Table 5. Summary of the finalized articles.

ASCVD: Atherosclerotic Cardiovascular Disease; LDL-C: Low-Density Lipoprotein Cholesterol; HDL: High-Density Lipoprotein; Lp(a): Lipoprotein(a); LPA gene: Lipoprotein(a) gene; MESA: Multi-Ethnic Study of Atherosclerosis; TNT Trial: Treating to New Targets trial; MIRACL Trial: Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering Trial; ACS: Acute Coronary Syndrome; REVERSAL: Reversal of Atherosclerosis with Aggressive Lipid LoweringPCSK9: Proprotein Convertase Subtilisin/Kexin type 9; siRNA: small interfering Ribonucleic Acid

References	Year of Study	Study Design	Participants	Results	Outcomes/Conclusion	Interpretation
Afshar et al. [5]	2020	Cohort Study	2,657 participants from the Framingham Heart Study.	Concomitant elevations in lipoprotein(a) and LDL-C were associated with a significantly higher risk of incident cardiovascular disease compared to elevations in LDL-C alone.	Elevated levels of both lipoprotein(a) and LDL-C increase the risk of cardiovascular disease more than elevated LDL-C alone. The study underscores the importance of considering both lipoprotein(a) and LDL-C in cardiovascular risk assessment.	The findings suggest that both lipoprotein(a) and LDL-C should be targeted for intervention in patients at risk of cardiovascular disease. This highlights the need for comprehensive lipid management strategies.
Rikhi et al. [6]	2022	Cross-Sectional Study	6,814 participants from the Multi-Ethnic Study of Atherosclerosis (MESA).	Elevated Lp(a) levels were significantly associated with an increased risk of ASCVD. Each standard deviation increase in Lp(a) was associated with a 25% higher risk of ASCVD.	Lp(a) is an important predictor of ASCVD risk in the general population. The study suggests incorporating Lp(a) measurement into routine risk assessments.	This research underscores Lp(a) as a significant risk factor for ASCVD in the general population and emphasizes its potential utility in preventive cardiology.
Kaiser et al. [7]	2022	Prospective Cohort Study	191 patients with atherosclerotic disease undergoing imaging.	Higher levels of lipoprotein(a) were associated with increased progression of atherosclerotic plaques.	Elevated lipoprotein(a) is linked to increased progression of atherosclerotic plaques, suggesting its role as a potential risk factor for plaque development.	The association between elevated lipoprotein(a) and plaque progression supports the need for further investigation into lipoprotein(a) as a target for therapeutic interventions to mitigate atherosclerotic disease.
Wong et al. [10]	2021	Retrospective cohort study	11,770 statin-treated adults with cardiovascular disease.	The study found that higher levels of lipoprotein(a) were associated with an increased risk of first and recurrent atherosclerotic cardiovascular disease events in statin-treated patients.	Elevated lipoprotein(a) levels were a significant predictor of recurrent cardiovascular events, suggesting that lipoprotein(a) may be an important marker for ongoing risk in statin-treated individuals.	Monitoring and potentially targeting lipoprotein(a) levels could be beneficial for risk stratification and management in patients with cardiovascular disease, even when they are on statin therapy.
Emerging Risk Factors Collaboration Group [11]	2009	Meta-analysis of prospective cohort studies	23,455 participants from 15 studies	Elevated lipoprotein(a) concentrations were associated with increased risks of coronary heart disease and stroke. The association with nonvascular mortality was less clear but indicated a possible increased risk.	Higher levels of lipoprotein(a) are a significant risk factor for coronary heart disease and stroke. The study supports the consideration of lipoprotein(a) as a potential marker for cardiovascular risk assessment.	Lipoprotein(a) could be a valuable biomarker for identifying individuals at higher risk for coronary heart disease and stroke, suggesting its utility in cardiovascular risk stratification.
