Lipoprotein(a) and CKD: Insights into New Therapeutic Opportunities

Patients with CKD are at a pronounced risk for cardiovascular events. Half of all patients with CKD stages 4−5 have CVD, and cardiovascular mortality accounts for nearly 50% of all deaths in patients with advanced CKD (stage 4) or ESKD (stage 5) compared with 26% in controls. 78 A meta-analysis of studies among non–dialysis-dependent CKD patients demonstrated an exponentially greater absolute risk for all-cause and CVD mortality with lower kidney function even after adjustments for established risk factors. 79 The high CVD burden in CKD motivates better understanding of the role of Lp(a) as a novel risk factor. In a systematic review of 15 prospective studies involving three different kidney disease populations (CKD, hemodialysis, and PD), elevated Lp(a) levels were associated with greater risks of CVD events and deaths in most studies adjusting for confounders. In brief, of the six studies in patients with different CKD stages, four showed significant associations with cardiovascular events, while two did not; of the eight studies in hemodialysis patients, six showed significant associations with either cardiovascular event, cardiovascular mortality, or all-cause mortality, while two studies did not. 80 The one study in PD patients showed a positive association between Lp(a) and greater risk of mortality. 81 Among these studies, the CRIC study stood out in terms of its large sample size and long follow-up duration and showed an independent association of elevated Lp(a) with MI and death in CKD. 82 In a CRIC subcohort with prevalent ASCVD at baseline and not on dialysis, elevated Lp(a) was associated with recurrent ASCVD events in nondiabetic CKD patients, but not in diabetic patients. 76 Recently, in >5000 patients with eGFR 30−60 ml/min per 1.73 m 2 or an eGFR >60 ml/min per 1.73 m 2 in the presence of overt albuminuria, elevated Lp(a) and genetic determinants of Lp(a) levels were associated with CVD at baseline and during follow-up, independent of traditional risk factors. 83 In this study, the number of K4 repeats and the presence of small apo(a) isoforms (≤22 K4 repeats)—both genetic determinants of Lp(a) levels—were significantly associated with prevalent CVD and incident major adverse cardiovascular events (MACEs). Notably, genetically predicted Lp(a) values versus measured Lp(a) levels led to even stronger associations. 83 The genetically predicted Lp(a) values were calculated based on a comprehensive LPA genetic risk score derived from 43 SNPs previously shown to be associated at genome-wide significance level with Lp(a) levels, 84 three other Lp(a)-decreasing variants (4925G>A and 4733G>A, and R21X) 85 – 87 and dominant apo(a) sizes. The use of genetic variants may offer several advantages including a better reflection of the life-long exposure to elevated Lp(a), minimization of confounding or reverse causation, and support for a causal association between Lp(a) and CVD risk. The question whether impaired kidney function increases Lp(a) levels or whether elevated Lp(a) causes kidney disease has been studied. Findings, including those in the aforementioned study, 83 provide support to the former, 64 , 67 , 68 , 88 but others, including Mendelian randomization studies, report a causal effect of Lp(a) on kidney disease. 76 , 89 , 90 One potential mechanism could be Lp(a) as the major carrier of proinflammatory OxPLs may contribute to kidney injury. Overall, observational studies largely support the role of elevated Lp(a) for CVD risk (Figure 1 D) and mortality across the CKD spectrum. Thus, studies exploring pharmacologic reduction in Lp(a) and subsequent effects on cardiovascular outcomes in this high-risk group are warranted. In this context, cardiovascular benefits of novel Lp(a)-lowering agents need to be demonstrated also in patients with different stages of CKD and/or treatment modalities. Notably, patients with urine protein-to-creatinine ratio ≥0.2 mg/mg 91 were excluded from the pelacarsen phase 2 trial 39 and patients with eGFR ≤30 ml/min per 1.73 m 2 or significant glomerular disease with urine protein-to-creatinine ratio ≥500 mg/g were also excluded from its phase 3 trial. 41 Similarly, the Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction-Outcomes trial and the A Study to Investigate the Effect of Lepodisiran on the Reduction of Major Adverse Cardiovascular Events in Adults With Elevated Lipoprotein(a) trial excluded patients with “severe kidney dysfunction” or patients with eGFR <15 ml/min per 1.73 m 2 , ongoing dialysis, diagnosis of active NS, or urine albumin-to-creatinine ratio of ≥5000 mg/g, respectively. Optimizing inclusion/exclusion criteria regarding CKD in clinical trials would provide insights into the broad applicability of Lp(a)-lowering therapies among diverse patients.

