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Existing and emerging strategies to lower Lipoprotein(a)

      Highlights

      • Statins, ezetimibe, and fibrates reduce cardiovascular risk without substantially affecting Lp(a) levels.
      • Conversely, therapies such as niacin and CETP inhibitors lower Lp(a) without substantially influencing cardiovascular risk.
      • PCSK9 monoclonal antibodies are the first drug class to lower Lp(a) levels and substantially reduce cardiovascular risk.
      • The clinical benefit of PCSK9 monoclonal antibodies is associated with baseline and on-treatment levels of Lp(a).
      • Apheresis is an expensive and invasive means of lowering Lp(a). Observational data suggest a substantial clinical benefit.
      • Targeted LPA therapeutics (ASO and siRNA) substantially reduce Lp(a). Clinical efficacy is under investigation.

      Abstract

      Abundant evidence links elevated levels of lipoprotein(a) (Lp(a)) to higher cardiovascular risk, leaving clinicians with the challenge of what measures to take to mitigate Lp(a)-associated risk. Some therapies that may reduce cardiovascular risk, such as aspirin, statins, fibrates, and ezetimibe, have little effect on Lp(a) and in some cases may even increase its concentration. Other agents that reduce levels of Lp(a), such as niacin or cholesteryl ester transfer protein inhibitors, have neutral or only slightly favorable effects on cardiovascular outcomes. The only currently available therapeutic approaches that lower Lp(a) and reduce cardiovascular risk are PCSK9 inhibitors and lipoprotein apheresis. For PCSK9 inhibitors, the magnitude of clinical benefit is associated with the baseline level of Lp(a) and appears to be associated with the degree of Lp(a) reduction. Antisense oligonucleotides and small interfering RNA agents targeting apolipoprotein(a) have the potential to reduce circulating Lp(a) concentrations by more than 70%. The results of cardiovascular outcomes trials will determine whether such substantial reductions in Lp(a) are associated with meaningful clinical benefit.

      Graphical abstract

      Keywords

      Substantial epidemiologic and genetic evidence, discussed in this thematic review series [
      • Arsenault B.J.
      • Kamstrup P.R.
      Lipoprotein(a) and cardiovascular and valvular diseases: a genetic epidemiological perspective.
      ], links elevated concentrations of lipoprotein(a) (Lp(a)) to the risk of incident or recurrent major adverse cardiovascular events (MACE). Clinicians face the challenge of what to do to mitigate Lp(a)-associated risk. Because Lp(a) concentration is under primary genetic control with modest influence of environmental factors, pharmacologic and apheresis strategies to lower Lp(a) levels have potential therapeutic importance. This article reviews existing and emerging approaches to lower Lp(a) concentration and the evidence that such reduction is associated with a reduction in the risk of MACE (Table 1).
      Table 1Approaches to lower the concentration of lipoprotein(a) and associated cardiovascular risk.
      TreatmentEffect of treatment on lipoprotein(a) concentrationEffect of treatment on cardiovascular risk
      NiacinReduction, 20% [
      • Sahebkar A.
      • Reiner Z.
      • Simental-Mendia L.E.
      • et al.
      Effect of extended-release niacin on plasma lipoprotein(a) levels: a systematic review and meta-analysis of randomized placebo-controlled trials.
      ]
      Neutral [
      • HPS2-THRIVE Collaborative Group
      • Landray M.J.
      • Haynes R.
      • et al.
      Effects of extended-release niacin with laropiprant in high-risk patients.
      ,
      • AIM-HIGH Investigators
      • Boden W.E.
      • Probstfield J.L.
      • et al.
      Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
      ]
      StatinsPossible increase, 0–10% [
      • Tsimikas S.
      • Gordts P.L.S.M.
      • Nora C.
      • et al.
      Statin therapy increases lipoprotein(a) levels.
      ]
      Reduced 20–30% [
      • Cholesterol Treatment Trialists' CTT Collaboration
      Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
      ]
      EzetimibePossible reduction, 0–5% [
      • Awad K.
      • Mikhailidis D.P.
      • Katsiki N.
      • et al.
      Effect of ezetimibe monotherapy on plasma lipoprotein(a) concentrations in patients with primary hypercholesterolemia: a systematic review and meta-analysis of randomized controlled trials.
      ,
      • Sahebkar A.
      • Simental-Mendia L.E.
      • Pirro M.
      • et al.
      Impact of ezetimibe on plasma lipoprotein(a) concentrations as monotherapy or in combination with statins: a systematic review and meta-analysis of randomized controlled trials.
      ]
      Reduced 6% when added to statin therapy [
      • Cannon C.P.
      • Blazing M.A.
      • Giugliano R.P.
      • et al.
      Ezetimibe added to statin therapy after acute coronary syndromes.
      ]
      Bempedoic acidNo effect [Esperion, data on file]Under investigation [

      www.ClinicalTrials.gov. NCT02993406. "Evaluation of Major Cardiovascular Events in Patients with, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated with Bempedoic Acid (ETC-1002) or Placebo (CLEAR Outcomes)." Accessed 24 April 2022.

      ]
      FibratesMinimal, possible increase in setting of hypertriglyceridemia [
      • Sahebkar A.
      • Simental-Mendia L.E.
      • Watts G.F.
      • et al.
      Comparison of the effects of fibrates versus statins on plasma lipoprotein(a) concentrations: a systematic review and meta-analysis of head-to-head randomized controlled trials.
      ,
      • Ko H.S.
      • Kim C.J.
      • Ryu W.S.
      Effect of fenofibrate on lipoprotein(a) in hypertriglyceridemic patients: impact of change in triglyceride level and liver function.
      ]
      Reduced 22% with gemfibrozil monotherapy [
      • Frick M.H.
      • Elo O.
      • Haapa K.
      • et al.
      Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease.
      ,
      • Rubins H.B.
      • Robins S.J.
      • Collins D.
      • et al.
      Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.
      ], non-significant reduction with fenofibrate [
      • FIELD Study Investigators
      Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study).
      ]
      Bile acid sequestrantsNo effect [
      • Eraikhuemen N.
      • Lazaridis D.
      • Dutton M.T.
      Emerging pharmacotherapy to reduce elevated lipoprotein(a) plasma levels.
      ]
      Reduced 20%
      CETP inhibitorsReduction up to 25% [
      • HPS3/TIMI55--REVEAL Collaborative Group
      • Bowman L.
      • Hopewell J.C.
      • et al.
      Effects of anacetrapib in patients with atherosclerotic vascular disease.
      ]
      Favorable (anacetrapib) [
      • Armitage J.
      • Holmes M.V.
      • Preiss D.
      Cholesteryl ester transfer protein inhibition for preventing cardiovascular events: JACC review topic of the week.
      ]; neutral (dalcetrapib, evacetrapib) [
      • Schwartz G.G.
      • Olsson A.G.
      • Abt M.
      • et al.
      Effects of dalcetrapib in patients with a recent acute coronary syndrome.
      ,
      • Lincoff A.M.
      • Nicholls S.J.
      • Riesmeyer J.S.
      • et al.
      Evacetrapib and cardiovascular outcomes in high-risk vascular disease.
      ]; unfavorable (torcetrapib) [
      • Barter P.J.
      • Caulfield M.
      • Eriksson M.
      • et al.
      Effects of torcetrapib in patients at high risk for coronary events.
      ]
      PCSK9 inhibitorsReduction, 20–25% [
      • Bittner V.A.
      • Szarek M.
      • Aylward P.E.
      • et al.
      Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome.
      ,
      • O'Donoghue M.L.
      • Fazio S.
      • Giugliano R.P.
      • et al.
      Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk.
      ,
      • Ray K.K.
      • Wright R.S.
      • Kallend D.
      • et al.
      Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol.
      ]
      Reduced by 15% with monoclonal antibodies [
      • Sabatine M.S.
      • Giugliano R.P.
      • Keech A.C.
      • et al.
      Evolocumab and clinical outcomes in patients with cardiovascular disease.
      ,
      • Schwartz G.G.
      • Steg P.G.
      • Szarek M.
      • et al.
      Alirocumab and cardiovascular outcomes after acute coronary syndrome.
      ]; not determined for small interfering RNA
      MipomersenReduction, 20–25% [
      • Santos R.D.
      • Raal F.J.
      • Catapano A.L.
      • et al.
      Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials.
      ]
      Not determined
      PelacarsenReduction, 75–80% [
      • Tsimikas S.
      • Karwatowska-Prokopczuk E.
      • Gouni-Berthold I.
      • et al.
      Lipoprotein(a) reduction in persons with cardiovascular disease.
      ]
      Under investigation [

      www.ClinicalTrials.gov. NCT04023552. "Assessing the Impact of Lipoprotein (A) Lowering with Pelacarsen (TQJ230) on Major Cardiovascular Events in Patients with CVD (Lp(a)HORIZON)." Accessed 24 April 2022.

      ]
      Small interfering RNAsReduction, 70–98% [
      • Koren M.J.
      • Moriarty P.M.
      • Neutel J.
      • et al.
      Safety, tolerability, and efficacy of single-dose AMG 890, a novel siRNA targeting Lp(a), in healthy subjects and subjects with elevated Lp(a).
      ,
      • Nissen S.E.
      • Wolski K.
      • Balog C.
      • et al.
      Single ascending dose study of a short interfering RNA targeting lipoprotein(a) production in individuals with elevated plasma lipoprotein(a) levels.
      ]
      Unknown
      ApheresisReduction, 70–80% [
      • Arai K.
      • Orsoni A.
      • Mallat Z.
      • et al.
      Acute impact of apheresis on oxidized phospholipids in patients with familial hypercholesterolemia.
      ,
      • Waldmann E.
      • Parhofer K.G.
      Lipoprotein apheresis to treat elevated lipoprotein (a).
      ,
      • Stefanutti C.
      • Mazza F.
      • Pasqualetti D.
      • et al.
      Lipoprotein apheresis downregulates IL-1 alpha, IL-6 and TNF-alpha mRNA expression in severe dyslipidaemia.
      ]
      Reduced by 70–90% [
      • Schettler V.J.J.
      • Peter C.
      • Zimmermann T.
      • et al.
      The German lipoprotein apheresis Registry (GLAR) − more than 7 years on.
      ,
      • Roeseler E.
      • Julius U.
      • Heigl F.
      • et al.
      Lipoprotein apheresis for lipoprotein(a)-associated cardiovascular disease: prospective 5 years of follow-up and apolipoprotein(a) characterization.
      ,
      • Jaeger B.R.
      • Richter Y.
      • Nagel D.
      • et al.
      Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events.
      ,
      • Rosada A.
      • Kassner U.
      • Vogt A.
      • et al.
      Does regular lipid apheresis in patients with isolated elevated lipoprotein(a) levels reduce the incidence of cardiovascular events?.
      ]