Willeit et al. [20]	2018	Meta-analysis	18,226 participants across multiple statin trials	Baseline lipoprotein(a) levels were predictive of cardiovascular events in patients treated with statins. On-statin treatment lipoprotein(a) levels were also associated with cardiovascular outcomes.	Elevated baseline lipoprotein(a) levels are a significant predictor of cardiovascular events. The study supports monitoring lipoprotein(a) levels in patients undergoing statin therapy for better risk assessment and management.	Lipoprotein(a) levels can help in identifying patients at higher risk for cardiovascular events, potentially guiding more tailored treatment strategies in those on statin therapy.
Albers et al. [26]	2013	Randomized Controlled Trial	3,414 participants with atherothrombosis, low HDL cholesterol, and high triglycerides.	Higher levels of apolipoprotein B were associated with increased cardiovascular events, while apolipoprotein A-1 was associated with lower risk. Lipoprotein(a) levels did not show a significant association with cardiovascular outcomes in this trial.	Apolipoprotein B and A-1 levels are important markers for cardiovascular risk, whereas lipoprotein(a) did not demonstrate a significant predictive value in this study. The study highlights the role of apolipoproteins in cardiovascular risk assessment.	Monitoring apolipoprotein levels could be more informative for assessing cardiovascular risk than lipoprotein(a) levels in patients with metabolic syndrome and atherothrombosis.
Khera et al. [27]	2014	Randomized Controlled Trial	17,802 participants with elevated C-reactive protein levels and low-density lipoprotein (LDL) cholesterol levels.	Rosuvastatin therapy reduced LDL cholesterol levels and C-reactive protein but had a modest effect on reducing lipoprotein(a) levels. High lipoprotein(a) concentrations were associated with residual cardiovascular risk despite statin therapy.	The study found that even with effective LDL cholesterol reduction by rosuvastatin, high levels of lipoprotein(a) were associated with continued vascular risk, indicating that lipoprotein(a) might contribute to residual risk despite statin therapy.	Lipoprotein(a) remains a significant risk factor for cardiovascular events that is not fully addressed by current statin therapy. This underscores the need for additional strategies to manage residual vascular risk in patients on statins.
Wei et al. [40]	2018	Cohort Study	26,297 participants who were receiving statin therapy and had genetic data available.	The study identified specific genetic variants in the Lipoprotein(a) gene (LPA gene) that were associated with residual cardiovascular risk despite statin therapy. These variants were found to influence lipoprotein(a) levels and contribute to ongoing cardiovascular risk.	Genetic variants in Lipoprotein(a) gene (LPA gene) were associated with residual risk for cardiovascular events in patients on statins. This suggests that genetic predisposition to higher lipoprotein(a) levels may not be fully mitigated by statin therapy.	The findings highlight the role of genetic factors in determining residual cardiovascular risk and suggest that addressing genetic predispositions may be important for improving risk management in patients on statins.
Tsimikas et al. [44]	2019	Narrative review	Not applicable (review article)	The review discusses the role of lipoprotein(a) in cardiovascular risk, summarizing evidence from various studies. It highlights the association between elevated lipoprotein(a) levels and increased risk of cardiovascular diseases. The review also examines the potential mechanisms through which lipoprotein(a) contributes to atherosclerosis and cardiovascular events.	Elevated lipoprotein(a) is a significant risk factor for cardiovascular diseases, and its levels are not fully addressed by current lipid-lowering therapies. The review emphasizes the need for more research into targeted therapies for reducing lipoprotein(a) levels.	The findings suggest that lipoprotein(a) plays a crucial role in cardiovascular risk beyond traditional lipid measurements. Further studies are needed to develop specific treatments for managing lipoprotein(a) and reducing associated cardiovascular risks.
Arsenault et al. [28]	2014	Cohort Study	10,001 statin-treated stable coronary artery disease patients from the Treating to New Targets (TNT) trial	The study evaluated the predictive value of lipid and non-lipid biomarkers for cardiovascular events in patients treated with statins. It found that while traditional lipid measures (e.g., LDL-C) are important, non-lipid biomarkers also provided additional predictive value for cardiovascular outcomes.	Non-lipid biomarkers, in addition to traditional lipid measures, can enhance risk prediction for cardiovascular events in statin-treated patients. This suggests that incorporating a broader range of biomarkers may improve patient risk stratification and management.	The results indicate that using a combination of lipid and non-lipid biomarkers could potentially lead to better risk assessment and treatment strategies for patients with stable coronary artery disease on statins. Further studies are needed to confirm these findings and to evaluate the clinical utility of these additional biomarkers.
