Three new studies published in Circulation highlight advances in lipid-lowering therapy, with early-stage data supporting a first-in-class oral PCSK9 inhibitor and two separate analyses showing that evolocumab reduces major cardiovascular events across a range of high-risk patients, including those with elevated Lp(a) and those with prior PCI but no history of MI.

In the first study, researchers tested the use of laroprovstat in treating patients with hypercholesterolemia. Laroprovstat is the first oral, small-molecule PCSK9 inhibitor in clinical development for lowering LDL cholesterol (LDL-C) levels.

Rick B. Vega, PhD, et al., assessed LDL uptake in HepG2 cells, as well as LDL-C levels in mice expressing human PCSK9. Additionally, they evaluated the safety, tolerability and pharmacologic effects of laroprovstat after single ascending doses in patients with LDL-C >70 and ≤190 mg/dL, and in multiple ascending doses to patients with LDL-C >100 receiving daily doses (1 mg or 30 mg vs. placebo) for 28 days following a rosuvastatin run-in period.

Overall findings showed the novel drug to be well tolerated, safe and able to be taken with or without food. In treatment-naive participants with hypercholesterolemia, researchers noted that the combination of rosuvastatin (20 mg) and laroprovstat (30 mg) led to an 80% reduction in LDL-C.

“Laroprovstat achieves rapid and robust lowering of [LDL-C] levels on top of a statin in treatment-naive participants with hypercholesterolemia,” note Vega and colleagues. “Laroprovstat dosed with a statin would enable most patients to achieve their [LDL-C] goal and may lead to a reduction of cardiovascular risk and improved cardiovascular outcomes.”

In a prespecified subgroup analysis of the VESALIUS-CV trial, evolocumab reduced the risk of major cardiovascular events in stable patients with prior PCI but no MI.

Researchers randomized 12,257 patients with atherosclerosis or high-risk diabetes without prior MI or stroke and LDL-C >90 mg/dL to evolocumab or placebo. The mean age of participants was 66 years, 31% were women and approximately 30% had undergone prior PCI.

Over a median follow-up period of 4.6 years, evolocumab lowered LDL-C and significantly reduced cardiovascular risk, including a 30% reduction in 3-point MACE and a 50% reduction in MI, with benefits emerging within six months. Additionally, study investigators observed lowered rates of urgent revascularization and modest reductions in cardiovascular and all-cause mortality.

“These findings support intensive LDL-C-lowering in patients who have undergone PCI even in the absence of prior MI,” said Brian A. Bergmark, MD, FACC, et al.

In another prespecified analysis of 7,557 patients with atherosclerosis or high-risk diabetes but without prior MI or stroke and who were enrolled in the VESALIUS-CV trial, researchers found that Lp(a) was independently associated with an increased risk of major coronary events, but not ischemic stroke.

Victorien Monguillon, MD, et al., found that higher baseline Lp(a) was associated with an increased risk of major coronary events, especially for MI. However, there was no association between Lp(a) and ischemic stroke. After 48 weeks, evolocumab reduced LDL-C by 66.8 mg/dL and Lp(a) by 38.0 nmol/L in patients with baseline Lp(a) >105 nmol/L compared with 61.1 mg/dL and 6.0 nmol/L in those with baseline Lp(a) ≤105 nmol/L. The relative reductions in risk of major coronary events were 41% in those with higher Lp(a) vs. 35% in those with lower Lp(a).