      1. Lipid-modifying agents

      1.1 PCSK9 inhibitors

      Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes intracellular degradation of LDL receptors, decreasing their density on the surface of hepatocytes, thereby reducing the clearance of LDL particles from circulation. Conversely, monoclonal antibodies targeting PCSK9 (e.g., evolocumab and alirocumab) or inhibitors of PCSK9 synthesis (e.g., inclisiran) increase LDL receptor density on the surface of hepatocytes, promote clearance of LDL particles, and reduce the circulating concentration of LDL cholesterol (LDL-C). An additional effect of PCSK9 inhibitors is to decrease the circulating concentration of Lp(a) by 19–27% [
      • Bittner V.A.
      • Szarek M.
      • Aylward P.E.
      • et al.
      Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome.
      ,
      • O'Donoghue M.L.
      • Fazio S.
      • Giugliano R.P.
      • et al.
      Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk.
      ,
      • Ray K.K.
      • Wright R.S.
      • Kallend D.
      • et al.
      Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol.
      ]. The mechanisms by which PCSK9 inhibitors decrease circulating Lp(a) concentration remain uncertain, but may include increased receptor-mediated clearance, decreased apolipoprotein(a) production, or decreased Lp(a) particle assembly due to reduced availability of apolipoprotein B [
      • Croyal M.
      • Tran T.T.
      • Blanchard R.H.
      • et al.
      PCSK9 inhibition with alirocumab reduces lipoprotein(a) levels in nonhuman primates by lowering apolipoprotein(a) production rate.
      ,
      • Nestel P.
      Lipoprotein(a) removal still a mystery.
      ,
      • Watts G.F.
      • Chan D.C.
      • Pang J.
      • et al.
      PCSK9 Inhibition with alirocumab increases the catabolism of lipoprotein(a) particles in statin-treated patients with elevated lipoprotein(a).
      ].
      To date, PCSK9 monoclonal antibodies are the only clinically available drug class shown to lower Lp(a) and to reduce cardiovascular risk. Two completed placebo-controlled cardiovascular outcomes trials evaluated the effects of PCSK9 monoclonal antibodies, added to background statin therapy, on the risk of MACE. The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial compared evolocumab with placebo in 27,564 patients with chronic atherosclerotic cardiovascular disease over a median follow-up of 2.2 years [
      • Sabatine M.S.
      • Giugliano R.P.
      • Keech A.C.
      • et al.
      Evolocumab and clinical outcomes in patients with cardiovascular disease.
      ]. The ODYSSEY OUTCOMES trial compared alirocumab with placebo in 18,924 patients with recent acute coronary syndrome over a median follow-up of 2.8 years [
      • Schwartz G.G.
      • Steg P.G.
      • Szarek M.
      • et al.
      Alirocumab and cardiovascular outcomes after acute coronary syndrome.
      ]. Together, these two trials comprise more than 100,000 patient-years of placebo-controlled observation. In both trials the risk of MACE was reduced with active treatment. In ODYSSEY OUTCOMES the incidence of death was also reduced [
      • Steg P.G.
      • Szarek M.
      • Bhatt D.L.
      • et al.
      Effect of alirocumab on mortality after acute coronary syndromes.
      ].
      Median baseline Lp(a) levels were 37 nmol/L (approximately 15 mg/dl) in FOURIER and 21 mg/dl (approximately 50 nmol/L) in ODYSSEY OUTCOMES, and remained stable over time in the placebo groups. Treatment with PCSK9 monoclonal antibodies resulted in 27% (FOURIER) and 23% (ODYSSEY OUTCOMES) median reductions in Lp(a). Absolute reductions in Lp(a) were directly related to baseline levels.
      Analyses of FOURIER and ODYSSEY OUTCOMES provided important observations regarding the relationship of Lp(a) levels to the risk of cardiovascular events in the placebo groups and the reduction of that risk with PCSK9 monoclonal antibodies. In the placebo groups of both trials, baseline Lp(a) levels were directly associated with the risk of MACE. For example, in FOURIER [
      • O'Donoghue M.L.
      • Fazio S.
      • Giugliano R.P.
      • et al.
      Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk.
      ], the risk of major coronary events (coronary heart disease death, non-fatal myocardial infarction, or urgent coronary revascularization) was 7.5% among those with Lp(a) at or below the median versus 9.9% among those with baseline Lp(a) above the median (Fig. 1A). In ODYSSEY OUTCOMES [
      • Szarek M.
      • Bittner V.A.
      • Aylward P.
      • et al.
      Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial.
      ], the rate of total cardiovascular events in the placebo group increased monotonically from 9.9 per 100 patient-years in the lowest baseline Lp(a) quartile (<6.7 mg/dl) to 14.6 per 100 patient-years in the highest baseline Lp(a) quartile (>59.6 mg/dl) (Fig. 2).
      Fig. 1
      Fig. 1(A) Risk of major coronary events in the FOURIER trial according to median baseline Lp(a) (37 nmol/L) and assigned treatment. Lp(a) was measured in 25,096 trial participants. The outcome of major coronary events was a secondary endpoint in the trial that included coronary heart disease death, myocardial infarction, or urgent revascularization. (B) Treatment hazard ratio (evolocumab/placebo) for major coronary events according to the difference in Lp(a) levels, adjusted for the difference in LDL-C. Each circle represents data from one decile of baseline Lp(a) concentration. Each 25 nmol/L difference in Lp(a) between treatment groups was associated with a 15% lower risk (95% CI 2%–26%; p = 0.02). Reproduced with permission [
      • O'Donoghue M.L.
      • Fazio S.
      • Giugliano R.P.
      • et al.
      Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk.
      ].
      Fig. 2
      Fig. 2Risk of total (first and subsequent) cardiovascular events in the ODYSSEY OUTCOMES trial according to baseline quartile of Lp(a) and assigned treatment.
      Lp(a) and cardiovascular outcomes were assessed in 18,924 patients with recent acute coronary syndrome. On the left, absolute event rates increased monotonically with increasing quartile of baseline Lp(a) in the placebo group (blue) and to a lesser extent in the alirocumab group (red). This resulted in significant gradient of relative risk reduction with alirocumab (ptrend = 0.045) with more robust treatment hazard ratio with increasing baseline Lp(a) quartile. Absolute risk reduction with alirocumab increased monotonically with baseline Lp(a) quartile (right). Reproduced with permission [
      • Szarek M.
      • Bittner V.A.
      • Aylward P.
      • et al.
      Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial.
      ,
      • Szarek M.
      • White H.D.
      • Schwartz G.G.
      • et al.
      Alirocumab reduces total nonfatal cardiovascular and fatal events: the ODYSSEY OUTCOMES trial.
      ].

