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Open research questions in Lipoproteins and Cardiovascular Health

81 unresolved questions extracted from the limitations and future-work sections of 890 Lipoproteins and Cardiovascular Health papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Adequately powered trials with pre-specified NMR-based endpoints are warranted to confirm whether ABG may offer cardiometabolic benefits in specific high- risk subgroups.

    Effects of aged black garlic (ABG10+®) on lipoprotein subclass composition in Grade I hypertension: a randomized, triple-blind controlled trial with sex-stratified sequential allocation · 2026 · DOI

  • Most studies suggest that effectiveness may be limited to a specific population group, particularly older adults and individuals with hyperlipidemia (22). The importance of this study lies in the fact that it provides evidence on ABG in the lipid profile, for which there is currently limited information (only three clinical trials).

    Effects of aged black garlic (ABG10+®) on lipoprotein subclass composition in Grade I hypertension: a randomized, triple-blind controlled trial with sex-stratified sequential allocation · 2026 · DOI

  • Machine learning models identified multiple clinical and laboratory variables associated with prevalent MACE in patients with markedly elevated LDL-C, integrating traditional cardiovascular determinants with potentially underrecognized modifiers.

    Machine learning-based identification of cardiovascular risk modifiers in patients with very high LDL cholesterol: A cross-sectional study · 2026 · DOI

  • In addition to IL34, eleven variants showed strong associations with a CVE-free phenotype and warrant further investigation to elucidate their biological mechanisms and potential relevance for cardiovascular disease prevention.

    Cardiovascular Resilience in Familial Hypercholesterolemia: Genomic Signatures from a Founder Population Highlight IL34 as a Candidate Gene Associated with Event-Free Survival · 2026 · DOI

  • Background/Objectives: The apolipoprotein B to apolipoprotein A1 (ApoB/A1) ratio has been proposed as a marker of cardiovascular risk, but its value for assessing extracranial and intracranial atherosclerosis beyond conventional lipid markers remains uncertain.

    Apolipoprotein B/A1 Ratio Improves Discrimination of Severe Atherosclerosis Beyond Conventional Lipid Markers in High-Risk Statin-Naive Patients · 2026 · DOI

  • In Uzbekistan, genetic evidence for FH remains limited and largely based on candidate-variant studies, and the diag- nostic yield of NGS for monogenic FH in CAD patients is not well defined. In this Discussion, we compared our findings with two contemporaneous limited studies conducted in Latvia [18] and Saint Petersburg [19].

    Genetic yield of next-generation sequencing for detecting monogenic familial hypercholesterolemia in uzbek patients with coronary artery disease · 2026 · DOI

  • 3) COENZYME Q10 SUPPLEMENTATION Coenzyme Q10 has been implicated in the pathogenesis of statin-induced myopathy, clinical trials evaluating (CoQ10) supplementation have produced inconsistent results. 4) GAPS IN EVIDENCE There is still limited understanding of why only certain individuals develop statin-induced myopathy despite widespread use of these drugs.

    STATIN INDUCED MYOPATHY: MECHANISMS, CLINICAL CHALLENGES AND ROLE OF LIPOPROTEIN (A) IN CARDIOVASCULAR RISK · 2026 · DOI

  • To date, the significance of Lp(a) as a CVD-related biomarker is consistently growing, but there are inconsistent findings from indi- vidual clinical studies on circulating Lp(a) in patients with metabolic- related steatosis/steatohepatitis (MASLD or NAFLD or MAFLD) (25–28, 32–40, 68–70).

    Circulating lipoprotein(a) levels and steatotic liver disease related to metabolic dysfunction in adults: an updated systematic review and meta-analysis · 2026 · DOI

  • Introduction and Objective: Although hypercholesterolemia risks are established in T1D, sex differences in LMT effectiveness are under-explored and may explain some of the loss of female vascular protection in T1D.

