Should pharmacotherapy targeting lipoprotein(a) be further expanded for patients with diabetes?

The risk of atherosclerotic cardiovascular disease (ASCVD) persists despite optimal low-density lipoprotein cholesterol (LDL-C) management, which is referred to as residual risk. Lipoprotein(a) [Lp(a)] is a particle assembled in the liver, comprising an LDL-like particle and apoprotein(a), which is covalently bound to apolipoprotein B (apoB). A large inter-individual variation of plasma Lp(a) concentrations is observed in the general population. Furthermore, Lp(a) concentrations vary between different ethnicities; generally high in African–American population and low in East Asian population. High Lp(a) levels are an independent risk factor for ASCVD and calcific aortic valve diseases. Both Lp(a) and LDL contain one apoB per particle, but the atherogenicity of Lp(a) is substantially greater than that of LDL.¹ Lifestyle changes and standard lipid-lowering treatments have minimal or no effect on Lp(a) levels. Thus far, interest in developing new drugs that can target Lp(a) has increased. PCSK9 inhibitors can reduce Lp(a) levels by 25–30%. However, pelacarsen, an antisense oligonucleotide that targets the Lp(a) gene in hepatocytes, has demonstrated strong Lp(a) reduction of 35–80% in Phase 2 trials.² The OCEAN(a)-DOSE trial evaluated the effects of the small interfering RNA, known as olpasiran, in patients (90% Caucasian) with ASCVD and Lp(a) levels of >60 mg/dL (150 nmol/L).³ Olpasiran decreased Lp(a) levels dose-dependently, 70.5–101.1% reductions by 10–225 mg. Phase 3 trials are ongoing to assess the effect of these drugs on cardiovascular events in patients diagnosed with ASCVD with elevated Lp(a) levels. Moreover, a recent study combined five prospective studies on a community basis and analysed the association between Lp(a) levels and ASCVD events by long-term (>20 years) follow-up.⁴ Notably, ASCVD risk increased despite an Lp(a) level of 75th–90th percentile [median: 25.9 mg/dl (65 nmol/L), adjusted hazard ratio: 1.18, and 95% confidence interval: 1.09–1.28]. Furthermore, the risk of elevated Lp(a) was constant across different races or ethnicities. Generally, the threshold value for Lp(a) elevation has been set at 125 nmol/L or 50 mg/dL, but the risk may already increase at levels lower than this value. This study revealed a stronger association between Lp(a) and ASCVD in patients with diabetes mellitus than in those without.⁴ Conversely, Lp(a) is less predictive of cardiovascular events in patients with metabolic syndrome than in those without.⁵ Therefore, further studies are necessary to evaluate drugs that target Lp(a) in patients with overt diabetes with lower Lp(a) levels than those set for ongoing clinical trials.

Conflicts of interest: None declared.

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