      1.1.1 Relationship of baseline Lp(a) levels to the clinical efficacy of PCSK9 monoclonal antibodies

      Importantly, both the FOURIER and ODYSSEY OUTCOMES trials demonstrated heterogeneity in the clinical efficacy of PCSK9 monoclonal antibody treatment according to the baseline level of Lp(a). In FOURIER [
      • O'Donoghue M.L.
      • Fazio S.
      • Giugliano R.P.
      • et al.
      Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk.
      ], the treatment hazard ratio (HR) with 95% confidence interval (CI) for major coronary events was 0.93 (0.80–1.08) and absolute risk reduction (ARR) 0.95% in patients with baseline Lp(a) at or below median, compared with treatment HR (95% CI) 0.77 (0.67–0.88) and ARR 2.49% among those with baseline Lp(a) above median (Fig. 1A). The FOURIER investigators also examined the treatment HR according to decile of baseline Lp(a) (Fig. 1B). Patients in the lowest deciles of baseline Lp(a) (with the smallest changes in Lp(a) with evolocumab, depicted on the left side of the plot) had treatment HR close to 1.0. In contrast, patients in the highest deciles of baseline Lp(a) (with the largest changes in Lp(a) with evolocumab, depicted on the right side of the plot) had the most robust treatment HR. The gradient of treatment HR across baseline Lp(a) deciles was significant (p = 0.02). Similarly, in ODYSSEY OUTCOMES [
      • Szarek M.
      • Bittner V.A.
      • Aylward P.
      • et al.
      Lipoprotein(a) lowering by alirocumab reduces the total burden of cardiovascular events independent of low-density lipoprotein cholesterol lowering: ODYSSEY OUTCOMES trial.
      ] the treatment HR for total cardiovascular events decreased monotonically from 0.95 (0.79–1.14) in the lowest quartile of baseline Lp(a) to 0.75 (0.64–0.88) in the highest quartile (ptrend = 0.045; Fig. 2). In parallel, ARR for total cardiovascular events increased from 0.5 (-1.6–2.7) per 100 patient-years in the lowest baseline Lp(a) quartile to 3.7 (0.9–6.4) per 100 patient-years in the highest baseline Lp(a) quartile.
      This heterogeneity in clinical efficacy is surprising because LDL-C reduction with PCSK9 inhibition did not vary greatly across baseline Lp(a) quantiles. For example, in FOURIER the median reduction in LDL-C with evolocumab was 61 mg/dL in patients with baseline Lp(a) at or below the median versus 59 mg/dL in patients with baseline Lp(a) above median [
      • Marston N.A.
      • Gurmu Y.
      • Melloni G.E.M.
      • et al.
      The effect of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition on the risk of venous thromboembolism.
      ]. In ODYSSEY OUTCOMES, alirocumab reduced LDL-C (corrected empirically for Lp(a) cholesterol) by a median 53.3 mg/dL in the lowest quartile of baseline Lp(a) versus 47.5 mg/dL in the highest quartile [
      • Schwartz G.G.
      • Steg P.G.
      • Szarek M.
      • et al.
      Peripheral artery disease and venous thromboembolic events after acute coronary syndrome: role of lipoprotein(a) and modification by alirocumab: prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial.
      ]. Thus, both trials demonstrated small relative and absolute clinical benefit of adding a PCSK9 monoclonal antibody to background statin therapy when Lp(a) levels were low, but substantial relative and absolute clinical benefit when Lp(a) levels were elevated, despite similar, large LDL-C reductions in both Lp(a) categories. It is unknown whether the apparent dependence of the clinical benefit of PCSK9 inhibition on Lp(a) levels reflects the modest reduction of circulating Lp(a) concentration, the coordinated reduction of both LDL-C and Lp(a), or that elevated Lp(a) is a marker for plaques amenable to stabilization through PCSK9 inhibition. It is also unknown whether a treatment benefit would have emerged in patients with low levels of Lp(a) had there been a longer observation period.
      A qualitatively similar association of the clinical benefit of a lipid-modifying agent with Lp(a) levels was recapitulated in the REVEAL trial that evaluated the cholesteryl ester transfer protein (CETP) inhibitor, anacetrapib. This is discussed in a subsequent section on CETP inhibitors.
      It is important to consider how these observations can be reconciled with prior meta-analyses of statin trials that have shown a consistent relationship between the absolute reduction of LDL-C and the relative reduction of cardiovascular risk [
      • Cholesterol Treatment Trialists’ (CTT) Collaboration
      • Fulcher J.
      • O’Connell R.
      • et al.
      Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials.
      ]. In these meta-analyses, Lp(a) was not measured in most of the component trials and was not considered in meta-analysis. Thus, patients with smaller or larger changes in LDL-C included those with higher or lower Lp(a) and it is not possible to determine the extent to which the meta-analytic relationships were influenced by the patients with higher Lp(a) concentration. Furthermore, meta-analyses of statin trials did not explore the effect of adding another potent lipid-lowering agent to high-intensity statin treatment. It is possible that Lp(a) becomes a key factor in determining lipoprotein-attributable residual risk and the potential for further risk reduction with lipid-modifying therapy when LDL-C is driven down to levels not usually attained with statins alone.
      Experimental and clinical data also provide insights that may align with the findings described above from FOURIER and ODYSSEY OUTCOMES. A substantial body of experimental data indicates that oxidized phospholipids play a critical role in pro-inflammatory phenotypic transformation of monocytes and allow their trans-endothelial penetration into the arterial wall [
      • Tsimikas S.
      A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies.
      ]. Lp(a) carries a sizable proportion of oxidized phospholipids in circulation. In an analysis of the EPIC (European Prospective Investigation of Cancer)-Norfolk cohort, higher concentrations of oxidized phospholipids on apolipoprotein B-containing particles were strongly associated with elevated risk of coronary heart disease events when Lp(a) was at least modestly elevated (>11.7 mg/dL), but not when Lp(a) concentration was low (≤7.25 mg/dL) [
      • Tsimikas S.
      • Mallat Z.
      • Talmud P.J.
      • et al.
      Oxidation-specific biomarkers, lipoprotein(a), and risk of fatal and nonfatal coronary events.
      ].
      On a background of intensive statin treatment, many patients achieve a “nominally controlled” level of LDL-C near 70 mg/dl. In a post hoc analysis of ODYSSEY OUTCOMES [
      • Schwartz G.G.
      • Szarek M.
      • Bittner V.A.
      • et al.
      Lipoprotein(a) and benefit of PCSK9 inhibition in patients with nominally controlled LDL cholesterol.
      ], the benefit of PCSK9 inhibition with alirocumab was evaluated in a subset of 4351 patients who had at least one of two pre-randomization LDL-C levels below 70 mg/dl (median 69.4 mg/dL). When that subgroup was further dichotomized at its median baseline Lp(a) level (13.7 mg/dL), a 30% reduction in MACE with alirocumab was observed in those with Lp(a) > 13.7 mg/dL, but no treatment benefit was observed in those with Lp(a) ≤13.7 mg/dl. In contrast, among patients with higher baseline LDL-C, a treatment benefit with alirocumab was evident irrespective of Lp(a) levels (Fig. 3). Findings were similar with or without adjustment for other clinical characteristics. Thus, elevated Lp(a) may be an important and modifiable risk factor among patients with nominally controlled levels of LDL-C on statin treatment.
      Fig. 3
      Fig. 3Effect of alirocumab on major adverse cardiovascular events by baseline LDL-C and Lp(a) categories.
      Patients in the ODYSSEY OUTCOMES trial were placed in a lower LDL-C category (n = 4351) if at least one pre-randomization LDL-C level was <70 mg/dl. In this category, median LDL-C was 69.4 mg/dl and median Lp(a) was 13.7 mg/dl. The other 14,573 trial participants were placed in a higher LDL-C category, in which median LDL-C was 94 mg/dl. Both LDL-C categories were dichotomized according to Lp(a) concentration of 13.7 mg/dl. In the lower LDL-C category, a treatment benefit of alirocumab was observed only when Lp(a) was above 13.7 mg/dl, with evidence of treatment-by-Lp(a) interaction. In the higher LDL-C category, treatment hazard ratios were similar and numerically favorable for alirocumab in both Lp(a) categories, without significant interaction. Results were similar with or without adjustment for other clinical characteristics. The findings suggest that Lp(a) modifies the effect of alirocumab treatment when LDL-C levels are nominally controlled on statin treatment. Reproduced with permission [
      • Schwartz G.G.
      • Szarek M.
      • Bittner V.A.
      • et al.
      Lipoprotein(a) and benefit of PCSK9 inhibition in patients with nominally controlled LDL cholesterol.
      ].

      1.1.2 Lp(a) and the effect of alirocumab on major adverse limb events

      Observational data indicate that incident peripheral artery disease may be more strongly associated with elevation of Lp(a) than either coronary or cerebrovascular disease [
      • Gurdasani D.
      • Sjouke B.
      • Tsimikas S.
      • et al.
      Lipoprotein(a) and risk of coronary, cerebrovascular, and peripheral artery disease: the EPIC-Norfolk prospective population study.
      ]. In the FOURIER trial, the risk of major adverse limb events (MALE, including acute limb ischemia, major amputation, or urgent limb revascularization for ischemia) was reduced substantially by treatment with evolocumab; however, the relationship of this effect to Lp(a) levels was not reported [
      • Bonaca M.P.
      • Nault P.
      • Giugliano R.P.
      • et al.
      Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk).
      ]. In ODYSSEY OUTCOMES [
      • Schwartz G.G.
      • Steg P.G.
      • Szarek M.
      • et al.
      Peripheral artery disease and venous thromboembolic events after acute coronary syndrome: role of lipoprotein(a) and modification by alirocumab: prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial.
      ] an important observation was that the risk of MALE in the placebo group and the reduction in that risk in the alirocumab group were strongly associated with the baseline level of Lp(a), but not with the level of LDL-Ccorrected (Fig. 4).
      Fig. 4
      Fig. 4Risk of major peripheral artery disease events according to baseline Lp(a) and corrected LDL-C in the ODYSSEY OUTCOMES trial.
      Major peripheral artery disease (PAD) events comprised a pre-specified outcome that included critical limb ischemia, limb revascularization or amputation for ischemia. LDL-C levels were corrected for the concentration of cholesterol in Lp(a) (LDL-Ccorrected) using an empiric formula. (A) The risk of major PAD events is shown for the placebo group according to baseline quartile of Lp(a) [left] or LDL-Ccorrected [right]. The risk of major PAD events increased with increasing quartiles of Lp(a), but did not show a relationship with quartiles of LDL-Ccorrected. (B) The treatment effect of alirocumab for major PAD events was significantly related to baseline Lp(a) quartile, but not with quartiles of LDL-Ccorrected. Reproduced with permission [
      • Schwartz G.G.
      • Steg P.G.
      • Szarek M.
      • et al.
      Peripheral artery disease and venous thromboembolic events after acute coronary syndrome: role of lipoprotein(a) and modification by alirocumab: prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial.
      ].

      1.1.3 Lp(a), venous thromboembolism, and PCSK9 inhibition

      An association of elevated Lp(a) with risk of venous thromboembolism is uncertain and controversial. Some epidemiologic and genetic analyses have associated the risk of venous thromboembolic events (VTE) with Lp(a) levels [
      • Dentali F.
      • Gessi V.
      • Marcucci R.
      • et al.
      Lipoprotein(a) as a risk factor for venous thromboembolism: a systematic review and meta-analysis of the literature.
      ,
      • Sticchi E.
      • Magi A.
      • Kamstrup P.R.
      • et al.
      Apolipoprotein(a) kringle-IV type 2 copy number variation is associated with venous thromboembolism.
      ], although another, larger genetic analysis did not demonstrate such an association using instrumental variable analysis with kringle IV type 2 repeats and single nucleotide polymorphisms [
      • Kamstrup P.R.
      • Tybjaerg-Hansen A.
      • Nordestgaard B.G.
      Genetic evidence that lipoprotein(a) associates with atherosclerotic stenosis rather than venous thrombosis.
      ,
      • Nordestgaard B.G.
      • Langsted A.
      Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology.
      ]. A meta-analysis of the FOURIER and ODYSSEY OUTCOMES trials showed significant 31% reduction in the relative risk of investigator-reported VTE with PCSK9 inhibition (p = 0.007) [
      • Marston N.A.
      • Gurmu Y.
      • Melloni G.E.M.
      • et al.
      The effect of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition on the risk of venous thromboembolism.
      ] (Fig. 5A). In the placebo group of FOURIER, there was greater risk of VTE in patients with levels of Lp(a) above versus below median, but no analogous relationship between risk of VTE and LDL-C levels above versus below median. The magnitude of VTE risk reduction with evolocumab was associated with baseline levels of Lp(a), but not LDL-C (Fig. 5B). Likewise, in ODYSSEY OUTCOMES the absolute reduction in Lp(a) with alirocumab, but not the reduction in corrected LDL-C, was associated with reduced risk of VTE [
      • Schwartz G.G.
      • Steg P.G.
      • Szarek M.
      • et al.
      Peripheral artery disease and venous thromboembolic events after acute coronary syndrome: role of lipoprotein(a) and modification by alirocumab: prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial.
      ]. Similar findings from two large, independent clinical trials suggest that elevated Lp(a) may contribute to the risk of VTE and that attenuation of that risk by PCSK9 inhibition is influenced by Lp(a) levels. The mechanisms underlying these associations are uncertain, but could be related to proinflammatory effects of Lp(a) on the venous endothelium. Effects of Lp(a) on thrombosis may also contribute and are discussed by Boffa in this thematic review series [
      • Boffa M.B.
      Beyond fibrinolysis: the confounding role of Lp(a) in thrombosis.
      ]. It is important to draw a distinction between the patients who participated in PCSK9 inhibitor outcomes trials and people who comprised epidemiologic cohorts. The former group is more likely to have characteristics associated with risk of VTE including older age, smoking, adiposity, and systemic inflammation [
      • Colling M.E.
      • Tourdot B.E.
      • Kanthi Y.
      Inflammation, infection and venous thromboembolism.
      ,
      • Gregson J.
      • Kaptoge S.
      • Bolton T.
      • et al.
      Cardiovascular risk factors associated with venous thromboembolism.
      ]. In addition, the distribution of Lp(a) concentrations is shifted to higher levels in a secondary prevention population. This may explain why a relationship of VTE with Lp(a) levels was apparent in FOURIER and ODYSSEY OUTCOMES but not in some prior epidemiologic analyses.
      Fig. 5
      Fig. 5(A) Meta-analysis for the effect of PCSK9 inhibitors on VTE. A meta-analysis of the FOURIER and ODYSSEY OUTCOMES trials demonstrates a consistent, favorable effect of PCSK9 inhibition on the incidence of venous thromboembolic events (deep venous thrombosis or pulmonary embolism). (B) In the FOURIER trial, the benefit of treatment with evolocumab on VTE was assessed according to the median baseline levels of LDL-C (left) and Lp(a) (right). Similar risk reduction was observed when baseline LDL-C was below or at least equal to the median (92 mg/dL). In contrast, there was no evidence of a treatment benefit when baseline Lp(a) was less than the median of 37 nmol/L, but substantial benefit when Lp(a) was that level or higher (pheterogeneity for absolute risk reduction = 0.037). This was despite similar reductions in LDL-C with evolocumab in both Lp(a) categories. Reproduced with permission [
      • Marston N.A.
      • Gurmu Y.
      • Melloni G.E.M.
      • et al.
      The effect of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition on the risk of venous thromboembolism.
      ].

