 mg/dl to -51.5 mg/dl, P<0.01). The SMD for LDL-C in studies with HIST was -59.3 mg/dl (TE -2.12, 95% CI -66.4 mg/dl to -52.2 mg/dl, P<0.01) while in studies with PCSK-9 inhibitors in addition to statins it was -97.72 mg/dl (TE -3.38, 95% -131.6 mg/dl to -63.82 mg/dl, P<0.01). For PAV, the pooled SMD of PAV of all included studies was -0.97 percentage points (TE -0.11, 95% CI −1.73 percentage points to −0.21 percentage points, P<0.01). The pooled SMD of PAV for HIST was -0.96 percentage points (TE -0.11, 95% CI -0.46 percentage points to -1.46 percentage points, P<0.01) while for PCSK-9 inhibitors in addition to HIST it was -1.92 percentage points (TE -0.24, 95% CI -3.47 percentage points to -0.37 percentage points, P<0.01). Subgroup analyses revealed a significant overall PAV reduction in therapy arms that achieved mean LDL-C levels below 70 mg/dL (TE -0.16, 95% CI -1.81 to -0.81 percentage points, P<0.01) with a mean follow-up LDL-C of 47 mg/dL (median 52 mg/dL, SMD -77.2 mg/dl). In contrast, therapy arms with a follow-up LDL-C greater than 70 mg/dL with an average follow-up LDL-C of 78 mg/dL and a SMD of -54.35 mg/dL showed no significant PAV change (TE -0.02, 95% CI -0.14 percentage points to 0.10 percentage points, P 0.78). There was a linear correlation between median achieved LDL-cholesterol within each therapy arm and changes in PAV (Figure 1).

Conclusions: We demonstrate that sufficient LDL-C reduction, particularly with PCSK-9 inhibitors added to HIST, significantly decreases both LDL-C and PAV. Comparatively, PAV regression appears driven by the extent of LDL-C reduction rather than specific active ingredients, with follow-up LDL-C levels <70 mg/dL showing the most impact on PAV regression.