Elevated serum lipoprotein(a) (Lp[a]) levels are linked to atherosclerotic cardiovascular disease (ASCVD) and stroke, currently with limited treatment options. This article discusses data from studies addressing investigational therapies for patients with elevated Lp(a), including data presented at the American College of Cardiology 74th Annual Scientific Session & Expo (ACC.25).

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Following this presentation, featured expert Steven E. Nissen, MD, MACC, was interviewed by Conference Reporter Associate Editor-in-Chief Rick Davis, MS, RPh. Clinical perspectives from Dr Nissen on these findings are presented here.

Approximately 20% of the global population has elevated Lp(a) levels, which are very strongly associated with both ASCVD and stroke. Elevated Lp(a) is primarily genetic in origin, and the vast majority of elevated levels are determined by the LPA gene. Unlike most other risk factors for CVD, we have really struggled with finding a way to treat this disorder.

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The most effective way to treat elevated Lp(a) that has emerged thus far is to prevent the LPA gene from producing apolipoprotein(a) (apo[a]). The most promising approach is to give an injectable nucleic acid–based therapeutic that is either DNA based (ie, an antisense oligonucleotide) or RNA based (ie, a small interfering RNA [siRNA]), both of which degrade the messenger RNA responsible for producing apo(a). If you do not generate apo(a), you do not make intact Lp(a) particles.

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There are several new therapies in development. The first was pelacarsen, an injectable antisense oligonucleotide that lowered Lp(a) by 80% in the phase 2 AKCEA-APO(a)-L_Rx trial. Pelacarsen is currently being studied in the large phase 3 Lp(a)HORIZON trial, which has been ongoing for several years with more than 8000 patients enrolled, all of whom have ASCVD. The study should conclude during the first half of 2026 and will be a pivotal study because the US Food and Drug Administration (FDA) and other global regulatory agencies will not approve any of these new drugs until they show a reduction in morbidity and mortality.

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Shortly after the Lp(a)HORIZON trial was started, data on olpasiran became available. Olpasiran is an siRNA given by injection every 3 months. Phase 2 data have shown a substantial maximal reduction in Lp(a) of nearly 100% with high doses of olpasiran, with sustained effects for several months. Olpasiran is currently being studied in the large phase 3 OCEAN(a)-Outcomes trial.

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There is also a drug known as zerlasiran, which has completed phase 1 and 2 trials. Data have shown zerlasiran to be effective at lowering Lp(a) with a durable effect when given multiple times per year, with a maximum Lp(a) reduction ranging from 90% to 98% with high doses.

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Lepodisiran is a noncanonical siRNA, a double-stranded RNA with a longer nucleotide sequence than traditional siRNA molecules. Like all the drugs in this class, lepodisiran is conjugated with the sugar N-acetylgalactosamine, which has a receptor in the liver that allows the drug to concentrate in hepatocytes. For reasons that are not entirely clear, lepodisiran appears to have a more durable effect, with reductions in Lp(a) of approximately 90% out to 300-plus days after injection in a very small phase 1 trial.

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At ACC.25, I reported the results of the larger phase 2 ALPACA trial of lepodisiran, which enrolled 320 participants. We studied 5 dose groups: lepodisiran 16 mg, 96 mg, or 400 mg at baseline and again at day 180; lepodisiran 400 mg at baseline and placebo at day 180; or placebo at baseline and at day 180. Participants in the ALPACA trial were required to have a serum Lp(a) concentration of 175 nmol/L or greater, and the median Lp(a) concentration at entry was elevated at approximately 250 nmol/L. The primary end point was the time-averaged reductions in serum Lp(a) from day 60 to day 180. There was a 93.9% reduction in the pooled 400-mg population during this time interval. The group that received two 400-mg doses (ie, 1 dose at baseline and 1 dose at day 180) had a 94.8% reduction in Lp(a) from day 30 all the way out to day 360. These are very substantial and durable effects with a 400-mg dose. Safety findings were favorable, with injection site reactions occurring in up to 11.6% of patients and isolated increases in liver enzymes occurring in up to 5.8%. We have an ongoing phase 3 trial, ACCLAIM-Lp(a), underway that includes both secondary and primary prevention patients and can be adapted based on the findings from the phase 2 trial.

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Another approach that has emerged recently is the oral therapy muvalaplin, a single, once-daily pill that blocks the association of apo(a) with apolipoprotein(b), preventing the formation of intact Lp(a) particles. In phase 1 and 2 studies, muvalaplin has shown the ability to reduce Lp(a) levels substantially.

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A few years ago, we studied Lp(a) levels in more than 48,000 people in 48 countries around the world, all of whom had ASCVD, but only 13.9% actually had prior measurements of Lp(a). So, we have a real education problem for both physicians and patients, and we will not know who to treat when these new drugs become available unless we begin to test more patients for the disorder.