      1.1.4 Lp(a), PCSK9 inhibition, and incident diabetes

      Observational cohort data have indicated inverse relationships between Lp(a) levels and prevalent type 2 diabetes, and in some cases incident type 2 diabetes [
      • Gudbjartsson D.F.
      • Thorgeirsson G.
      • Sulem P.
      • et al.
      Lipoprotein(a) concentration and risks of cardiovascular disease and diabetes.
      ,
      • Mora S.
      • Kamstrup P.R.
      • Rifai N.
      • et al.
      Lipoprotein(a) and risk of type 2 diabetes.
      ,
      • Paige E.
      • Masconi K.L.
      • Tsimikas S.
      • et al.
      Lipoprotein(a) and incident type-2 diabetes: results from the prospective Bruneck study and a meta-analysis of published literature.
      ,
      • Ye Z.
      • Haycock P.C.
      • Gurdasani D.
      • et al.
      The association between circulating lipoprotein(a) and type 2 diabetes: is it causal?.
      ]. These relationships have been most pronounced at low levels of Lp(a). The mechanism underlying these associations is unknown, but an inverse association of Lp(a) levels with measures of insulin resistance has been reported [
      • Kaya A.
      • Onat A.
      • Yuksel H.
      • et al.
      Lipoprotein(a)-activated immunity, insulin resistance and new-onset diabetes.
      ,
      • Vaverkova H.
      • Karasek D.
      • Halenka M.
      • et al.
      Inverse association of lipoprotein (a) with markers of insulin resistance in dyslipidemic subjects.
      ]. A key question is whether pharmacologic reduction of Lp(a) increases the risk of developing type 2 diabetes, analogous to the effect of intensive statin treatment [
      • Preiss D.
      • Seshasai S.R.
      • Welsh P.
      • et al.
      Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis.
      ]. This question was investigated in a post hoc analysis of the ODYSSEY OUTCOMES trial, in which incident diabetes was adjudicated by a blinded panel of experts on the basis of adverse event, laboratory, and medication data [
      • Schwartz G.G.
      • Szarek M.
      • Bittner V.A.
      • et al.
      Relation of lipoprotein(a) levels to incident type 2 diabetes and modification by alirocumab treatment.
      ]. There were several noteworthy observations from this analysis. First, median Lp(a) concentration was lower in patients with diabetes at baseline than in patients without diabetes at baseline, consistent with prior observations of an inverse association of Lp(a) with prevalent diabetes. Second, in patients in the placebo group who did not have diabetes at baseline, there was an inverse relationship between Lp(a) and incident diabetes, with HR (95% CI) 1.04 (1.02–1.06; p < 0.001) per 10 mg/dL lower baseline lipoprotein(a) (Fig. 6, in blue). Third, although alirocumab treatment did not affect the overall incidence of type 2 diabetes compared to placebo, alirocumab modified the relationship between baseline Lp(a) and incident diabetes (Fig. 6, in red, interaction p = 0.006). In patients with low Lp(a) the risk of incident diabetes was reduced with alirocumab, while in patients with higher baseline levels of Lp(a) (who experienced more substantial reductions in Lp(a) with alirocumab) the risk of incident diabetes appeared to be increased compared to placebo. Within the alirocumab group, each 10 mg/dl reduction in Lp(a) from baseline to month 4 of treatment was associated with an adjusted HR (95% CI) of 1.08 (1.04–1.12; p = 0.0001) for incident diabetes after month 4. Because these are findings from a post hoc analysis, they must be considered hypothesis-generating. A majority of the patients without diabetes at baseline had prediabetes, so that relatively small changes in glycemic measures could have resulted in a new diagnosis of diabetes. In addition, 89% of patients in ODYSSEY OUTCOMES received background treatment with a high-intensity statin regimen, which may increase the propensity for incident diabetes. Notwithstanding these considerations, the findings raise the possibility that therapeutic reduction of Lp(a) may increase the risk of incident diabetes in patients with high baseline Lp(a) levels. The test of this hypothesis awaits results from trials with drugs that target the mRNA transcript of the LPA gene, discussed later in this article. Other aspects of the relationship between Lp(a) and diabetes are reviewed by Ward and Lamina in this thematic review series [
      • Lamina C.
      • Ward N.C.
      Lp(a) and diabetes mellitus.
      ].
      Fig. 6
      Fig. 6Spline analysis of the probability of incident type 2 diabetes by baseline Lp(a) and treatment group in the ODYSSEY OUTCOMES trial.
      Among 13,460 trial participants without diabetes at baseline, 1324 developed type 2 diabetes during the trial. In the placebo group, there was an inverse, monotonic relationship between Lp(a) levels and incident diabetes [HR (95% CI) 1.04 (1.02–1.06; p < 0.001) per 10 mg/dL lower baseline lipoprotein(a)]. Treatment with alirocumab significantly modified that relationship (pinteraction = 0.006) with lower risk of incident diabetes compared to placebo when Lp(a) was low and greater risk when Lp(a) was high. The curves cross at a baseline Lp(a) level of approximately 50 mg/dl. Within the alirocumab group, each 10 mg/dl decrease in Lp(a) from baseline was associated with an adjusted HR (95% CI) for incident diabetes of 1.08 (1.04–1.12; p = 0.0001). Reproduced with permission [
      • Schwartz G.G.
      • Szarek M.
      • Bittner V.A.
      • et al.
      Relation of lipoprotein(a) levels to incident type 2 diabetes and modification by alirocumab treatment.
      ].

      1.1.5 Summary: PCSK9 monoclonal antibodies

      PCSK9 monoclonal antibodies comprise the only approved drug class that has been shown to simultaneously reduce levels of Lp(a) and the risk of cardiovascular events. Moreover, a relationship between these effects was evident in the FOURIER and ODYSSEY OUTCOMES trials [
      • Bittner V.A.
      • Szarek M.
      • Aylward P.E.
      • et al.
      Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome.
      ,
      • Schwartz G.G.
      • Steg P.G.
      • Szarek M.
      • et al.
      Peripheral artery disease and venous thromboembolic events after acute coronary syndrome: role of lipoprotein(a) and modification by alirocumab: prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial.
      ]. Importantly, a pronounced reduction in cardiovascular risk with PCSK9 inhibition was observed in patients with elevated Lp(a) levels, and was achieved with only 16–22% reduction of Lp(a) levels in the highest baseline Lp(a) quartile [
      • Bittner V.A.
      • Szarek M.
      • Aylward P.E.
      • et al.
      Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome.
      ,
      • O'Donoghue M.L.
      • Fazio S.
      • Giugliano R.P.
      • et al.
      Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk.
      ,
      • Schwartz G.G.
      • Steg P.G.
      • Szarek M.
      • et al.
      Peripheral artery disease and venous thromboembolic events after acute coronary syndrome: role of lipoprotein(a) and modification by alirocumab: prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial.
      ]. This raises the question whether the clinical benefit of PCSK9 monoclonal antibodies, added to statin in patients with elevated Lp(a), is directly related to the reduction of circulating Lp(a) concentration, related to the coordinated reduction of both circulating LDL-C and Lp(a) concentrations, or alternatively whether an elevated Lp(a) level is a marker for plaque characteristics amenable to stabilization by intensive reduction of atherogenic lipoproteins.

      1.1.6 Inclisiran

      Inclisiran is a double-stranded small interfering RNA that suppresses PCSK9 mRNA translation and reduces PCSK9 protein synthesis, resulting in reduced plasma levels of PCSK9 and LDL-C. In the ORION-10 and ORION-11 trials, Lp(a) was reduced by 25.6% and 18.6%, respectively, from baseline medians of 57 nmol/L and 42 nmol/L, respectively, with inclisiran compared with placebo, whereas LDL-C reductions were ∼50% [
      • Ray K.K.
      • Wright R.S.
      • Kallend D.
      • et al.
      Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol.
      ]. Inclisiran therefore provides similar Lp(a) and LDL-C reductions as monoclonal antibodies against PCSK9, with the potential advantage of twice-yearly instead of twice-monthly or monthly dosing. ORION-4 is ongoing to determine the potential benefit of inclisiran on clinical events [

      www.clinicaltrials.gov accessed 24 Apr 2022.NCT03705234. "A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease (ORION-4).

      ]. Inclisiran is approved by the European Medicines Agency and the US Food and Drug Administration, with similar indications for LDL-C lowering in adults as the other PCSK9 inhibitors [
      ,

      https://www.novartis.us/sites/www.novartis.us/files/leqvio.pdf. Leqvio (inclisiran) US prescribing information. Accessed 24 April 2022.

      ].