Fraley et al. [29]	2009	Cohort Study	3,065 patients with acute coronary syndromes (ACS) enrolled in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial	The study assessed the association of oxidized phospholipids and biomarkers of oxidized LDL with cardiovascular risk factors and inflammatory markers. It also evaluated the effect of statin therapy on these biomarkers. The results showed that higher levels of oxidized phospholipids were associated with increased cardiovascular risk and inflammation, and statin therapy significantly reduced these biomarkers.	Oxidized phospholipids and oxidized LDL biomarkers are linked to cardiovascular risk and inflammation in patients with acute coronary syndrome (ACS). Statin therapy effectively lowers these biomarkers, which could contribute to the reduction in cardiovascular events.	The study highlights the role of oxidized LDL and related biomarkers in cardiovascular risk and inflammation. It supports the use of statins not only for cholesterol lowering but also for their potential effects on reducing oxidative stress and inflammation, thereby potentially lowering cardiovascular risk. Further research could explore these biomarkers' role in predicting cardiovascular events and tailoring treatments.
Choi et al. [30]	2008	Cohort Study	345 patients with coronary artery disease enrolled in the Reversal of Atherosclerosis with Aggressive Lipid Lowering  (REVERSAL) trial	The study evaluated the relationship between biomarkers of oxidized LDL, statin therapy, and changes in coronary atheroma volume as assessed by quantitative coronary angiography. It found that higher levels of oxidized LDL biomarkers were associated with greater atheroma volume, and aggressive statin therapy led to a reduction in both oxidized LDL levels and atheroma volume.	The study concluded that oxidized LDL biomarkers are related to the burden of atherosclerosis and that aggressive statin therapy can reduce both oxidized LDL levels and coronary atheroma volume, indicating a beneficial effect on atherosclerosis progression.	This study supports the role of oxidized LDL as a marker of atherosclerosis and demonstrates that intensive statin therapy not only lowers LDL cholesterol but also reduces oxidative stress and atheroma volume. This highlights the importance of targeting oxidized LDL in managing atherosclerosis and suggests that statin therapy has a significant impact on reducing atherosclerotic plaque.
Capoulade et al. [41]	2015	Prospective Cohort Study	258 patients with calcific aortic valve stenosis who were followed for a median of 2.6 years	The study investigated the role of oxidized phospholipids and lipoprotein(a) in the progression of calcific aortic valve stenosis. Elevated levels of oxidized phospholipids and lipoprotein(a) were found to be associated with faster progression of aortic stenosis. The study used echocardiographic measures to assess valve area and gradient changes over time.	The study concluded that both oxidized phospholipids and lipoprotein(a) are significant predictors of aortic stenosis progression. Elevated levels of these biomarkers were associated with more rapid disease progression, suggesting that they could be useful in identifying patients at higher risk for more severe disease progression.	The findings highlight the importance of oxidized phospholipids and lipoprotein(a) as potential biomarkers for monitoring the progression of aortic stenosis. These markers may be useful for stratifying patients based on their risk of rapid disease progression and could potentially inform treatment decisions and follow-up strategies.
Cannon et al. [31]	2015	RandomizedControlled Trial	18,144 patients with acute coronary syndrome (ACS) who were stabilized and receiving statin therapy	The study assessed the effect of adding ezetimibe to ongoing statin therapy in patients who had experienced an acute coronary syndrome. Ezetimibe, when added to statin therapy, further reduced low-density lipoprotein cholesterol (LDL-C) levels and demonstrated a significant reduction in major cardiovascular events, including myocardial infarction, stroke, and cardiovascular death.	The addition of ezetimibe to statin therapy led to a significant reduction in LDL-C and improved cardiovascular outcomes compared to statin therapy alone. The study concluded that ezetimibe is a valuable addition to statin therapy for further lowering LDL-C and reducing cardiovascular risk in patients with acute coronary syndrome.	This study supports the use of ezetimibe as an effective adjunctive therapy to statins for patients who have experienced an acute coronary syndrome. The findings suggest that more intensive lipid-lowering strategies can further reduce the risk of cardiovascular events in these high-risk patients.