    2197-P: The Impact of Lipid-Modifying Therapy (LMT) on 30-Year Non-HDL Cholesterol and Cardiovascular Disease (CVD) Is Similar by Sex in Type 1 Diabetes (T1D) · 2026 · DOI

  • The study used a cross-sectional design, which captures data at a single point in time. This limita- tion restricts the ability to draw causal inferences regarding the relationships between hypertension, dyslipidemia, and lifestyle factors. The study relied on self-reported questionnaires to collect infor- mation on lifestyle behaviors, including smoking, dietary habits, and physical activity. This method is subject to biases, such as recall and social desir- ability biases, potentially leading to inaccuracies in the reported data. Although the study includ- ed a relatively large sample of 448 participants, the specific population may not fully represent broader demographics. Factors such as ethnici- ty, socioeconomic status, and geographic location may limit the generalizability of the findings to other populations. While efforts were made to analyze various health behaviors and metabolic parameters, the study may not have adequately controlled for all potential confounding factors (e.g., genetic predispositions, medication adher- ence, comorbid conditions). This limitation could affect the strength and interpretation of the ob- served associations. These limitations should be considered when interpreting the findings, as they can influence the applicability and reliability of the results. Future research addressing these lim- itations can help clarify the interrelations between hypertension, cholesterol status, and cardiovascu- lar risk awareness.

    Prevalence of dyslipidemia, arterial hypertension, and other risk factors in patients after cardiovascular events — a retrospective study in a Polish population · 2026 · DOI

  • This meta-analysis has several strengths. First, it systematically synthesizes evidence from RCTs, which represent the highest level of clinical evidence and minimize the risk of bias. The inclusion of both general hypercholesterolemic populations and a genetically high-risk subgroup—HeFH—allowed for a more nuanced evaluation of inclisiran’s efficacy. The consistently significant reduction in both LDL-C and PCSK9 levels across studies highlights the biological plausibility and therapeutic potential of inclisiran, even in the presence of clinical heterogeneity. Moreover, sensitivity and subgroup analyses were conducted to assess the robustness of the results and identify potential effect modifiers of the treatment, thereby strengthening the credibility of the findings. Nevertheless, several limitations should be acknowledged in interpreting our results. The number of included studies, particularly those evaluating PCSK9 outcomes, was limited, reducing the statistical power to draw definitive conclusions regarding this biomarker. Additionally, most trials used a fixed dose of inclisiran (300 mg), preventing assessment of dose-response effects or optimization of alternative dosing strategies. The inclusion of studies with small sample sizes and outlier values—such as extreme SDs—may have inflated between-study heterogeneity (I²=100%). Furthermore, the follow-up periods in most trials were relatively short, limiting our ability to assess long-term cardiovascular outcomes, safety profiles, and patient adherence. A substantial proportion of records identified in the initial search (200 out of 268, approximately 75%) could not be Int J Cardiovasc Acad 2026;12(1):1-13 Nusantara et al. Inclisiran and LDL-C Reduction: A Meta-Analysis retrieved due to restricted access, institutional limitations, or lack of full-text availability. This introduces a potential non-retrieval (accessibility) bias, which may influence the completeness of the evidence base and the assessment of publication bias. Nevertheless, all available full-text RCTs evaluating inclisiran were retrieved, and the final 11 RCTs likely represent the complete set of eligible evidence currently available in English. The meta-regression results revealed that heterogeneity remained very high (I²>99%) even after adjusting for sample size and follow-up duration, suggesting that important moderators may be unmeasured or unreported. This limits our ability to fully account for between-study variability. At least one included study was judged to have a high risk of bias, which may influence the certainty of the pooled estimates.

    Assessing the Impact of Inclisiran on LDL-C and PCSK9 Reduction in Hypercholesterolemic Patients: A Meta-analysis of Cardiovascular Metabolic Prevention · 2026 · DOI

  • The optimal level of PCSK9 activity for long-term cardiac health remains unclear. Maintaining physiologically low—but not absent—PCSK9 activity may be optimal, but this paradigm has important implications for next-generation therapies, particularly permanent gene-editing strategies aimed at complete PCSK9 ablation that require further study.

