Metformin-induced PCSK9 inhibition further decreases LDL-C following statin treatment in non-diabetic patients with coronary artery disease and hyperlipoproteinemia(a)

Abstract

Abstract Purpose: Previous studies have revealed that metformin can downregulate PCSK9 expression in vitro, which provides a strong rationale for a possible beneficial impact on lowering atherogenic lipoprotein particles by metformin combination therapy. We aimed to investigate whether adding metformin could counteract the adverse effect of statins on PCSK9 and thus further improve lipid profiles in non-diabetic patients with CAD and hyperlipoproteinemia(a). Methods: This was an open-label, placebo-controlled, randomized trial (ChiCTR1900026925). Non-diabetic CAD patients with hyperlipoproteinemia(a) were randomized 1:1 to CLA (Cholesterol-Lowering Agents alone: atorvastatin+/-ezetimibe, n=38) and Met+CLA groups (metformin plus CLA, n=33). The primary endpoint was the therapeutic effect of 1-month metformin combination treatment on the LDL-C, Lp(a), and PCSK9 levels, analyzed using an enzymatic-based method, latex-enhanced immunoturbidimetric assay, and ELISA, respectively. Atherogenic lipoprotein particle components were assessed by nuclear magnetic resonance spectroscopy. Results: In our study, baseline medium LDL-C, Lp(a), and PCSK9 levels were 76.18 mg·dL-1, 201.30 nmol·L-1, and 80.54 ng·mL-1, respectively. After one month, metformin combination treatment significantly reduced LDL-C (-20.81%, P<0.001), allowing 72% of the patients to achieve guideline-recommended LDL-C goals. Additionally, there were notable drops in PCSK9 levels (-15.03%, P<0.001), but not in Lp(a) levels. Moreover, metformin plus CLA lowered LDL particle number (LDL-P) markedly more than CLA alone (-10.65% vs 1.45%，P=0.009), attributed mainly to a decrease in small-dense LDL particle (sdLDL-P) number in the Met+CLA group. Mechanistically, we demonstrated that metformin inhibited human hepatocellular cell PCSK9 expression induced by statins. Conclusion: One-month metformin combination treatment resulted in an incremental reduction of LDL-C levels in non-diabetic CAD patients with hyperlipoproteinemia(a) via inhibiting PCSK9 expression. Trial registration: Chinese Clinical Trial Registry identifier: ChiCTR1900026925 (10/26/2019)