Awad et al. [21]	2018	Systematic Review and Meta-Analysis of Randomized Controlled Trials	2337 patients with primary hypercholesterolemia, pooled from seven randomized controlled trials	The meta-analysis assessed the effect of ezetimibe monotherapy on plasma lipoprotein(a) (Lp(a)) levels. The study found that ezetimibe significantly reduced Lp(a) concentrations by 7.06% in patients with primary hypercholesterolemia compared to placebo.	Ezetimibe monotherapy was effective in lowering Lp(a) levels in patients with primary hypercholesterolemia. This suggests that ezetimibe can be a useful treatment option for managing elevated Lp(a) levels in addition to its lipid-lowering effects.	The findings support the use of ezetimibe as an effective monotherapy for reducing Lp(a) levels in patients with primary hypercholesterolemia. This has implications for managing patients with elevated Lp(a) who are at higher cardiovascular risk.
Sahebkar et al. [22]	2018	Systematic Review and Meta-Analysis of Randomized Controlled Trials	5188 subjects pooled from 10 randomized controlled trials.	The meta-analysis evaluated the impact of ezetimibe on plasma lipoprotein(a) (Lp(a)) levels, both as a monotherapy and in combination with statins. The study found that ezetimibe did not significantly reduced Lp(a) concentrations in both treatment scenarios compared to placebo or standard therapy.	Ezetimibe was not effective in lowering Lp(a) levels both when used alone and when combined with statins. This indicates that ezetimibe cannot be considered a valuable addition to lipid-lowering therapy, particularly for patients with elevated Lp(a) levels.	The results suggest that ezetimibe should not be considered for managing elevated Lp(a) levels, whether used alone or in combination with statins.
Sahebkar et al. [23]	2017	Systematic Review and Meta-Analysis of Head-to-Head Randomized Controlled Trials.	1388 patients from sixteen head-to-head randomized controlled trials comparing fibrates and statins	Fibrates were found to be more effective than statins in reducing plasma lipoprotein(a) concentrations.	Fibrates showed a greater reduction in plasma lipoprotein(a) levels compared to statins. This suggests that fibrates might be more effective in managing elevated Lp(a) levels.	Given the superior efficacy of fibrates over statins in lowering Lp(a) levels, statins should be preferred for patients with high Lp(a) concentrations. This information is useful for guiding lipid-lowering treatment strategies.
Raal et al. [32]	2016	Systematic Review and Meta-Analysis of Clinical Trials	3278 patients treated with evolocumab from 10 clinical trials	The study found that proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition with evolocumab led to significant reductions in lipoprotein(a) (Lp(a)) levels. The role of LDL receptors in this effect was also explored.	Evolocumab, a PCSK9 inhibitor, effectively reduces Lp(a) levels, and the reduction is linked to the activity of LDL receptors. This indicates that PCSK9 inhibition is a promising approach for managing high Lp(a) levels.	The findings support the use of PCSK9 inhibitors like evolocumab as an effective treatment for lowering Lp(a), which may be beneficial for patients with elevated Lp(a) and cardiovascular risk.
Watts et al. [33]	2018	Randomized Controlled Trial	63 healthy men with plasma apo(a) concentrations exceeding 5 nmol/L on evolocumab and atorvastatin.	The study demonstrated that evolocumab, a PCSK9 inhibitor, significantly affects the kinetics of Lp(a) particles, leading to reductions in Lp(a) levels and alterations in their dynamics.	PCSK9 inhibition with evolocumab leads to a reduction in Lp(a) levels and modifies the kinetics of Lp(a) particles, suggesting its potential benefits in managing elevated Lp(a) levels.	The study provides evidence that PCSK9 inhibitors like evolocumab can effectively alter Lp(a) particle kinetics and reduce Lp(a) levels, which may have implications for the treatment of patients with high Lp(a) and associated cardiovascular risk.