      1.2 Niacin

      Niacin, an essential micronutrient, exerts substantial effects on lipoprotein metabolism at pharmacologic doses (e.g., 2 g daily), with effects of raising the concentration of high-density lipoprotein (HDL) cholesterol and lowering triglycerides, LDL-C, and Lp(a). In a meta-analysis of 14 randomized placebo-controlled trials comprising 9013 patients, extended-release niacin reduced Lp(a) by a mean of 23% [
      • Sahebkar A.
      • Reiner Z.
      • Simental-Mendia L.E.
      • et al.
      Effect of extended-release niacin on plasma lipoprotein(a) levels: a systematic review and meta-analysis of randomized placebo-controlled trials.
      ]. The effect of niacin to lower Lp(a) concentration is likely due to decreased apolipoprotein(a) production rate. Modulation of Lp(a) metabolism by niacin discussed in detail by Watts and Lambert in this thematic review series [
      • Chemello K.
      • Chan D.C.
      • Lambert G.
      • Watts G.F.
      Recent advances in demystifying the metabolism of lipoprotein (a).
      ].
      Two placebo-controlled trials have evaluated the cardiovascular efficacy of extended-release niacin (with or without the anti-flushing agent laropiprant) added to background simvastatin treatment. These trials were AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) trial (n = 3414) and HPS2-THRIVE (Heart Protection Study 2–Treatment of HDL to Reduce the Incidence of Vascular Events) trial (n = 25,673) [
      • HPS2-THRIVE Collaborative Group
      • Landray M.J.
      • Haynes R.
      • et al.
      Effects of extended-release niacin with laropiprant in high-risk patients.
      ,
      • AIM-HIGH Investigators
      • Boden W.E.
      • Probstfield J.L.
      • et al.
      Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
      ]. Neither trial demonstrated cardiovascular efficacy of niacin and HPS2-THRIVE revealed an excess of serious non-cardiovascular adverse events. In AIM-HIGH, with median baseline Lp(a) concentration 33.8 nmol/L, each 1–standard deviation increment of baseline Lp(a) (88.7 nmol/L) was associated with a HR of 1.22 for MACE in the placebo group. Niacin reduced Lp(a) by a placebo-corrected mean of 19.6%, with greater absolute Lp(a) reduction as baseline Lp(a) concentration increased. However, there was no interaction of baseline Lp(a) and treatment on MACE [
      • Albers J.J.
      • Slee A.
      • O'Brien K.D.
      • et al.
      Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis intervention in metabolic syndrome with low HDL/high triglyceride and impact on global Health outcomes).
      ]. In HPS2-THRIVE Lp(a) was reduced with niacin/laropiprant to a similar extent as with niacin in AIM-HIGH. Smaller proportional reductions in Lp(a) were observed in patients with lower isoform size and higher circulating Lp(a) concentration. Because Lp(a) was measured in only in a subset of patients, relationships between Lp(a) levels at baseline or on treatment and the risk of MACE could not be determined [
      • Parish S.
      • Hopewell J.C.
      • Hill M.R.
      • et al.
      Impact of apolipoprotein(a) isoform size on lipoprotein(a) lowering in the HPS2-THRIVE study.
      ].
      In the absence of evidence that reduction of Lp(a) with niacin is associated with a cardiovascular benefit and with evidence of adverse effects of niacin treatment, niacin is not recommended as a mean of lowering Lp(a) concentration.

      1.3 CETP inhibitors

      CETP mediates the transfer of cholesteryl ester from HDL particles to apolipoprotein B–containing particles, including very-low-density lipoprotein (VLDL) and LDL particles, in exchange for triglyceride. As a consequence, all CETP inhibitors (including torcetrapib, dalcetrapib, anacetrapib, and evacetrapib) raise the circulating concentration of HDL cholesterol. In addition, these compounds lower the concentration of Lp(a) and potent CETP inhibitors (i.e., all of the above except dalcetrapib) lower concentrations of apolipoprotein B and LDL-C. Reductions in Lp(a) with CETP inhibitors have ranged from approximately 10% with torcetrapib [
      • Arsenault B.J.
      • Petrides F.
      • Tabet F.
      • et al.
      Effect of atorvastatin, cholesterol ester transfer protein inhibition, and diabetes mellitus on circulating proprotein subtilisin kexin type 9 and lipoprotein(a) levels in patients at high cardiovascular risk.
      ] and dalcetrapib [
      • Schwartz G.G.
      • Ballantyne C.M.
      • Barter P.J.
      • et al.
      Association of lipoprotein(a) with risk of recurrent ischemic events following acute coronary syndrome: analysis of the dal-outcomes randomized clinical trial.
      ] to 25–31% with anacetrapib [
      • HPS3/TIMI55--REVEAL Collaborative Group
      • Bowman L.
      • Hopewell J.C.
      • et al.
      Effects of anacetrapib in patients with atherosclerotic vascular disease.
      ] and evacetrapib. In the case of anacetrapib, the reduction in Lp(a) concentration was shown to be due to reduced apolipoprotein (a) production rate [
      • Thomas T.
      • Zhou H.
      • Karmally W.
      • et al.
      CETP (cholesteryl ester transfer protein) inhibition with anacetrapib decreases production of lipoprotein(a) in mildly hypercholesterolemic subjects.
      ]. All four of the above CETP inhibitors have been evaluated in large cardiovascular outcomes trials. Despite substantial, notionally favorable lipoprotein changes only anacetrapib demonstrated a modestly favorable clinical effect [
      • Armitage J.
      • Holmes M.V.
      • Preiss D.
      Cholesteryl ester transfer protein inhibition for preventing cardiovascular events: JACC review topic of the week.
      ]. Compared to placebo, anacetrapib reduced LDL-C by a mean of 17%, Lp(a) by a mean of 25%, and the risk of MACE by 9% (p = 0.004) [
      • HPS3/TIMI55--REVEAL Collaborative Group
      • Bowman L.
      • Hopewell J.C.
      • et al.
      Effects of anacetrapib in patients with atherosclerotic vascular disease.
      ]. The relationship of treatment effect to Lp(a) levels was evaluated in three pre-defined quantiles of baseline Lp(a), <15, 15 to <55, and ≥55 nmol/L. Event rate ratios (95% CI) were 0.96 (0.86–1.07), 0.91 (0.80–1.03), and 0.85 (0.75–0.96), respectively, with interaction p = 0.14. At present, no CETP inhibitor is approved for therapeutic use, and therefore this approach is not available to clinicians as a means of lowering Lp(a) or reducing cardiovascular risk.

      1.4 Statins

      Clinical trials of statin therapy have shown mixed results on Lp(a) levels. In the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), rosuvastatin had no effect on median Lp(a) level but did shift overall Lp(a) distribution toward higher percentiles [
      • Nissen S.E.
      • Wolski K.
      • Balog C.
      • et al.
      Single ascending dose study of a short interfering RNA targeting lipoprotein(a) production in individuals with elevated plasma lipoprotein(a) levels.
      ]. Rosuvastatin therapy had similar benefits in participants with levels of Lp(a) above or below the median, with no significant interaction, but participants with higher levels of Lp(a) remained at increased residual risk for cardiovascular events. In a meta-analysis of 7 placebo-controlled statin trials that evaluated associations of Lp(a) and cardiovascular events (fatal or non-fatal coronary heart disease, stroke, or revascularization) in a total of 29,069 patients, cardiovascular risk increased at categorical Lp(a) levels ≥30 mg/dL at baseline and ≥50 mg/dL on statin; statin therapy did not significantly change Lp(a) levels [
      • Willeit P.
      • Ridker P.M.
      • Nestel P.J.
      • et al.
      Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.
      ], and importantly a significant relationship between Lp(a) levels and cardiovascular risk was observed despite statin treatment. Another meta-analysis of 6 trials including 5256 patients randomized to receive atorvastatin, pitavastatin, pravastatin, rosuvastatin, or placebo indicated a significant 11% increase in the ratio of geometric mean Lp(a) level from baseline with statin therapy, ranging from 8.5% to 19.6% in the statin groups and −0.4% to −2.3% in the placebo groups, in the 3 placebo-controlled trials and a significant 9% increase in the ratio of geometric means for atorvastatin to pravastatin, ranging from 11.6% to 20.4% in the pravastatin group and 18.7% to 24.2% in the atorvastatin group, in the 3 statin-vs-statin trials; the investigators found that incubating HepG2 hepatocytes with atorvastatin increased expression of LPA mRNA and apolipoprotein(a) protein [
      • Tsimikas S.
      • Gordts P.L.S.M.
      • Nora C.
      • et al.
      Statin therapy increases lipoprotein(a) levels.
      ]. However, a meta-analysis of 39 placebo-controlled trials with various statin drugs including 24,448 patients indicated a non-significant 0.1% increase in Lp(a) with statin versus placebo groups with no significant differences among individual statin agents or for different intensities of statin treatment. Based on these findings, the investigators concluded that statins do not produce clinically important changes in Lp(a) [
      • de Boer L.M.
      • Oorthuys A.O.J.
      • Wiegman A.
      • et al.
      Statin therapy and lipoprotein(a) levels: a systematic review and meta-analysis.
      ].

      1.5 Ezetimibe

      An effect of ezetimibe on Lp(a) is not clear from the available published data. In a meta-analysis of 7 trials of ezetimibe monotherapy in a total of 2337 patients with primary hypercholesterolemia, ezetimibe 10 mg/day significantly reduced Lp(a) level by 7.1%, but the investigators concluded that this small reduction would not be clinically significant [
      • Awad K.
      • Mikhailidis D.P.
      • Katsiki N.
      • et al.
      Effect of ezetimibe monotherapy on plasma lipoprotein(a) concentrations in patients with primary hypercholesterolemia: a systematic review and meta-analysis of randomized controlled trials.
      ]. In contrast, a meta-analysis of 10 trials of ezetimibe in a total of 5188 patients found no effect of ezetimibe on Lp(a) level, and subgroup analyses indicated no effect with ezetimibe monotherapy versus placebo or ezetimibe with statin vs statin alone [
      • Sahebkar A.
      • Simental-Mendia L.E.
      • Pirro M.
      • et al.
      Impact of ezetimibe on plasma lipoprotein(a) concentrations as monotherapy or in combination with statins: a systematic review and meta-analysis of randomized controlled trials.
      ].

      1.6 Bempedoic acid

      Bempedoic acid is an oral lipid-modifying agent that inhibits adenosine triphosphate citrate lyase, upstream from HMG-CoA reductase, to decrease cholesterol biosynthesis in the liver, upregulate the LDL receptor, and increase clearance of LDL. Although randomized, double-blind, placebo-controlled clinical trials have established safety, tolerability, and LDL-C–lowering efficacy of bempedoic acid alone or administered as bempedoic acid/ezetimibe combination tablet [
      • Ballantyne C.M.
      • Bays H.
      • Catapano A.L.
      • et al.
      Role of bempedoic acid in clinical practice.
      ], no benefit on Lp(a) lowering has been reported. Phase 2 trial data suggested small increases in Lp(a) with bempedoic acid, but the changes were not statistically significant (Esperion Therapeutics, data on file), and a clinical trial of bempedoic acid combined with PCSK9 inhibitor versus PCSK9 inhibitor alone found no difference in the change from baseline of Lp(a) between treatment groups (+2.2 ± 24.8% versus +3.7 ± 27.7%, respectively; n = 56) [
      • Rubino J.
      • MacDougall D.E.
      • Sterling L.R.
      • et al.
      Lipid lowering with bempedoic acid added to a proprotein convertase subtilisin/kexin type 9 inhibitor therapy: a randomized, controlled trial.
      ].

