Lipoprotein(a): novel target and emergence of novel therapies to lower cardiovascular disease risk

Abstract

Purpose of review: This article summarizes recent observations on the role of lipoprotein(a) [Lp(a)] as a risk factor mediating cardiovascular disease.

Recent findings: Lp(a) is a highly prevalent cardiovascular risk factor, with levels above 30 mg/dl affecting 20-30% of the global population. Up until now, no specific therapies have been developed to lower Lp(a) levels. Three major levels of evidence support the notion that elevated Lp(a) levels are a causal, independent, genetic risk factor for cardiovascular disease: epidemiologic studies and meta-analyses, genome-wide association studies and Mendelian randomization studies. Recent studies also have noted that individuals with low levels of Lp(a) are associated with a higher risk of incident type 2 diabetes mellitus, and conversely individuals with high levels have a lower risk, but this association does not appear to be causal. Novel therapies to lower Lp(a) include PCSK9 inhibitors and antisense oligonucleotides directly preventing translation of apolipoprotein(a) mRNA.

Summary: With this robust and expanding clinical database, a reawakening of interest in Lp(a) as clinical risk factor is taking place. Trials are underway with novel drugs that substantially lower Lp(a) and may reduce its contribution to cardiovascular disease.

Figure 1

Three levels of evidence, epidemiological studies and meta-analyses, instrument variable analyses and genome-wide association studies, demonstrate the increasing risk for CVD due to elevated Lp(a). Reprinted with permission from Erqou et al [1], Kamstrup et al [5] and Clarke et al [6].

Figure 2

Demonstration of residual risk of elevated Lp(a) in the JUPITER, AIM-HIGH and LIPID trials, in setting of very aggressive statin therapy and well-controlled LDL-C levels. The Forest plot shows a study level meta-analysis of these 3 recent reports from these trials. Shown are baseline Lp(a) levels of AIM-HIGH niacin and placebo arms, baseline Lp(a) levels in the LIPID trial and baseline Lp(a) levels in the entire JUPITER arm and in the group receiving rosuvastatin and the hazard ratio of the highest quartile and recurrent CVD events.

Figure 3

Mean percent change in Lp(a) and OxPL-apoB with time by treatment group in the multi-dose cohorts (A) Lp(a). (B) OxPL-apoB; the datapoints for days 22 and 29 in the 100 mg and 200 mg doses are not displayed in the graph (but were used in the statistical analysis) because the mean percent change values were skewed by two outliers with very low OxPL-apoB concentrations. The shaded area represents the dosing window and arrows indicate dosing at days 1, 3, 5, 8, 15, and 22. Lp(a)=lipoprotein(a). OxPL-apoB=oxidized phospholipids on apolipoprotein B. *p=0.020, †p≤0.008, ‡p≤0.001. P values are for the primary efficacy endpoint at day 36 as determined by the Exact Wilcoxon Rank Sum comparing ISIS-APO(a)_Rx versus placebo. P values are only shown for the primary efficacy endpoint at day 36. Reprinted with permission from Tsimikas et al [47].