    LDL receptor-independent mechanisms of proprotein convertase subtilisin/kexin type 9 in cardiovascular pathophysiology · 2026 · DOI

  • Comparative studies assessing how novel therapeutic platforms (oral small-molecule inhibitors, vaccines, and gene-editing technologies) differentially modulate LDLR-dependent and LDLR-independent pathways will be essential for defining their optimal clinical roles.

    LDL receptor-independent mechanisms of proprotein convertase subtilisin/kexin type 9 in cardiovascular pathophysiology · 2026 · DOI

  • Expanding indications beyond atherosclerosis represents a promising direction. The involvement of PCSK9 in thrombosis, myocardial injury, and CAVD suggests therapeutic potential in acute coronary syndromes, heart failure remodeling, and valvular heart disease—areas where effective disease-modifying pharmacotherapies remain limited.

    LDL receptor-independent mechanisms of proprotein convertase subtilisin/kexin type 9 in cardiovascular pathophysiology · 2026 · DOI

  • Long-term safety of profound PCSK9 suppression requires careful evaluation. Preclinical data indicating metabolic and myocardial consequences of complete PCSK9 deficiency raises important considerations for permanent gene-editing approaches, with insufficient data distinguishing between partial, reversible inhibition and lifelong ablation.

    LDL receptor-independent mechanisms of proprotein convertase subtilisin/kexin type 9 in cardiovascular pathophysiology · 2026 · DOI

  • Patient stratification based on non-lipid risk profiles warrants further investigation. Clinical and imaging data suggest that individuals with elevated inflammatory burden, enhanced platelet reactivity, high Lp(a), or early valvular calcification may derive disproportionate benefit from PCSK9-ITs beyond LDL-C reduction, but biomarker-guided strategies need development.

    LDL receptor-independent mechanisms of proprotein convertase subtilisin/kexin type 9 in cardiovascular pathophysiology · 2026 · DOI

  • Dissecting pathway-specific inhibition remains a priority. Current monoclonal antibodies primarily block the interaction between PCSK9 and LDLR, while leaving the CHRD intact, leaving key inflammatory and immune effects through receptors such as CAP1, CD36, and MHC-I unaddressed.

    LDL receptor-independent mechanisms of proprotein convertase subtilisin/kexin type 9 in cardiovascular pathophysiology · 2026 · DOI

  • A limitation of this study is the potentially insufficient statistical power in certain subgroups, which may explain nonsignificant findings. The study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Non-invasive Clinical Research Ethics Committee of Eskişehir Osmangazi University (protocol code 16 and date of approval Unmeasured potential confounders, such as March 19, 2024). detailed dietary intake, may have influenced LDL-C target attainment.

    Challenges in achieving low-density lipoprotein targets: a cross-sectional study in statin users · 2026 · DOI

