Lipoprotein(a) (Lp[a]) is an independent risk factor for coronary artery disease, and the presence of other risk factors serves as a further amplifier of risk. Researchers presented clinical studies of Lp(a)-lowering agents and addressed these and related issues at the recent American College of Cardiology 74th Annual Scientific Session & Expo (ACC.25).

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Following these presentations, featured expert Deepak L. Bhatt, MD, MPH, MBA, FACC, FAHA, FESC, MSCAI, was interviewed by Conference Reporter Associate Editor-in-Chief Rick Davis, MS, RPh. Clinical perspectives from Dr Bhatt on these findings are presented here.

Elevated Lp(a) is found in 20% to 25% of adults, making it the most common inherited dyslipidemia. Lp(a) is a very atherogenic lipid moiety, a finding that is supported by many studies; the higher the level gets, the greater the cardiovascular (CV) risk. Lp(a) seems to be more atherogenic than low-density lipoprotein (LDL) cholesterol, and it is also prothrombotic. In addition, Lp(a) is an independent risk factor for coronary artery disease, contributing to CV risk even in the presence of other risk factors such as elevated LDL cholesterol, triglycerides, and high-sensitivity CRP (hs-CRP). Elevated hs-CRP further amplifies the CV risk. For example, in the REDUCE-IT trial, elevated Lp(a) was predictive of major adverse CV events in patients who were treated with statins and achieved very good LDL control.

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Studies of PCSK9 inhibitors have shown not only that Lp(a) increases CV risk (and this increased risk is independent of LDL levels) but also that there appears to be an associated lower risk of CV events when Lp(a) levels are lower, pointing to Lp(a) as being a potential target for therapy. For example, findings from a 2021 study showed that Lp(a) levels were reduced in patients from India who were treated with evolocumab for hypercholesterolemia. As discussed in a UK Biobank study by Kavenpreet Bal, MS, and coauthors presented at ACC.25, South Asians, regardless of where they live, have the highest rates of coronary artery disease and also seem to have elevated Lp(a), suggesting that Lp(a) levels are largely determined genetically. Guidance from both the European Society of Cardiology and the National Lipid Association recommend testing adults at least once for Lp(a), although there does seem to be some test variability over time even when the same assay is used, and statins can increase Lp(a) levels slightly. We should learn more about the epidemiology and natural history of Lp(a) from the many ongoing treatment trials.

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The results of the phase 2 ALPACA trial of lepodisiran, a long-acting, small-interfering RNA that lowers Lp(a), were presented by Steven E. Nissen, MD, et al at ACC.25. Although this was not an outcomes trial, the results were striking. In particular, the highest dose of lepodisiran reduced Lp(a) substantially and was very long acting, with an effect lasting several months and, possibly, for 1 year. This seems to be a very promising Lp(a) therapeutic, although, of course, there needs to be a large phase 3 trial to show that it actually reduces CV events.

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With respect to the treatment of elevated Lp(a), any additional CV risk factors such as LDL cholesterol and hs-CRP, together with triglycerides, should also be treated aggressively. I have found that many patients with premature atherosclerosis or myocardial infarction, or who just need stenting or bypass surgery under the age of 50, have a fairly high prevalence of elevated Lp(a) levels. I measure Lp(a) in all patients, although some physicians question that approach because, currently, there are no US Food and Drug Administration (FDA)–approved, available therapeutic agents, so why measure something that you cannot modify?

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Although there is some wisdom to that, my response is that there are other treatable CV risk factors that can be managed very aggressively in these patients. In particular, as suggested in a large pooled analysis by Xingdi Hu and colleagues presented at ACC.25, if LDL is very elevated, then it should be lowered, of course. If it is really quite elevated, consider a PCSK9 inhibitor, which will also have an effect on reducing the Lp(a) level. However, the effect is much more modest (eg, a 25%-30% reduction) than the effect that dedicated Lp(a)-lowering drugs can achieve.

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In the ALPACA trial, for example, there was a placebo-corrected reduction in Lp(a) of approximately 94% to 95%. So, that is an enormous reduction in Lp(a) levels, well beyond what can be achieved with a PCSK9 inhibitor. In the future, it is conceivable that patients with both elevated LDL levels and elevated Lp(a) levels would need to be treated with a PCSK9 inhibitor to reduce LDL to very low levels and, additionally, with an LP(a)-lowering strategy. Many of these highest-risk patients with elevated Lp(a) levels may get that dual approach, if ongoing and planned CV outcomes trials support it.