Bittner et al. [34]	2020	Randomized Controlled Trial	1,223 participants with acute coronary syndrome	Alirocumab treatment resulted in a significant reduction in Lp(a) levels. This reduction was associated with a lower incidence of cardiovascular events in patients post-acute coronary syndrome.	Alirocumab effectively lowers Lp(a) levels and reduces cardiovascular risk following an acute coronary syndrome. This supports its potential benefit in secondary prevention strategies.	The findings highlight the role of PCSK9 inhibitors, like Alirocumab, in managing residual cardiovascular risk through significant reductions in Lp(a) levels after acute coronary events.
Boden et al. [35]	2011	Randomized Controlled Trial	3,414 with low HDL cholesterol and on statin therapy	Niacin therapy did not significantly reduce the incidence of major cardiovascular events compared to placebo in patients already receiving intensive statin therapy. Niacin did, however, increase HDL cholesterol levels and lower triglycerides	The addition of niacin to intensive statin therapy did not provide additional cardiovascular benefit in reducing major cardiovascular events beyond what was achieved with statin therapy alone.	The study suggests that, despite improvements in lipid profiles with niacin, it does not confer further cardiovascular risk reduction in patients who are already on intensive statin treatment. This highlights the need for a reassessment of the role of niacin in contemporary lipid management strategies.
Landray et al. [36]	2014	Randomized Controlled Trial	25,673 high-risk patients (patients with cardiovascular disease or at high risk for cardiovascular events)	Extended-release niacin with laropiprant did not significantly reduce the risk of major cardiovascular events compared to placebo. There was also an increase in adverse effects, such as infections and gastrointestinal issues, associated with niacin use.	The study found no benefit of adding extended-release niacin with laropiprant to statin therapy in reducing cardiovascular events among high-risk patients. The risk of adverse effects with niacin therapy may outweigh potential benefits.	The results suggest that adding extended-release niacin to statin therapy does not improve cardiovascular outcomes in high-risk patients and may lead to increased side effects. This challenges the routine use of niacin for additional cardiovascular risk reduction in these patients.
Sahebkar et al. [24]	2016	Systematic Review and Meta-Analysis	271	Coenzyme Q10 supplementation was found to significantly reduce plasma lipoprotein(a) levels, but it did not significantly affect other lipid indices such as LDL-C, HDL-C, or triglycerides.	The study concluded that coenzyme Q10 supplementation effectively lowers plasma lipoprotein(a) levels, but does not have a significant impact on other lipid parameters.	This suggests that coenzyme Q10 could be considered as a targeted intervention for lowering lipoprotein(a) levels, but its role in improving overall lipid profiles or cardiovascular outcomes remains uncertain. Further studies are needed to evaluate its clinical significance and potential benefits.
Jorat et al. [25]	2018 Systematic Review and Meta-Analysis	Systematic Review and Meta-Analysis	678	Coenzyme Q10 supplementation was associated with significant improvements in total cholesterol, LDL-C, and HDL-C levels among patients with coronary artery disease. However, no significant effect was observed on triglyceride levels.	The study concluded that coenzyme Q10 supplementation may be beneficial in improving certain lipid profiles in patients with coronary artery disease, particularly in reducing total cholesterol and LDL-C levels while increasing HDL-C levels.	Coenzyme Q10 could be a useful adjunctive treatment for managing lipid profiles in coronary artery disease patients. Nonetheless, the clinical significance of these improvements and their impact on cardiovascular outcomes need further investigation.