  • particularly in those individuals at the greatest risk of first and recurrent events. It is important that both patients and prescribers are reassured about the safety of achieving very low levels of LDL-C as demonstrated repeatedly in clinical trials and registries [43–45, 69–72]. The main pathway for optimal LLT post ACS can be divided into three sections (Figs. 2, 3, 4, 5): • Diagnosis and stratification • Target-driven LLT • Support and follow-up The recommendations for optimal LLT in ASCVD patients, including very high-risk/extremely high-risk individuals such as those with ACS, are presented below, as a main treatment pathway, with additional pathways for some specific clinical practice scenarios. The pathways are based upon the principles of LDL-C reduction: the earlier the better, the lower the better, the longer the better [77, 78]. The pathways are also firmly based on the EAS/ESC guidelines for the management of dyslipidaemias, albeit with a greater emphasis on reducing delays in starting lipid-lowering, In the diagnosis and stratification stage, some patient groups are identified for special pathways. These include patients with FH or extremely high ASCVD risk (Sect. 6.2.1; Fig. 3), statin intolerance (Sect. 6.2.2; Fig. 4), and ASCVD with metabolic disorders (pre-diabetes/metabolic syndrome/diabetes) (Sect. 6.2.3; Fig. 5). In the previous version of the recommendations (April 2021), as we then were introducing the upfront lipid-lowering combination therapy for the first time, we put a lot of attention into the baseline level of LDL-C in very high-risk Optimal Lipid-Lowering Management in ACS Patients 1566 M. Banach et al. Fig. 2 Overall pathway of optimal LLT in ASCVD patients. The pathway is divided into three stages: (1) diagnosis and stratification; (2) target-driven lipid-lowering therapy; (3) support and follow-up. Special pathways are provided for specific treatment groups, including those with extreme CV risk (as defined in this document), familial hypercholesterolaemia, statin intolerance, and diabetes/metabolic disorders. At each step of LLT, adherence should be carefully monitored. ACS acute coronary syndrome, ASCVD atherosclerotic cardiovascular disease, CV cardiovascular, FDC fixed dose combination, HeFH heterozygous familial hypercholesterolaemia, HIS high intensity statin, LDL-C low-density lipoprotein cholesterol, LLT lipid-lowering therapy, PCSK9I proprotein convertase subtilisin/kexin type 9 inhibitor patients.

    2024 Recommendations on the Optimal Use of Lipid-Lowering Therapy in Established Atherosclerotic Cardiovascular Disease and Following Acute Coronary Syndromes: A Position Paper of the International Lipid Expert Panel (ILEP) · 2024 · DOI

  • Abstract Background : Although vast clinical evidence supports the oxidative CVD hypothesis, little is known on the effects of statins on LDL/HDL oxidative functionality.

    Antioxidative Effects of Rosuvastatin in Low-to-Moderate Cardiovascular Risk Subjects · 2022 · DOI

  • CONCLUSION: The current Austrian routine lipid management using mainly moderate-intensity or high-intensity statin monotherapy is insufficient to attain ESC/EAS guideline goals, in particular the more stringent 2019 recommendations, a situation comparable to other participating European countries.

    Lipid lowering therapy in primary and secondary prevention in Austria: are LDL-C goals achieved? · 2021 · DOI

  • The exact cause of statin-induced NODM is not clearly known and several pathophysiologic mechanisms have been proposed, which include modification of the lipoprotein particle size, inhibition of HMG-CoA reductase, decreased expression of GLUT 4, and decreased adiponectin and ubiquinone levels, including others, which all lead to either increase in insulin resistance or decrease in insulin secretion.

    New onset diabetes mellitus induced by statins: current evidence · 2017 · DOI

  • The efficacy of aggressive lipid-lowering regimens on atherosclerosis regression (versus progression stabilization) in familial hypercholesterolaemia has not been conclusively established. Randomized controlled trials comparing conventional versus novel combination therapies with serial coronary plaque burden imaging in FH patients are needed.

    Current Treatment of Familial Hypercholesterolaemia · 2014 · DOI

  • The relationship between specific LDL-receptor gene sequence variants and cardiovascular risk stratification in FH patients requires further investigation beyond the 64 specific variants examined in prior studies. Genotype-phenotype correlation studies in larger, ethnically diverse FH cohorts are needed to personalize risk prediction and treatment intensity.

    Current Treatment of Familial Hypercholesterolaemia · 2014 · DOI

  • Despite the availability of novel potent LDL-C reducing agents such as lomitapide and mipomersen, the paper identifies that a significant proportion of diagnosed FH patients fail to reach treatment goals and remain undertreated. Comparative effectiveness studies examining adherence barriers and optimal sequencing of statins, ezetimibe, and newer agents in heterozygous versus homozygous FH populations are lacking.

    Current Treatment of Familial Hypercholesterolaemia · 2014 · DOI

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