      1.7 Fibrates

      Fibrates remain a potentially important drug class for patients with cardiovascular disease. Gembrozil reduced cardiovascular events in patients untreated with statins [
      • Frick M.H.
      • Elo O.
      • Haapa K.
      • et al.
      Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease.
      ,
      • Rubins H.B.
      • Robins S.J.
      • Collins D.
      • et al.
      Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.
      ]. Although the primary outcomes of trials with fenofibrate and bezafibrate have been neutral [
      • FIELD Study Investigators
      Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study).
      ,
      • ACCORD Study Group
      Effects of combination lipid therapy in type 2 diabetes mellitus.
      ,
      • BIP Study Group
      Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease: the Bezafibrate Infarction Prevention (BIP) Study.
      ], favorable trends were observed in patients with hypertriglyceridemia and a large cardiovascular outcomes trial with pemafibrate is in progress [
      • Pradhan A.D.
      • Paynter N.P.
      • Everett B.M.
      • et al.
      Rationale and design of the pemafibrate to reduce cardiovascular outcomes by reducing triglycerides in patients with diabetes (PROMINENT) study.
      ]. Most data indicate no significant effect of fibrates on Lp(a) concentration [
      • Sahebkar A.
      • Simental-Mendia L.E.
      • Watts G.F.
      • et al.
      Comparison of the effects of fibrates versus statins on plasma lipoprotein(a) concentrations: a systematic review and meta-analysis of head-to-head randomized controlled trials.
      ]. However, an inverse relationship between plasma triglyceride and Lp(a) levels has long been recognized [
      • McConathy W.J.
      • Trieu V.N.
      • Klor H.U.
      • et al.
      Lp(a) and plasma triglyceride-rich lipoproteins.
      ] and was observed in recent cohorts [
      • Bittner V.A.
      • Szarek M.
      • Aylward P.E.
      • et al.
      Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome.
      ,
      • O'Donoghue M.L.
      • Fazio S.
      • Giugliano R.P.
      • et al.
      Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk.
      ]. In patients with significant hypertriglyceridemia, fibrate treatment may be associated with an increase in Lp(a), in turn associated with the degree of fibrate-induced triglyceride-lowering [
      • Ko H.S.
      • Kim C.J.
      • Ryu W.S.
      Effect of fenofibrate on lipoprotein(a) in hypertriglyceridemic patients: impact of change in triglyceride level and liver function.
      ].

      1.8 Bile acid sequestrants

      The bile acid sequestrants (colesevalem, cholestyramine, and colestipol) interrupt the enterohepatic circulation of bile acids, thereby increasing the conversion of cholesterol into bile acids and upregulating the LDL receptor. They have not been shown to affect Lp(a) levels [
      • Eraikhuemen N.
      • Lazaridis D.
      • Dutton M.T.
      Emerging pharmacotherapy to reduce elevated lipoprotein(a) plasma levels.
      ].

      1.9 Mipomersen

      Mipomersen is a second-generation antisense oligonucleotide targeting apolipoprotein B. A meta-analysis of 4 trials including 382 patients (with or without FH) found a 26% reduction in Lp(a) level with weekly injections of mipomersen 200 mg for 26 weeks [
      • Santos R.D.
      • Raal F.J.
      • Catapano A.L.
      • et al.
      Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials.
      ]. A study of mipomersen in 14 healthy volunteers found a 21% reduction in Lp(a) with weekly injections of mipomersen 150 mg for 7 weeks, and the investigators determined that the Lp(a) reduction was primarily because of a 27% increase in fractional catabolic rate, with no significant change in production rate in the overall study population, although change in production rate was predictive of Lp(a) reduction in some individuals [
      • Nandakumar R.
      • Matveyenko A.
      • Thomas T.
      • et al.
      Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects.
      ].

      1.10 Antisense oligonucleotides and small interfering RNA agents targeting LPA

      Given the modest efficacy of currently available lipid-modifying therapies to reduce elevated Lp(a) levels, genetic approaches have been developed to inhibit Lp(a) synthesis by targeting the mRNA transcript of LPA, the gene encoding apolipoprotein(a) [
      • Tsimikas S.
      • Moriarty P.M.
      • Stroes E.S.
      Emerging RNA therapeutics to lower blood levels of Lp(a): JACC Focus Seminar 2/4.
      ]. Investigational agents that use antisense oligonucelotides or small interfering RNA are being tested in clinical trials to determine Lp(a)-lowering efficacy (Table 2), safety and tolerability, and potential for cardiovascular disease risk reduction.
      Table 2Approaches to lower the concentration of Lipoprotein(a) by targeting LPA.
      AgentMechanism of actionEffect of treatment on lipoprotein(a) concentrationClinical trial phase
      Pelacarsen (formerly AKCEA-APO(a)-LRX, TQJ230)Antisense to apo(a)Phase 2: reduction, 35–80% [
      • Tsimikas S.
      • Karwatowska-Prokopczuk E.
      • Gouni-Berthold I.
      • et al.
      Lipoprotein(a) reduction in persons with cardiovascular disease.
      ]
      Phase 3 outcomes trial ongoing [

      www.ClinicalTrials.gov. NCT04023552. "Assessing the Impact of Lipoprotein (A) Lowering with Pelacarsen (TQJ230) on Major Cardiovascular Events in Patients with CVD (Lp(a)HORIZON)." Accessed 24 April 2022.

      ]
      Olpasiran (formerly AMG-890, ARO-LPA)siRNA to apo(a)Phase 1: reduction, 70–95% [
      • Koren M.J.
      • Moriarty P.M.
      • Neutel J.
      • et al.
      Safety, tolerability, and efficacy of single-dose AMG 890, a novel siRNA targeting Lp(a), in healthy subjects and subjects with elevated Lp(a).
      ]
      Phase 2 ongoing [

      www.ClinicalTrials.gov. NCT04270760. "Olpasiran Trials of Cardiovascular Events and LipoproteiN(a) Reduction - DOSE Finding Study." Accessed 24 April 2022.

      ]
      SLN360siRNA to apo(a)Phase 1: reduction, 46–98% [
      • Nissen S.E.
      • Wolski K.
      • Balog C.
      • et al.
      Single ascending dose study of a short interfering RNA targeting lipoprotein(a) production in individuals with elevated plasma lipoprotein(a) levels.
      ,
      • Nissen S.E.
      • Wolski K.
      • Balog C.
      • et al.
      Single ascending dose study of a short interfering RNA targeting lipoprotein(a) production in individuals with elevated plasma lipoprotein(a) levels.
      ]
      Phase 2 planned
      Pelacarsen (formerly IONIS-APO(a)-LRX, AKCEA-APO(a)-LRX, TQJ230) is a second-generation antisense oligonucleotide that targets apolipoprotein(a) mRNA and is conjugated to N-acetylgalactosamine (GalNAc), which enables specific targeting to hepatocytes and provides increased drug potency, less systemic toxicity, and less-frequent dosing [
      • Viney N.J.
      • van Capelleveen J.C.
      • Geary R.S.
      • et al.
      Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials.
      ]. Sustained dose-dependent Lp(a) reductions of 35–80% were reported in patients with Lp(a) ≥60 mg/dL (≥150 nmol/L) and cardiovascular disease [
      • Tsimikas S.
      • Karwatowska-Prokopczuk E.
      • Gouni-Berthold I.
      • et al.
      Lipoprotein(a) reduction in persons with cardiovascular disease.
      ], and an outcomes study is ongoing to determine the potential of pelacarsen for cardiovascular risk reduction in patients with established cardiovascular disease and elevated Lp(a) (≥70 mg/dL) [

      www.ClinicalTrials.gov. NCT04023552. "Assessing the Impact of Lipoprotein (A) Lowering with Pelacarsen (TQJ230) on Major Cardiovascular Events in Patients with CVD (Lp(a)HORIZON)." Accessed 24 April 2022.

      ].
      GalNAc conjugation has also been used in developing small interfering RNA to silence apolipoprotein(a) mRNA in hepatocytes. Olpasiran (formerly AMG-890, ARO-LPA) is a GalNAc-conjugated siRNA agent reported to reduce Lp(a) by 71–96% in patients with baseline Lp(a) ≥70 nmol/L to ≤199 nmol/L and by 75–89% in patients with baseline Lp(a) ≥200 nmol/L, with no safety concerns identified, in a single-dose study in 68 patients [
      • Koren M.J.
      • Moriarty P.M.
      • Neutel J.
      • et al.
      Safety, tolerability, and efficacy of single-dose AMG 890, a novel siRNA targeting Lp(a), in healthy subjects and subjects with elevated Lp(a).
      ]. A phase 1 single ascending dose clinical trial is ongoing to evaluate safety, pharmacokinetics, and pharmacodynamics in 80 subjects with elevated Lp(a) [

      www.ClinicalTrials.gov. NCT03626662. "Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of AMG 890 in Subjects with Elevated Plasma Lipoprotein(a)." Accessed 24 April 2022.

      ], and a phase 2 dose-finding study is ongoing in 290 patients with Lp(a) ≥200 nmol/L and atherosclerotic cardiovascular disease [

      www.ClinicalTrials.gov. NCT04270760. "Olpasiran Trials of Cardiovascular Events and LipoproteiN(a) Reduction - DOSE Finding Study." Accessed 24 April 2022.

      ]. Another GalNAc-conjugated small interfering RNA against apolipoprotein(a) mRNA, SLN360, potently reduced LPA but not APOB mRNA in cultured hepatocytes and lowered circulating Lp(a) by up to 95% in cynomolgus monkeys [
      • Willeit P.
      • Ridker P.M.
      • Nestel P.J.
      • et al.
      Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.
      ], [
      • Rider D.
      • Swerdlow D.
      • Eisermann M.
      • et al.
      Pre-clinical safety assessment of SLN360, a novel short interfering ribonucleic acid targeting LPA, developed to address elevated lipoprotein (a) in cardiovascular disease.
      ]. Safety and tolerability of SLN360 was reported in a phase 1 study in 32 patients with elevated Lp(a) (≥150 nmol/L) [
      • Nissen S.E.
      • Wolski K.
      • Balog C.
      • et al.
      Single ascending dose study of a short interfering RNA targeting lipoprotein(a) production in individuals with elevated plasma lipoprotein(a) levels.
      ]. Over an observation period of 150 days, a single dose of placebo or SLN360 30, 100, 300, or 600 mg produced maximal median percentage changes in Lp(a) from baseline of −10%, −46%, −86%, −96%, and −98%, respectively. A majority of patients treated with SLN360 experienced mild to moderate injection site reactions, compared to 1 of 8 patients treated with placebo.