IL-6, a hormone-like cytokine mostly produced by T cells, upregulates hepatic apo(a) mRNA expression through response elements in the promoter region of the LPA gene. 92 Among the six IL-6-REs present in the LPA promoter, IL-6-response element six at −46 to −40 is a major regulatory element associated with apo(a) upregulation in the presence of IL-6. 92 Various inflammatory conditions, including rheumatoid arthritis, have been associated with elevated Lp(a), indicating a role for the innate immune system. 93 , 94 Moreover, elevated levels of IL-6 and IL-6 receptor polymorphisms have been associated with CVD risk. 94 In patients with rheumatoid arthritis, IL-6 receptor blockade by tocilizumab reduced Lp(a) by approximately 30%−37% 95 ; although data on Lp(a) effects of tocilizumab in patients with CKD is limited. Supporting a link between Lp(a) and inflammation, anti-inflammatory agents have been associated with Lp(a) modulation in CKD. 96 Inflammation mediated by IL-6 has been a target of studies involving patients with CKD with elevated C-reactive protein (CRP)—a high-risk group with significant unmet need (Table 2 ). This approach was based on studies demonstrating increased concentrations of both CRP and IL-6, but not LDL-C or HDL-C, predicted recurrent MACE and total mortality in CKD patients taking statins. 97 The data highlighted a major role of residual inflammation in CVD risk in CKD and provided support for testing novel inflammation-inhibiting agents. Lipoprotein(a) and IL-6–based and proprotein convertase subtilisin/kexin type 9–based therapies in relation to kidney function ALI, alirocumab; ASCVD, atherosclerotic cardiovascular disease; CRP, C-reactive protein; CVD, cardiovascular disease; EVO, evolocumab; FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; GMR, geometric mean ratio; IKF, impaired kidney function; LDL-C, LDL cholesterol; Lp(a), lipoprotein(a); ODYSSEY, Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab; PCSK9, proprotein convertase subtilisin/kexin type 9; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor; RESCUE, Randomized Evaluation of Patients with Stable Angina Comparing Utilization of Noninvasive Examinations. Kidney function assessed with eGFR of ≥90, 60−90, 20−60 ml/min per 1.73 m 2 for the reserved kidney function, stage 2 CKD, and stage ≥3 CKD groups, respectively. A 2024 phase 2b dose-finding study in patients with CKD randomized to 2.5, 5, or 10 mg dose of a mAb directed against the IL-6 ligand (clazakizumab) demonstrated up to 92% reduction in CRP relative to placebo among adults with CVD and/or DM receiving maintenance dialysis and with CRP of ≥2 mg/L 98 (Table 2 ). The Lp(a) levels were reduced by 38%, 37%, and 52%, respectively, across the increasing dose groups. 98 The efficacy and safety of another agent (ziltivekimab) was tested in patients with CKD with eGFR 10−60 ml/min per 1.73 m 2 and CRP ≥2 mg/L in Randomized Evaluation of Patients with Stable Angina Comparing Utilization of Noninvasive Examinations, a randomized, double-blind, phase 2 trial. 99 Ziltivekimab administration at doses of 7.5, 15, or 30 mg for 12 weeks resulted in concurrent dose-dependent reductions in CRP (77%, 88%, and 92%, respectively) and Lp(a) (16%, 20%, and 25%, respectively) compared with placebo. 99 The extent of Lp(a) reduction was modest compared with that observed with clazakizumab despite both agents resulting in a similar extent of CRP reduction. Currently, the cardiovascular efficacy of ziltivekimab is being investigated in an ongoing outcome trial in patients with established CVD, CKD (stages 3–4), and elevated CRP (A Research Study to Look at How Ziltivekimab Works Compared to Placebo in People With Cardiovascular Disease, CKD and Inflammation; NCT05021835 ). 100 While Lp(a)-lowering might be an important mechanism contributing to MACE reduction in this high-risk group, any potential Lp(a)-attributable contribution would depend on its baseline values and the extent of reduction. Although the extent of the effect of IL-6-inhibition on Lp(a) is inferior to those of siRNA or ASO-based Lp(a)-lowering agents, 1 , 38 it is tempting to speculate that the former, due to its concurrent effects on both inflammation and apo(a) synthesis, could exert multiple cardiovascular benefits. However, future studies are needed to establish the relative contribution of cardiovascular benefits due to anti-inflammatory and Lp(a)-lowering effects. Lp(a) has been shown to be five to six times more atherogenic than LDL at equimolar levels. 