Emerging Pharmacological Therapies in the Treatment of Atherosclerosis: A Review

here is now considerable diversity in the pharmacologic management of atherosclerosis, which goes well beyond a statin-only strategy for lowering LDL-C. While intensive LDL-C lowering continues to be the backbone of ASCVD prevention, therapies targeting other pathways, such as hepatic PCSK9 synthesis, ATP-citrate lyase, CETP, lipoprotein(a) [Lp(a)], and vascular inflammation, have been gaining increased attention. Two newer drugs, bempedoic acid and colchicine, have already shown cardiovascular outcome benefits in the right indication and in the appropriate population. In a selected group of patients with coronary disease, low-dose colchicine has also been shown to have cardiovascular benefits. But variations between clinical trials suggest that it may be more or less effective in different patients, with different clinical characteristics and at different stages of treatment. Another significant development is inclisiran, which can achieve long-lasting PCSK9 suppression along with significant LDL-C lowering effects and is administered only twice a year as a maintenance dose. Similarly, obicetrapib has shown very significant effects on LDL-C and other atherogenic lipoproteins. However, it remains to be seen whether it will have a place in routine cardiovascular prevention, pending confirmation of cardiovascular benefit in dedicated outcome studies. The emergence of Lp(a)-targeted therapy may be one of the biggest breakthroughs in preventive cardiology, as it is a largely genetically determined condition and has historically not had a targeted treatment. Efforts to directly target an important element of genetically determined residual cardiovascular risk have shown remarkably large reductions in circulating Lp(a) levels with Pelacarsen, olpasiran, lepodisiran, zerlasiran, and muvalaplin. The big unknown, though, is whether the significant decreases in Lp(a) levels will lead to a decrease in the number of myocardial infarctions, strokes, cardiovascular deaths, and other big adverse cardiovascular events. Selected inflammatory pathways are modifiable therapeutically to decrease cardiovascular events with the use of canakinumab and colchicine. By comparison, the ZEUS trial in patients with ziltivekimab showed that a significant reduction in inflammatory markers does not always lead to cardiovascular benefits. This study highlights that biological plausibility and successful modulation of the biomarker does not necessarily mean that outcomes for patients will improve, and that the effects of modulation in different inflammatory pathways may be very different. In general, the future of atherothrombotic drug therapy will be more personalized and mechanism-based, with treatment directed towards the primary drivers of cardiovascular risk that remain after pharmacotherapy. However, new therapies should be used in addition to existing evidence-based therapy, especially high-intensity LDL-C lowering therapy. All new therapies must be shown to provide a cardiovascular benefit with good safety, treatment burden, accessibility, and cost-effectiveness in well-powered randomized controlled outcome studies before they can be widely used in the clinic. In sum, this integration of novel classes of therapies—lipid-lowering, Lp(a)-directed, and anti-inflammatory—has the potential to significantly broaden the scope for prevention of recurrent ASCVD events and the global burden of atherosclerotic cardiovascular disease.  

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