      2. Drugs other than lipid-modifying agents

      2.1 Aspirin

      Aspirin was shown to reduce apolipoprotein(a) expression in cultured hepatocytes [
      • Kagawa A.
      • Azuma H.
      • Akaike M.
      • et al.
      Aspirin reduces apolipoprotein(a) (apo(a)) production in human hepatocytes by suppression of apo(a) gene transcription.
      ], leading to investigation of its clinical effects on Lp(a) concentration. In a prospective observational study in 70 patients with a history of coronary artery disease or stroke, Lp(a) concentration was measured before and 6 months after the initiation of aspirin 81 mg daily, implemented as part of standard care [
      • Akaike M.
      • Azuma H.
      • Kagawa A.
      • et al.
      Effect of aspirin treatment on serum concentrations of lipoprotein(a) in patients with atherosclerotic diseases.
      ]. Patients were dichotomized according to baseline Lp(a) concentration of 30 mg/dl. There was a 15% decrease in Lp(a) from baseline among patients with initial Lp(a) concentration at this level or above, but no change in Lp(a) among those with lower baseline levels. Although patients with acute ischemic events were excluded to avoid acute phase effects, the uncontrolled design leaves uncertainty whether the initial measurements reflected steady-state conditions. However, in a placebo-controlled investigation in 56 patients with chronic atherosclerotic cardiovascular disease, these investigators found no effect of aspirin on Lp(a) concentration over 3 months of treatment, irrespective of baseline concentration [
      • Akaike M.
      • Azuma H.
      • Kagawa A.
      • et al.
      Effect of aspirin treatment on serum concentrations of lipoprotein(a) in patients with atherosclerotic diseases.
      ].
      In a post hoc analysis of the Women's Health Study [
      • Chasman D.I.
      • Shiffman D.
      • Zee R.Y.
      • et al.
      Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy.
      ], the effect of randomized treatment with aspirin or placebo was examined in 25,131 initially healthy White women according to the minor allele of rs3798220 in the LPA gene, which was carried by 3% of participants and is associated with high circulating Lp(a) concentration. Non-carriers, heterozygotes, and homozygotes for the minor allele had median baseline Lp(a) concentrations of 10.0, 79.5, and 153.9 mg/dl, respectively. In the placebo group, minor allele carriers had a higher risk of MACE, with the caveat of a small number of events. Aspirin reduced the risk of MACE in minor allele carriers, but not in non-carriers, with a significant interaction of carrier status and treatment. Lp(a) concentration was not measured under treatment with aspirin or placebo.
      In summary, there is no convincing evidence that aspirin lowers Lp(a) concentration. However, it is a possible that a benefit of aspirin to prevent MACE depends upon Lp(a) concentration. This hypothesis remains to be tested in a prospective fashion.

      2.2 Hormones

      Estrogen and its analogues reduce transcription of the LPA gene [
      • Boffelli D.
      • Zajchowski D.A.
      • Yang Z.
      • et al.
      Estrogen modulation of apolipoprotein(a) expression. Identification of a regulatory element.
      ,
      • Zysow B.R.
      • Kauser K.
      • Lawn R.M.
      • et al.
      Effects of estrus cycle, ovariectomy, and treatment with estrogen, tamoxifen, and progesterone on apolipoprotein(a) gene expression in transgenic mice.
      ]. In the Women's Health Study, Lp(a) at entry was modestly lower among 12,075 participants who were active users of hormone replacement therapy (median 9.4 mg/dl) compared to 15,661 participants who did not use hormone replacement therapy (11.6 mg/dl) [
      • Suk Danik J.
      • Rifai N.
      • Buring J.E.
      • et al.
      Lipoprotein(a), hormone replacement therapy, and risk of future cardiovascular events.
      ]. In a meta-analysis of 107 randomized controlled trials of hormone replacement therapy (generally conjugated equine estrogen or 17-beta estradiol with medroxyprogesterone) in post-menopausal women comprising 33,315 patients, hormone replacement therapy was associated with a median 25% decrease in Lp(a) [
      • Salpeter S.R.
      • Walsh J.M.
      • Ormiston T.M.
      • et al.
      Meta-analysis: effect of hormone-replacement therapy on components of the metabolic syndrome in postmenopausal women.
      ]. In the Heart and Estrogen/progestin Replacement Study (HERS), which compared hormone replacement therapy with placebo in post-menopausal women with coronary artery disease [
      • Shlipak M.G.
      • Simon J.A.
      • Vittinghoff E.
      • et al.
      Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause.
      ], baseline median (quartile 1–quartile 3) Lp(a) levels were 25 (7–55) mg/dl. In the placebo group, the risk of MACE increased with baseline Lp(a) quartile. With hormone replacement therapy, the mean decrease in Lp(a) was 5 mg/dl, ranging from nil in the lowest baseline Lp(a) quartile to approximately 12 mg/dl in the highest quartile. Although there was no overall benefit of hormone replacement therapy on MACE, the treatment hazard ratio for hormone replacement therapy was favorable in patients with baseline Lp(a) above the median (interaction p = 0.03). In the absence of an overall benefit of hormone replacement therapy to reduce cardiovascular risk in post-menopausal women, estrogen is not recommended to lower Lp(a) levels in that population. However, similar to aspirin, available data raise the hypothesis that hormone replacement therapy might provide cardiovascular benefit in patients with elevated levels of Lp(a).
      In unblinded or uncontrolled studies, testosterone treatment was associated with lower Lp(a) levels [
      • Hislop M.S.
      • St Clair Gibson A.
      • Lambert M.I.
      • et al.
      Effects of androgen manipulation on postprandial triglyceridaemia, low-density lipoprotein particle size and lipoprotein(a) in men.
      ,
      • Marcovina S.M.
      • Lippi G.
      • Bagatell C.J.
      • et al.
      Testosterone-induced suppression of lipoprotein(a) in normal men; relation to basal lipoprotein(a) level.
      ,
      • Zmunda J.M.
      • Thompson P.D.
      • Dickenson R.
      • et al.
      Testosterone decreases lipoprotein(a) in men.
      ]. However, randomized, controlled trials did not confirm that testosterone or anabolic steroids affect Lp(a) concentration [
      • Giannoulis M.G.
      • Jackson N.
      • Shojaee-Moradie F.
      • et al.
      Effects of growth hormone and/or testosterone on very low density lipoprotein apolipoprotein B100 kinetics and plasma lipids in healthy elderly men: a randomised controlled trial.
      ,
      • Hartgens F.
      • Rietjens G.
      • Keizer H.A.
      • et al.
      Effects of androgenic-anabolic steroids on apolipoproteins and lipoprotein (a).
      ,
      • Miller K.K.
      • Biller B.M.
      • Schaub A.
      • et al.
      Effects of testosterone therapy on cardiovascular risk markers in androgen-deficient women with hypopituitarism.
      ].
      Thyromimetic agents have been shown to reduce both LDL-C and Lp(a), but previous programs were discontinued because of concerns about adverse effects. However, more selective agents are being studied for treatment of nonalcoholic steatohepatitis. These liver-selective thyromimetics reduce hepatic fat substantially and also have beneficial lipid effects, without adverse extrahepatic effects [
      • Angelin B.
      • Kristensen J.D.
      • Eriksson M.
      • et al.
      Reductions in serum levels of LDL cholesterol, apolipoprotein B, triglycerides and lipoprotein(a) in hypercholesterolaemic patients treated with the liver-selective thyroid hormone receptor agonist eprotirome.
      ,
      • Zhao M.
      • Xie H.
      • Shan H.
      • et al.
      Development of thyroid hormones and synthetic thyromimetics in non-alcoholic fatty liver disease.
      ].