101 Thus, it would be of interest to study Lp(a)-lowering effects of anti-cytokine therapies in relation to Lp(a)'s risk mediating properties, including its OxPL content and to LPA genetic variants in CKD. The discovery of PCSK9 in the early 2000s marked a new era in pharmacologic management of hypercholesterolemia. 102 Studies using PCSK9-inhibitors (PCSK9is) demonstrated that besides reducing LDL-C these agents reduced Lp(a) in high-risk patients treated with statins conferring cardiovascular benefits. 103 – 107 Statins have a limited efficacy of cardiovascular protection in patients with advanced CKD and ESKD on hemodialysis, 78 , 108 , 109 although the reasons are not fully understood. This could be related to multiple factors, including the potential Lp(a)-increasing effect of statins 110 (Figure 2 ), higher Lp(a) levels in advanced versus early CKD stages, 57 and higher PCSK9 levels. 111 Among nondialysis CKD patients (stages 2−4), the PCSK9 level was correlated with the Lp(a) level and patients with CKD taking statins had higher PCSK9 levels compared with those not taking statins. 111 Mechanisms by which PCSK9i reduce Lp(a) are not fully understood. Proposed mechanisms include decreased syntheses of apoB and Lp(a), reduced availability of LDL to bind to apo(a), and enhanced Lp(a) uptake and removal by LDL-receptors or other hepatic receptors 112 – 114 (Figure 2 ). However, a role of LDL-receptor-mediated uptake in Lp(a) clearance has not been firmly established as findings either supporting or contradicting this have been published. 112 , 113 , 115 – 120 Contrasting effects of statins versus PCSK9is on Lp(a) in comparison with their effects on LDL-C. Both statins and PCSK9is reduce LDL-C levels through mechanisms associated with LDL receptor upregulation. Statins have been shown to increase Lp(a) levels through a mechanism involving an increase in LPA mRNA and apo(a) production. In contrast, PCSK9is reduce Lp(a) levels, and this is facilitated by a lesser competition from LDL-C for binding to potential receptors such as LDL receptor and/or a decreased production of apo(a) during treatments with PCSK9is. LDL-C, LDL cholesterol; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor. PCSK9i may confer CVD benefits in patients with CKD as well, although limited data exist due to exclusion of patients with advanced CKD or ESKD in clinical trials. A post hoc efficacy analysis among hypercholesterolemic patients with or without kidney function impairment pooled from eight phase 3 ODYSSEY trials demonstrated Lp(a) reductions at week 24 ranging from 23% to 30%. 121 LDL-C reductions ranged from 46% to 62%. Only 10% of this cohort had kidney function impairment (eGFR 30─59 ml/min per 1.73 m 2 ) and >99% of the entire cohort were on statins. It was concluded that in hypercholesterolemic individuals, where nearly all were on statin treatment, alirocumab lowered LDL-C regardless of impaired kidney function, with comparable safety profiles to controls. Similarly, in the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial among patients with established ASCVD, evolocumab (EVO) reduced Lp(a) at week 48 by approximately 27%. 106 Patients with higher baseline Lp(a) levels experienced greater absolute reductions and tended to derive greater coronary benefit from PCSK9-inhibition manifested as lower rates of CHD, death, MI, or urgent revascularization. 106 Of note, a 15% reduction in CHD risk for every 25 nmol/L reduction in Lp(a) was observed and this effect was independent of LDL-C lowering. 