Patients with general dyslipidemia have several treatment options, and several investigational agents are in late-stage trials. Although there is currently no US Food and Drug Administration (FDA)–approved treatment for elevated lipoprotein(a) (Lp[a]), a number of investigational agents are also currently in development. Updates on some of these investigational agents for general dyslipidemia and elevated Lp(a) levels are provided in this article, including an angiopoietin-like 3 (ANGPTL3) antibody therapy discussed 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.

We are on the verge of conquering elevated low-density lipoprotein (LDL) cholesterol as a risk factor for cardiovascular disease. Between high-dose statins, ezetimibe, bempedoic acid, and PCSK9 inhibitors, we are doing very well, and new drugs for decreasing LDL levels are in development. One of the most interesting is obicetrapib, which is a highly active CETP inhibitor that has shown the ability to lower LDL cholesterol by up to 40% with a single, once-daily pill that can be added on top of statins and ezetimibe. Obicetrapib is moving along quickly in development and is currently in several phase 3 trials, including a large cardiovascular outcomes trial, PREVAIL.

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In the realm of PCSK9 inhibitors, we recently had an addition to the armamentarium of monoclonal antibodies, which have been around for a while: the small interfering RNA (siRNA) inclisiran. This siRNA is very durable, can be given twice a year, and can lower LDL cholesterol by up to 50%.

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In addition, there are other new targets emerging, one of which is elevated triglycerides and remnant cholesterol, and this is being targeted now with some additional drugs in development. These include agents targeting apolipoprotein CIII (APOC3), which is involved in triglyceride metabolism, and ANGPTL3, which is also being studied in some trials for hypertriglyceridemia. Although we have yet to show that these triglyceride-lowering drugs can reduce morbidity and mortality, they are promising. At least one of them (ie, plozasiran, which is an siRNA-based therapeutic targeting APOC3) effectively lowers triglycerides and has moved along quickly in development. Further, a phase 2 study on an ANGPTL3 antibody was featured in the ACC.25 conference journal. So, there are several potential additional therapies for general dyslipidemia in development.

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With respect to elevated Lp(a) levels, the clear strategy that most opinion leaders would currently recommend is to treat every other risk factor in those patients as aggressively as possible. Reduce LDL to below 55 mg/dL, lower blood pressure to reach a systolic blood pressure closer to 120 mm Hg than 130 mm Hg, get patients off the couch and exercising, and make sure that their body mass index is within the normal range of less than 25 kg/m². We can do things for these patients, which is another reason why Lp(a) needs to be measured more often because, in fact, we want to be able to manage the other risk factors until we have additional therapies on the market that are specifically directed at Lp(a).

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The first of these therapies is pelacarsen, which is currently being studied in the phase 3 Lp(a)HORIZON trial. If the trial is successful, filing for FDA approval will be carried out as an urgent matter, given the fact that elevated Lp(a) is an untreatable disorder. If the trial is successful, I hope that the FDA will review it quickly, make a decision, and provide approval for pelacarsen or other current investigational agents based on their ability to lower Lp(a) and reduce cardiovascular morbidity and mortality.