      3. Apheresis

      Lipoprotein apheresis removes apolipoprotein B–containing lipoproteins, including Lp(a), and provides greater Lp(a) reductions than available drugs. Lp(a) level is reduced by 70–80% acutely after treatment but rebounds between treatments, which are typically weekly, biweekly, or less frequently, resulting in mean interval Lp(a) reduction of 25–40% [
      • Arai K.
      • Orsoni A.
      • Mallat Z.
      • et al.
      Acute impact of apheresis on oxidized phospholipids in patients with familial hypercholesterolemia.
      ,
      • Waldmann E.
      • Parhofer K.G.
      Lipoprotein apheresis to treat elevated lipoprotein (a).
      ,
      • Stefanutti C.
      • Mazza F.
      • Pasqualetti D.
      • et al.
      Lipoprotein apheresis downregulates IL-1 alpha, IL-6 and TNF-alpha mRNA expression in severe dyslipidaemia.
      ]. Large absolute reductions in Lp(a) appear necessary for clinical benefit on cardiovascular risk reduction [
      • Burgess S.
      • Ference B.A.
      • Staley J.R.
      • et al.
      Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a mendelian randomization analysis.
      ], and lipoprotein apheresis has been shown to reduce cardiovascular events in individuals treated for elevated Lp(a) [
      • Moriarty P.M.
      • Gray J.V.
      • Gorby L.K.
      Lipoprotein apheresis for lipoprotein(a) and cardiovascular disease.
      ]. In a prospective randomized, sham-controlled, single-blinded, crossover study conducted in England in 20 patients with refractory angina and Lp(a) > 500 mg/L, apheresis resulted in significant improvements in the primary endpoint of change in quantitative myocardial perfusion reserve assessed by cardiovascular magnetic resonance as well as in the secondary endpoints of atheroma burden, exercise capacity, symptoms, and quality of life [
      • Khan T.Z.
      • Hsu L.Y.
      • Arai A.E.
      • et al.
      Apheresis as novel treatment for refractory angina with raised lipoprotein(a): a randomized controlled cross-over trial.
      ]. Given the invasiveness of the procedure, however, large randomized controlled trials are lacking, but cumulative, consistent observational and cohort data support an important role of lipoprotein apheresis for secondary prevention in patients with elevated Lp(a), despite some uncertainty as to the precise magnitude of event reduction, because of the observational nature of the following reported study results. Without a control group, it is difficult to interpret event counts before and after initiation of apheresis and to determine effect size.
      Substantial observational data supporting clinical benefit with Lp(a) reduction by apheresis have been generated in Germany (Fig. 7), where apheresis for elevated Lp(a) (>60 mg/dL, with LDL-C <100 mg/dL [2.59 mmol/L]) and progressive cardiovascular disease (coronary artery disease, peripheral arterial occlusive disease, or cerebrovascular disease) has been indicated and reimbursed since 2008. Available apheresis methods in Germany include lipid filtration, immunoadsorption, dextran sulfate adsorption, heparin-induced extracorporeal LDL precipitation, and direct adsorption of lipoproteins. In 7-year data from the German Lipoprotein Apheresis Registry (2012–2020), including retrospective and prospective observational data on 2055 patients treated regularly with lipoprotein apheresis for high LDL-C and/or high Lp(a) and who also had progressive atherosclerotic cardiovascular disease (>47,000 apheresis treatments in 82 German apheresis centers, acute median Lp(a) reduction rate was 72.4% (68.2% for LDL-C) and major adverse coronary event reduction during 2 years of apheresis treatment was 78%; patients with only increased Lp(a) levels (>60 mg/dL; LDL-C <100 mg/dL [<2.6 mmol/L]) had higher 2-year event reduction (84% versus 72% in patients with only increased LDL-C levels (>100 mg/dL [>2.6 mmol/L]; Lp(a) < 60 mg/dL) [
      • Schettler V.J.J.
      • Peter C.
      • Zimmermann T.
      • et al.
      The German lipoprotein apheresis Registry (GLAR) − more than 7 years on.
      ].
      Fig. 7
      Fig. 7Composite of apheresis studies demonstrating substantial reductions in both Lp(a) and major coronary event rates with lipid apheresis in patients with elevated Lp(a).
      See text for descriptions of studies [
      • Schettler V.J.J.
      • Peter C.
      • Zimmermann T.
      • et al.
      The German lipoprotein apheresis Registry (GLAR) − more than 7 years on.
      ,
      • Roeseler E.
      • Julius U.
      • Heigl F.
      • et al.
      Lipoprotein apheresis for lipoprotein(a)-associated cardiovascular disease: prospective 5 years of follow-up and apolipoprotein(a) characterization.
      ,
      • Jaeger B.R.
      • Richter Y.
      • Nagel D.
      • et al.
      Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events.
      ,
      • Rosada A.
      • Kassner U.
      • Vogt A.
      • et al.
      Does regular lipid apheresis in patients with isolated elevated lipoprotein(a) levels reduce the incidence of cardiovascular events?.
      ] and discussion of limitations.
      In prospective 5-year follow-up from the German observational Pro(a)LiFe-Study, which included 170 patients with elevated Lp(a) (>60 mg/dL; LDL-C <100 mg/dL [<2.6 mmol/L]) and progressive cardiovascular disease who were enrolled during 2008–2010, mean Lp(a) level was reduced from 108.1 mg/dL before apheresis by a mean of 68.1% with a single apheresis treatment, and the mean annual cardiovascular event rate was reduced by 85%, from 0.58 ± 0.53 2 years before regular apheresis to 0.11 ± 0.15 during the subsequent 5 years (p < 0.0001) [
      • Roeseler E.
      • Julius U.
      • Heigl F.
      • et al.
      Lipoprotein apheresis for lipoprotein(a)-associated cardiovascular disease: prospective 5 years of follow-up and apolipoprotein(a) characterization.
      ]. In another German longitudinal multicenter cohort study, in 120 patients with coronary artery disease and Lp(a) ≥214 nmol/L (95th percentile) who received lipid-lowering medications alone until maximally tolerated doses were ineffective and then received combined lipid apheresis and lipid-lowering medication, median Lp(a) was reduced from 400 nmol/L by 73% with apheresis treatment, and mean annual per-patient major adverse coronary event rate was reduced by 86%, from 1.056 to 0.144 (p < 0.0001) [
      • Jaeger B.R.
      • Richter Y.
      • Nagel D.
      • et al.
      Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events.
      ]. Similarly, in a retrospective German study in 37 patients receiving regular apheresis, Lp(a) was reduced from a mean of 112 mg/dL before apheresis by 68% after apheresis, and event-free survival rate was significantly improved from 38% before apheresis to 75% during apheresis (p < 0.0001) [
      • Rosada A.
      • Kassner U.
      • Vogt A.
      • et al.
      Does regular lipid apheresis in patients with isolated elevated lipoprotein(a) levels reduce the incidence of cardiovascular events?.
      ].
      In the United States, an indication for apheresis in patients with Lp(a) > 60 mg/dL and LDL-C >100 mg/dL who have either documented coronary artery disease or documented peripheral artery disease was approved relatively recently, in 2020 [
      • Nugent A.K.
      • Gray J.V.
      • Gorby L.K.
      • et al.
      Lipoprotein apheresis: first FDA indicated treatment for elevated lipoprotein(a).
      ], and only the dextran sulfate cellulose adsorption device is currently available. In a small series of 14 patients at a single U.S. apheresis center, who had Lp(a) > 50 mg/dL (>80th percentile), LDL-C <100 mg/dL, and cardiovascular disease and received biweekly apheresis (including with heparin-induced extracorporeal LDL precipitation before it was discontinued), at mean 4-year follow-up, mean Lp(a) was reduced from 138 mg/dL at baseline to 51 mg/dL (−63%) acutely after apheresis, and incidence of MACE was reduced from 36 before initiation of apheresis to 2 during aphereisis (−94%) [
      • Moriarty P.M.
      • Gray J.V.
      • Gorby L.K.
      Lipoprotein apheresis for lipoprotein(a) and cardiovascular disease.
      ]. An American Lipoprotein Apheresis Registry (ALAR) is being developed to evaluate the utility of apheresis to reduce both Lp(a) level and clinical cardiovascular event risk [
      • Nugent A.K.
      • Gray J.V.
      • Gorby L.K.
      • et al.
      Lipoprotein apheresis: first FDA indicated treatment for elevated lipoprotein(a).
      ].
      The potential benefit of Lp(a) reduction with apheresis for secondary prevention of cardiovascular disease events is unclear not only because of the absence of large randomized controlled outcome trials but also because most available lipoprotein apheresis methods remove all apolipoprotein B–containing lipoproteins, including LDL as well as Lp(a), therefore obscuring the effect attributable to each lipoprotein. However, an Lp(a)-specific method used for 18 months in an angiographic study conducted at 2 centers in Russia, in 30 patients with angiographically confirmed coronary heart disease, Lp(a) > 50 mg/dL, and LDL-C ≤100 mg/dL on statin, led to atherosclerosis regression measured by both percent diameter stenosis and minimum lumen diameter [
      • Safarova M.S.
      • Ezhov M.V.
      • Afanasieva O.I.
      • et al.
      Effect of specific lipoprotein(a) apheresis on coronary atherosclerosis regression assessed by quantitative coronary angiography.
      ].

      4. Conclusion

      Several pharmacologic approaches and apheresis lower Lp(a) levels to varying degrees (Box 1). While an elevated level of Lp(a) predicts, and likely contributes to, the risk of MACE, it was not until the advent of PCSK9 inhibitors that a pharmacologic approach was identified that reduced Lp(a) and substantially reduced the risk of MACE. In two large trials together comprising over 100,000 patient-years of placebo-controlled observation, the reduction of cardiovascular risk with PCSK9 inhibitors was closely associated with levels of Lp(a). Even so, PCSK9 inhibition affects levels of several atherogenic lipoproteins and it remains uncertain whether, and to what extent, Lp(a) reduction under PCSK9 inhibition is causally related to cardiovascular risk reduction. Similarly, apheresis effectively lowers Lp(a) levels and appears to reduce the risk of MACE, but also may affect other plasma components in addition to Lp(a). Recent scientific statements including those from the American Heart Association [
      • Reyes-Soffer G.
      • Ginsberg H.N.
      • Berglund L.
      • et al.
      Lipoprotein(a): a genetically determined, causal, and prevalent risk factor for atherosclerotic cardiovascular disease: a scientific statement from the American heart association.
      ], National Lipid Association [
      • Wilson D.P.
      • Jacobson T.A.
      • Jones P.H.
      • et al.
      Use of lipoprotein(a) in clinical practice: a biomarker whose time has come. A scientific statement from the National Lipid Association.
      ], and Heart UK [
      • Cegla J.
      • Neely R.D.G.
      • France M.
      • et al.
      HEART UK consensus statement on Lipoprotein(a): a call to action.
      ] have highlighted current areas of uncertainty regarding the role of Lp(a) and its therapeutic reduction in determining and modifying cardiovascular risk. The definitive test of the Lp(a)–MACE hypothesis will be forthcoming in randomized, placebo-controlled trials with drugs that specifically target Lp(a).
      On lowering Lp(a)
      • Lipid-modifying therapies including statins, ezetimibe, and fibrates reduce cardiovascular risk without substantially affecting Lp(a) levels. Conversely, lipid-modifying therapies such as niacin and CETP inhibitors lower Lp(a) levels without substantially influencing cardiovascular risk.
      • PCSK9 monoclonal antibodies are the first class of pharmacologic agents to lower Lp(a) levels and substantially reduce cardiovascular risk. The clinical benefit of PCSK9 monoclonal antibodies is associated with baseline and on-treatment levels of Lp(a).
      • •Apheresis is an effective but expensive and invasive means of lowering Lp(a). Observational data suggest a substantial clinical benefit of this approach.
      • •Targeted LPA therapeutics, including antisense oligonucleotide and small interfering RNA molecules, substantially reduce Lp(a) levels. Their clinical efficacy is being investigated in ongoing trials.

      Declaration of competing interests

      Dr. Schwartz has received research support to the University of Colorado from AstraZeneca , Resverlogix , Sanofi , Silence Therapeutics, and The Medicines Company and to the Medical Research Service of the US Department of Veterans Affairs from Pfizer and Roche . Dr. Schwartz is co-inventor of pending US patent 62/806,313 (“Methods for Reducing Cardiovascular Risk”) assigned in full to the University of Colorado.
      Dr. Ballantyne has received grant/research support (to his institution) from Abbott Diagnostic, Akcea, Amgen , Arrowhead , Esperion, Ionis, Novartis , Regeneron , and Roche Diagnostic, and has been a consultant for Abbott Diagnostics , Althera, Amarin , Amgen , Arrowhead , AstraZeneca , Denka Seiken, Esperion, Genentech , Gilead , Illumina , Matinas BioPharma Inc, Merck , New Amsterdam, Novartis , Novo Nordisk , Pfizer , Regeneron , Roche Diagnostic, and Sanofi-Synthelabo.

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