106 In FOURIER, the median percent reduction in LDL-C from baseline at week 4 was 66% with EVO. 122 Another FOURIER analysis according to kidney function demonstrated similar extent of LDL-C lowering (approximately 58%−59%) and relative clinical efficacy (hazard ratio: 0.82−0.89) of EVO versus placebo across the groups with eGFR ≥90, 60−90, and 20−60 ml/min per 1.73 m 2 123 (Table 2 ). Overall, absolute reduction in the composite of cardiovascular death, MI, or stroke with EVO was greater with more advanced CKD. 123 As the trial excluded patients with eGFR <20 ml/min per 1.73 m 2 , questions remain regarding the safety and efficacy of PCSK9i in more severe CKD and their effects on CVD. In addition, relative contributions of LDL-C-lowering versus Lp(a)-lowering to PCSK9-inhibition-induced CVD risk reduction in relation to kidney function remain to be determined. While data on the role of apo(a) sizes in the context of Lp(a)-lowering with PCSK9-inhibition in CKD are lacking, we previously demonstrated that alirocumab-induced Lp(a)-lowering effect was not associated with apo(a) isoform sizes and/or phenotypes in hypercholesterolemic patients. 124 This finding may suggest that CKD patients with elevated Lp(a) may benefit from Lp(a)-lowering with PCSK9-inhibition regardless of their genetically determined apo(a) phenotypes and/or exposure to apo(a)-size-specific Lp(a) increases. More studies are needed to determine the kidney effects and cardiovascular benefits of PCSK9-inhibition in individuals at high risk of disease progression and in patients with the most advanced degrees of kidney dysfunction, lacking effective therapeutic options to improve outcomes. Glycemic control improves microvascular events such as nephropathy in diabetic patients, 125 but it does less for macrovascular events. 126 , 127 In the past decade, data from cardiovascular outcome trials in diabetic patients of newer glucose-lowering drugs such as sodium-glucose cotransporter 2 inhibitors (SGLT2is) 128 – 130 or glucagon-like peptide 1 receptor agonists (GLP-1RAs) 131 – 134 have become available, and these studies demonstrate significant reductions in MACE. Further shedding light into the SGLT2i-induced cardioprotective effect based on genetics, a recent population based study 135 found a lower risk of heart failure, MI, CHD, and all-cause mortality in individuals with a functional variant in the solute carrier family 5 member 2 ( SLC5A2 ) gene, encoding SGLT2, which mimics pharmacologic SGLT2i. These drugs have also been associated with an array of beneficial pleiotropic effects, including reductions in body weight and BP and increases in HDL-C and broad kidney protective effects. The latter included lower risks of progressive albuminuria, kidney impairment, dialysis, doubling of serum creatinine, and death attributable to kidney insufficiency. 128 , 129 , 136 Several meta-analyses have confirmed that SGLT2is and GLP-1RAs provide comparable cardio- and/or kidney-protective benefits in patients with DM and CKD, 137 independently of baseline BP, 138 statin use, 139 and obesity. 140 Data on the effect of SGLT2is or GLP-1RAs on Lp(a) are scarce. The results primarily from small studies in patients with DM and high cardiovascular risk have been mixed. SGLT2is, dapagliflozin and empagliflozin, in patients with DM or heart failure did not significantly change Lp(a). 141 – 143 A small study comparing the effect of empagliflozin and liraglutide, a GLP-1RA, on cardiometabolic factors in diabetic adults reported a modest decrease in Lp(a) at 3 months with liraglutide compared with empagliflozin. 144 However, another study of liraglutide among overweight/obese patients with prediabetes did not find any significant change in Lp(a). 145 A 6-month treatment with dulaglutide, a GLP-1RA, resulted in a small significant Lp(a) reduction in diabetic patients. 146 It is of interest to note the presence of an inverse association between Lp(a) level and the risk of DM. 147 – 149 While any causal nature of the association remains to be determined, the risk of MACE among diabetic patients is positively associated with Lp(a) levels similar to nondiabetic patients. 150 – 153 Moreover, a meta-analysis found that elevated Lp(a) was independently associated with higher risk of diabetic nephropathy. 154 Studies investigating how the presence and severity of CKD modifies the effect of SGLT2i and incretin mimetics on Lp(a) and whether apo(a) sizes modulate this relationship are currently lacking.

