Pleiotropic effects of bempedoic acid on endothelial function and arterial stiffness: a preliminary study

Background

Bempedoic acid is a novel lipid-lowering agent that reduces circulating low- density lipoprotein cholesterol (LDL) levels by inhibiting ATP citrate lyase, a key enzyme upstream of HMG-CoA reductase. While other lipid-lowering therapies such as statins and PCSK9 inhibitors have demonstrated pleiotropic vascular benefits, including improvements in endothelial function and aortic stiffness, these effects have not been thoroughly evaluated for bempedoic acid in clinical settings.

Methods

This observational, longitudinal, single-center study enrolled statin-intolerant patients eligible for bempedoic acid therapy based on predefined clinical criteria. The enrollment period spanned April 2023 to September 2024. The study's primary endpoints were the consistency and extent of LDL reduction after 3 months of therapy, and the effect of bempedoic acid on vascular function parameters. Endothelial function was assessed using the Reactive Hyperemia Index (RHI) via peripheral arterial tonometry (EndoPAT), while aortic stiffness was evaluated using pulse wave velocity (PWV), measured with the SphygmoCor system. Baseline measurements were compared with follow-up values at 3 months. Results Seventy-five patients with hypercholesterolemia (mean age 71.4 ± 7.9 years; 60% men) were enrolled. At 3-month follow-up, bempedoic acid had significantly improved the lipid parameters: LDL decreased from 157.6 ± 19.2 to 77.4 ± 24.9 mg/dl (Δ = –80.2 ± 36.4, P < 0.001), HDL increased from 50 ± 9.2 to 54 ± 8.8 mg/dl (Δ = +4 ± 2.3, P < 0.001), triglycerides decreased from 160.8 ± 26.6 to 77.6 ± 14.9 mg/dl (Δ = –83.2 ± 30.9, P < 0.001), and total cholesterol from 239 ± 21 to 145 ± 39 mg/dl (Δ = –94 ± 45, P < 0.001). Endothelial function (RHI), improved from 1.36 ± 0.47 to 1.77 ± 0.40 (Δ = +0.41 ± 0.6, P < 0.001), and arterial stiffness (PWV) decreased from 10.1 ± 1.21 to 9.2 ± 1.26 m/s (Δ = –0.9 ± 0.4, P < 0.001). Correlation analysis showed that ΔRHI was inversely associated with ΔLDL reduction (r = −0.391, P = 0.001) and ΔTC reduction (r = −0.359, P = 0.002), and positively associated with HDL increase (r = 0.367, P = 0.001). Similarly, ΔPWV correlated positively with ΔLDL (r = 0.260, P = 0.024) and ΔTC reductions (r = 0.342, P = 0.003), and inversely with HDL increase (r = –0.423, P < 0.001). No significant changes in creatinine, uric acid, or glycemic parameters were observed, supporting the short-term safety of bempedoic acid.

Conclusion

Bempedoic acid therapy significantly improved endothelial function and reduced arterial stiffness, in parallel with lipid profile improvement. These vascular benefits were achieved without adverse changes in renal function or uric acid levels, supporting the efficacy and short-term safety of bempedoic acid as a therapeutic option, particularly for statin-intolerant patients.