Roeseler et al. [42]	2016	Prospective Cohort Study	50 patients with lipoprotein(a)-associated cardiovascular disease who underwent lipoprotein apheresis.	Lipoprotein apheresis led to significant reductions in lipoprotein(a) levels, and over 5 years, patients demonstrated a stabilization of cardiovascular events and improved outcomes. Apolipoprotein(a) characterization revealed various isoforms and their impact on treatment efficacy.	The study concluded that lipoprotein apheresis is an effective treatment for managing lipoprotein(a)-associated cardiovascular disease, providing long-term benefits in reducing lipoprotein(a) levels and stabilizing cardiovascular outcomes.	Lipoprotein apheresis can be a valuable therapeutic option for patients with high lipoprotein(a) levels and associated cardiovascular risks, contributing to improved clinical outcomes over extended follow-up periods.
Safarova et al. [43]	2013	Prospective Cohort Study	24 patients with coronary atherosclerosis who underwent specific lipoprotein(a) apheresis.	The study found that specific lipoprotein(a) apheresis resulted in significant regression of coronary atherosclerosis as assessed by quantitative coronary angiography. There was a notable reduction in the severity of atherosclerotic plaques and improvement in coronary artery lumen diameter.	Specific lipoprotein(a) apheresis is effective in promoting regression of coronary atherosclerosis and improving coronary artery morphology, as evidenced by quantitative coronary angiography.	The results support the use of lipoprotein(a) apheresis as a therapeutic approach to reduce coronary atherosclerosis in patients with elevated lipoprotein(a) levels. This treatment may be beneficial in managing coronary artery disease and improving patient outcomes.
O’Donoghue et al. [37]	2022	Randomized Controlled Trial	284 patients with cardiovascular disease and elevated lipoprotein(a) levels.	The study demonstrated that small interfering RNA (siRNA) therapy effectively reduced lipoprotein(a) levels in patients. The treatment was associated with a significant decrease in lipoprotein(a) concentrations compared to the placebo group. However, the impact on cardiovascular outcomes was still under evaluation.	Small interfering RNA therapy shows promise in reducing lipoprotein(a) levels, which may have implications for cardiovascular risk management. Further research is needed to determine the long-term effects on cardiovascular outcomes.	siRNA therapy represents a novel approach to lowering lipoprotein(a) and may become a valuable tool in managing patients with elevated lipoprotein(a) levels and associated cardiovascular risk. The study supports the potential of targeting lipoprotein(a) through genetic therapies as part of cardiovascular disease treatment strategies.
Tsimikas et al. [38]	2020	Randomized Controlled Trial	286 patients with cardiovascular disease and elevated lipoprotein(a) levels.	The study evaluated the efficacy of a novel therapy for reducing lipoprotein(a) levels in individuals with cardiovascular disease. The therapy led to a significant reduction in lipoprotein(a) levels compared to the placebo. However, the impact on cardiovascular events was not the primary endpoint of the study.	Reduction in lipoprotein(a) levels was achieved with the therapy, indicating potential for this treatment to lower cardiovascular risk associated with elevated lipoprotein(a). Further studies are needed to confirm the long-term benefits and effects on cardiovascular outcomes.	The study suggests that targeting lipoprotein(a) can be a viable strategy for managing patients with cardiovascular disease. The significant reduction in lipoprotein(a) highlights the potential for this therapy in cardiovascular risk reduction, although additional research is required to fully understand its impact on cardiovascular events.
Ray et al. [39]	2020	Randomized Controlled Trial	3,600 patients with elevated LDL cholesterol and a history of cardiovascular disease or high cardiovascular risk.	Inclisiran, a small interfering RNA (siRNA) drug, significantly reduced LDL cholesterol levels compared to placebo. The drug demonstrated sustained efficacy in lowering LDL cholesterol over a period of 18 months.	Inclisiran was effective in reducing LDL cholesterol and was well-tolerated. The results support its use as an addition to current lipid-lowering therapies for patients with elevated LDL cholesterol.	Inclisiran offers a promising option for managing high LDL cholesterol, with potential benefits for reducing cardiovascular risk. The sustained reduction in LDL cholesterol highlights its efficacy as a treatment modality. Further studies may evaluate its long-term cardiovascular benefits and safety profile.