It is becoming increasingly clear that nongenetic factors also influence Lp(a) levels. Of such factors, current evidence clearly supports a role for diet, hormones, and related conditions and kidney disease in modifying Lp(a) levels 18 , 45 (Table 1 D). Regarding diets, substantial evidence indicates that reducing saturated fatty acid intake increases Lp(a) while lowering LDL-C. 46 – 49 Studies have suggested that consuming a plant-based, low-fat diet for 2 weeks may not significantly alter Lp(a) among nondiabetic adults, 50 while consuming a defined plant-based diet for 4 weeks can significantly reduce Lp(a) by 16% in overweight/obese adults. 51 Furthermore, low-fat diets with higher intakes of fruits and vegetables increased Lp(a) in healthy women, 52 while a diet rich in saturated fatty acid from dairy foods did not increase Lp(a) in hyperlipidemic individuals. 53 There is considerably less certainty regarding other environmental factors. The results from studies on physical activity/exercise have been inconsistent, ranging from no to minimal or moderate change in Lp(a), potentially modulated by age and the type, intensity, and duration of exercise. 18 , 45 Hormone replacement therapy (HRT) in postmenopausal women lowers Lp(a) levels with oral therapy being more effective than transdermal estradiol; the type of HRT, dose of estrogen, and addition of progesterone do not modify the Lp(a)-lowering effect of HRT. 18 , 54 , 55 Among premenopausal women with endometriosis, treatment with danazol, an anabolic steroid, reduced Lp(a) levels, while increasing LDL-C and decreasing HDL cholesterol (HDL-C). 56 As discussed below, kidney diseases result in marked elevations in Lp(a) levels, albeit dependent on disease stages, dialysis modalities, and apo(a) phenotypes.

CKD is a prevalent condition associated with high inflammation, elevated Lp(a), and CVD risk. Most available evidence suggests that elevated Lp(a) is a risk factor for CVD in patients with CKD. Besides lipid-lowering therapies, inflammation-inhibiting drugs show promise as therapeutic agents with substantial Lp(a)-lowering potential in CKD. Lp(a) particles contribute to inflammation initiation, plaque formation, and vascular disease progression through its lipid 29 and OxPL 25 components. At an equimolar basis, Lp(a) is considerably more atherogenic than LDL, 101 underscoring the need for a better understanding of the role of Lp(a) in CVD in CKD. Technologic innovations are enabling in-depth cardiovascular studies at an increasingly granular level through multiomics pathway analyses. Studies targeting these areas are needed to inform our understanding of the specific contribution of Lp(a) to CVD development and identify new therapeutic targets. Insights from such studies will also be important to addressing the unresolved issues regarding Lp(a) assembly, metabolism, and physiologic function. Studies in patients with CKD may therefore shed light on mechanisms underlying cardiovascular benefits of lowering elevated Lp(a) in the general and high-risk patient populations.

