Newer and Emerging LDL-C Lowering Agents and Implications for ASCVD Residual Risk

Rikhi, Rishi; Shapiro, Michael D.

doi:10.3390/jcm11154611

Cited by 6 publications

(10 citation statements)

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“…It is significant that many people using statin therapy still have a residual risk of developing ASCVD and cannot meet their target LDL-C targets [ 4 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. This residual risk, which may amount to 50% after optimal statin treatment, is the consequence of both immunological and lipid disturbances [ 18 , 19 , 20 , 21 , 22 , 23 ]. Regarding the lipid disorders, the role of triglyceride-rich lipoproteins (TRLs) and their remnants has come to the forefront in the past decade [ 24 , 25 , 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Triglyceride-Rich Lipoprotein Metabolism: Key Regulators of Their Flux

Gugliucci

2023

JCM

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The residual risk for arteriosclerotic cardiovascular disease after optimal statin treatment may amount to 50% and is the consequence of both immunological and lipid disturbances. Regarding the lipid disturbances, the role of triglyceride-rich lipoproteins (TRLs) and their remnants has come to the forefront in the past decade. Triglycerides (TGs) stand as markers of the remnants of the catabolism of TRLs that tend to contain twice as much cholesterol as compared to LDL. The accumulation of circulating TRLs and their partially lipolyzed derivatives, known as “remnants”, is caused mainly by ineffective triglyceride catabolism. These cholesterol-enriched remnant particles are hypothesized to contribute to atherogenesis. The aim of the present narrative review is to briefly summarize the main pathways of TRL metabolism, bringing to the forefront the newly discovered role of apolipoproteins, the key physiological function of lipoprotein lipase and its main regulators, the importance of the fluxes of these particles in the post-prandial period, their catabolic rates and the role of apo CIII and angiopoietin-like proteins in the partition of TRLs during the fast-fed cycle. Finally, we provide a succinct summary of the new and old therapeutic armamentarium and the outcomes of key current trials with a final outlook on the different methodological approaches to measuring TRL remnants, still in search of the gold standard.

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Section: Introductionmentioning

confidence: 99%

Triglyceride-Rich Lipoprotein Metabolism: Key Regulators of Their Flux

Gugliucci

2023

JCM

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“…For the past 30 years, statin therapy has been the cornerstone for the reduction in the risk of atherosclerotic cardiovascular disease (ASCVD). Low-density lipoprotein cholesterol (LDL-C) and ASCVD have been definitively linked in numerous investigations carried out throughout this time [ 1 , 2 ]. As a result of this relationship, drugs that lessen overall lifetime exposure to LDL-C have been successful in lowering the risk of ASCVD [ 1 , 2 ].…”

mentioning

confidence: 99%

“…Low-density lipoprotein cholesterol (LDL-C) and ASCVD have been definitively linked in numerous investigations carried out throughout this time [ 1 , 2 ]. As a result of this relationship, drugs that lessen overall lifetime exposure to LDL-C have been successful in lowering the risk of ASCVD [ 1 , 2 ]. For the secondary prevention of cardiovascular disease (CVD), the European Society of Cardiology (ESC) reduced the target value for low-density lipoprotein cholesterol (LDL-C) from 1.8 mmol/L to 1.4 mmol/L in 2019.…”

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confidence: 99%

“…This is due to the important role ANGPTL3 plays in this process as supported by animal and human loss of function studies. Indeed, the ANGPTL3 monoclonal antibody evinacumab not only reduces TG but also LDL-C, probably because ANGPTL3 inhibits endothelial lipase levels [ 1 , 2 , 4 ]. The results from clinical trials demonstrated the efficacy and safety of evinacumab as an additional treatment for HoFH.…”

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confidence: 99%

“…Evinacumab, on the other hand, decreases LDL-C levels without relying on LDLR activity. Therefore, it can be regarded as a key weapon in the arsenal of HoFH patients who failed to meet their minimal guideline-recommended LDL-C goals despite receiving several classes of lipid-lowering therapies and LDL apheresis, or it can be used as a substitute for patients who cannot receive apheresis or lomitapide [ 2 , 4 ]. The catabolic residues of TRL (remnants) are important pathogenic factors that explain the residual risk of ASCVD after optimal LDL-C levels have been obtained.…”