An elevated level of lipoprotein(a) (Lp[a]) is a strong genetically determined risk factor for cardiovascular disease (CVD) and recent evidence underscores its risk factor role in high-risk patient groups. The Lp(a)-attributable risk is strongest for myocardial infarction (MI) and aortic valve stenosis, followed by peripheral artery disease and heart failure. 1 For these conditions, the relative risks are as high as 1.7−3.0 times for individuals with the top 5% Lp(a) levels. The corresponding relative risks are 1.2−1.6 times for ischemic stroke, CVD mortality, and all-cause mortality. 1 Alternatively, genetically determined low Lp(a) levels are linked to a reduced risk of coronary heart disease (CHD), peripheral artery disease, stroke, heart failure, and aortic valve stenosis. 2 Like LDL, Lp(a) consists of a lipid-rich core with an embedded apolipoprotein B-100 but has another unique protein, apolipoprotein(a) (apo[a]) 3 (Figure 1 A). Apo(a) is different from others as it is hydrophilic, carbohydrate-rich, and not embedded in the core. While LDL is common across species, Lp(a) is found only in humans and old-world primates. 4 – 6 Apo(a), encoded by the LPA gene, consists of a repeated loop structure termed Kringles (K), analogous to the plasminogen Kringle structure. 3 , 7 The hypervariable number of the Lp(a) K4 type-2-repeat determines apo(a) isoform size, and smaller sizes are associated with higher Lp(a) levels 3 , 8 – 10 (Table 1 A). The effect of the apo(a) size on Lp(a) level is further modified by functional single-nucleotide polymorphisms (SNPs) in the LPA gene with, in some cases, pronounced effects on Lp(a). 11 Notably, some SNPs are in linkage equilibrium with apo(a) size variability. 11 – 13 Particularly two SNPs have received considerable attention (rs10455872 and rs3798220) as they tag small apo(a) 11 , 12 , 14 (Table 1 A). Overall, the final circulating Lp(a) is a result of a complex interplay between apo(a) size and LPA SNPs with Lp(a)-increasing and/or Lp(a)-decreasing effect 11 (Figure 1 B). Beyond the extensive interindividual variability, Lp(a) levels differ between populations. Individuals of African ancestry have higher Lp(a) levels compared with Caucasians, and in addition, levels differ across Asian populations with higher levels in Indian compared with Chinese populations. 9 , 15 – 21 Lp(a) structure, genetics, circulating concentration, and relationship to kidney and CVDs. Structurally, Lp(a) consists of a lipid-rich core and one molecule of each of the two apos, apoB-100, and apo(a) (A). Apo(a) is unique to Lp(a) with a repeated loop structure termed K, where its K4 type 2 is present in a hypervariable copy number, resulting in an extensive apo(a) size variability. At the genetic level, apo(a) size variability is the key regulator of Lp(a) levels (B). In general, smaller apo(a) sizes with fewer number of K4 repeats are associated with higher plasma Lp(a) levels; however, this association can be modulated in some cases by the presence of SNPs in the LPA gene with considerable Lp(a)-increasing or Lp(a)-decreasing effects (B). In circulation, for most individuals, plasma Lp(a) level is presented as a mixed particle population with both smaller and larger apo(a) sizes (C). Beyond genetics, circulating Lp(a) level has been shown to be modulated by nongenetic factors, where CKD, inflammation, and lowering of dietary SFA intake increase the levels (C). An elevated level of Lp(a) is a strong risk factor for ASCVD, thrombosis, and aortic valve calcification (D). apo(a), apolipoprotein(a); apo, apolipoprotein; ASCVD, atherosclerotic cardiovascular disease; CVD, cardiovascular disease; K, Kringle; Lp(a), lipoprotein(a); SFA, saturated fatty acid; SNP, single nucleotide polymorphism. Overview of key observations on lipoprotein(a) ACCLAIM-Lp(a), A Study to Investigate the Effect of Lepodisiran on the Reduction of Major Adverse Cardiovascular Events in Adults With Elevated Lipoprotein(a); apo(a), apolipoprotein(a); ASO, antisense oligonucleotides; HORIZON, Assessing the Impact of Lipoprotein (a) Lowering With Pelacarsen (TQJ230) on Major Cardiovascular Events in Patients With CVD; HRT, hormone replacement therapy; K, Kringle; Lp(a), lipoprotein(a); OCEAN(a), Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction; siRNA, small-interfering RNA; SNP, single-nucleotide polymorphism. Although LDL and Lp(a) share similar features, their metabolic pathways differ. In contrast to LDL cholesterol (LDL-C), apo(a) synthesis is under strong genetic regulation 22 but the steps leading to formation of the Lp(a) particle remain unresolved. Furthermore, Lp(a) clearance pathways have not been firmly identified. 23 , 24 Recent studies have identified important molecular components of Lp(a) as having atherogenic importance, including oxidized phospholipids (OxPL), 25 lipoprotein-associated phospholipase A 2 , 26 , 27 and proprotein convertase subtilisin/kexin type 9 (PCSK9). 28 Lp(a) particles enter the vessel wall and initiate inflammation, plaque formation, and vascular disease progression through its lipid 29 and OxPL 25 components. The restricted species expression of Lp(a) 4 – 6 has limited opportunities for animal models and advances in basic science have largely been limited to genetic studies. Clinical guidelines recommend universal screening for Lp(a) at least once in a person's lifetime to identify high-risk individuals. 22 , 30 – 34 This recommendation recognizes the highly heritable nature of elevated Lp(a) primarily mediated through the presence of an inverse association between Lp(a) level and the genetically determined size of its apo(a) component. While clinical laboratories commonly report Lp(a) levels as mg/dl, the preferred measurement is to use nmol/L given standardization challenges due to apo(a) size variability. 35 – 37 A number of guidelines have addressed clinical management of Lp(a) including levels associated with CVD risk. 22 , 30 , 33 , 34 At present, a plasma level >50 mg/dl, or approximately >125 nmol/L, represents a high CVD risk range (Table 1 B). However, as pointed out in these guidelines, any assessment of Lp(a)-attributable risk needs to be comprehensive and take multiple factors into account. In recent years, considerable progress has been made toward developing agents that lower Lp(a) (Table 1 C). Several compounds with a potent Lp(a)-lowering efficacy (>95%), including antisense oligonucleotides (ASO) and small-interfering RNAs (siRNAs), have been developed and are currently being tested for their efficacy to reduce cardiovascular outcomes in clinical trials. 1 , 38 For example, pelacarsen, a hepatocyte-directed ASO targeting the LPA gene mRNA, which safely and dose-dependently reduced Lp(a) by up to 80% in a phase 2 clinical trial, is currently in a phase 3 trial (Assessing the Impact of Lipoprotein (a) Lowering With Pelacarsen (TQJ230) on Major Cardiovascular Events in Patients With CVD, NCT04023552 ) testing the long-term cardiovascular benefits of Lp(a)-lowering. 38 – 41 Other ongoing phase 3 trials include those using siRNA-based compounds, the Olpasiran Trials of Cardiovascular Events and Lipoprotein(a) Reduction-Outcomes Trial ( NCT05581303 ) and the A Study to Investigate the Effect of Lepodisiran on the Reduction of Major Adverse Cardiovascular Events in Adults With Elevated Lipoprotein(a) trial ( NCT06292013 ) 38 , 42 , 43 (Table 1 C). Given the high prevalence of elevated Lp(a) affecting 20%−30% of the world's population, 15 the results of these ongoing clinical trials are highly anticipated. As discussion of these ongoing trials is out of the scope of the current review, we invite the readers to review recent papers with details. 1 , 38 , 44