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confidence: 99%

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Beyond LDL: Understanding Triglyceride-Rich Lipoproteins to Tackle Residual Risk

Gugliucci

2023

JCM

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Effect of phosphodiesterase type 5 inhibitors on major adverse cardiovascular events and overall mortality in a large nationwide cohort of men with erectile dysfunction and cardiovascular risk factors: A retrospective, observational study based on healthcare claims and national death index data

Kloner

Stanek

Crowe

et al. 2023

The Journal of Sexual Medicine

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Background Treatment with phosphodiesterase type 5 inhibitors (PDE-5is) is effective in treating erectile dysfunction (ED). Aim The objective of this study was to determine the effect of PDE-5is on the incidence of major adverse cardiovascular (CV) events (MACE; composite outcome of CV death, hospitalization for myocardial infarction, coronary revascularization, stroke, heart failure, and unstable angina pectoris) and overall mortality. Methods A retrospective observational cohort study was conducted in a large US claims database in men with ≥1 diagnosis of ED without prior MACE within 1 year, from January 1, 2006, to October 31, 2020. The exposed group had ≥1 claim for PDE-5i and the unexposed group had no claims for PDE-5i, and the groups were matched up to 1:4 on baseline risk variables. Outcome The primary outcome was MACE and the secondary outcomes were overall mortality and individual components of MACE, determined by multivariable Cox proportional hazard modeling. Results Matched plus multivariable analyses showed that MACE was lower by 13% in men exposed (n = 23 816) to PDE-5is (hazard ratio [HR] 0.87; 95% CI 0.79-0.95; P = .001) vs nonexposure (n = 48 682) over mean follow-up periods of 37 and 29 months, respectively, with lower incidence of coronary revascularization (HR 0.85; 95% CI 0.73-0.98; P = .029), heart failure (HR 0.83; 95% CI 0.72-0.97; P = .016), unstable angina (HR 0.78; 95% CI 0.64-0.96; P = .021), and CV death (HR 0.61; 95% CI 0.41-0.90; P = .014) with PDE-5i exposure. Phosphodiesterase type 5 inhibitor–exposed men had a 25% lower incidence of overall mortality (HR 0.75; 95% CI 0.65-0.87; P < .001). Men without coronary artery disease (CAD) but with CV risk factors at baseline showed a similar pattern. In the main study cohort, men in the highest quartile of PDE-5i exposure had the lowest incidence of MACE (HR 0.45; 95% CI 0.37-0.54; P < .001) and overall mortality (HR 0.51; 95% CI 0.37-0.71; P < .001) vs the lowest exposure quartile. In a subgroup with baseline type 2 diabetes (n = 6503), PDE-5i exposure was associated with a lower MACE risk (HR 0.79; 95% CI 0.64-0.97; P = .022). Clinical Implications PDE-5is may have cardioprotective effects. Strengths and Limitations Strengths are the large numbers of participants and consistency of the data; limitations include the retrospective nature of the study and unknown confounders. Conclusions In a large population of US men with ED, PDE-5i exposure was associated with lower incidence of MACE, CV death, and overall mortality risk compared to non-exposure. Risk reduction correlated with PDE-5i exposure level.

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Newer and Emerging LDL-C Lowering Agents and Implications for ASCVD Residual Risk

Cited by 6 publications

References 57 publications

Triglyceride-Rich Lipoprotein Metabolism: Key Regulators of Their Flux

Triglyceride-Rich Lipoprotein Metabolism: Key Regulators of Their Flux

Beyond LDL: Understanding Triglyceride-Rich Lipoproteins to Tackle Residual Risk

Effect of phosphodiesterase type 5 inhibitors on major adverse cardiovascular events and overall mortality in a large nationwide cohort of men with erectile dysfunction and cardiovascular risk factors: A retrospective, observational study based on healthcare claims and national death index data

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