Introduction
Atherosclerotic cardiovascular disease (ASCVD) remains a significant global health challenge, necessitating effective lipid-lowering therapies beyond traditional statins. This article discusses emerging therapies aimed at reducing cardiovascular risk through lipid modulation.
Emerging Lipid-Lowering Therapies
Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors (PCSK9i): These agents enhance the clearance of low-density lipoprotein cholesterol (LDL-C) by up-regulating hepatic LDL receptors. They have shown efficacy in patients with familial hypercholesterolemia and those not achieving LDL-C goals with statins alone 1.
Inclisiran: A small interfering RNA molecule that inhibits PCSK9, requiring only biannual dosing. This therapy has the potential to improve adherence to lipid-lowering regimens 2.
Bempedoic Acid: This agent lowers LDL-C upstream from statins and serves as an alternative for patients with statin intolerance. It has demonstrated significant LDL-C reduction without the adverse effects associated with some other therapies 2.
Angiopoietin-like Protein 3 (ANGPTL3) Inhibitors: These inhibitors have shown promise in effectively lowering LDL-C and triglyceride levels, particularly in patients with refractory hypercholesterolemia, independent of LDL receptor activity 1.
Combination Therapies: The use of fixed-dose combinations (FDC) of high-intensity statins with ezetimibe has been associated with greater LDL-C reductions compared to statin monotherapy. Studies indicate that this approach significantly increases the proportion of patients achieving LDL-C targets 3.
Clinical Implications
The integration of these novel therapies into clinical practice is essential for addressing the residual cardiovascular risk that persists despite statin therapy. Current evidence suggests that a multi-faceted approach, including personalized medicine strategies, is necessary to optimize lipid management and improve patient outcomes 14.
Conclusion
Emerging lipid-lowering therapies present new opportunities for reducing cardiovascular risk in patients inadequately managed by statins. Continued research and clinical application of these therapies are vital for enhancing cardiovascular health and addressing the unmet needs in lipid management.
References
Editorial: New and emerging lipid-lowering therapies for reducing cardiovascular risk: beyond statins.
Commentary: Beyond 10-year risk: A cost-effectiveness analysis of statins for the primary prevention of cardiovascular disease.
2022: the year in cardiovascular disease – the year of upfront lipid lowering combination therapy.
Association Between Intensity of Low-Density Lipoprotein Cholesterol Reduction With Statin-Based Therapies and Secondary Stroke Prevention: A Meta-analysis of Randomized Clinical Trials.
New and Emerging Therapies for Reduction of LDL-Cholesterol and Apolipoprotein B: JACC Focus Seminar 1/4.
What are the latest advancements in lipid-lowering therapies beyond statins?
Latest Advancements in Lipid-Lowering Therapies
Emerging Therapies: New lipid-lowering therapies are being developed to address the limitations of current treatments, particularly for patients with residual cardiovascular risk despite statin therapy. These include monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) and antisense oligonucleotides targeting apolipoprotein B and apolipoprotein CIII, which are in various stages of clinical trials [4][5].
Bempedoic Acid: This small molecule ATP citrate lyase inhibitor has been shown to reduce low-density lipoprotein cholesterol (LDL-C) by an additional 20% beyond the reduction achieved by statins [4].
Combination Therapies: Fixed combinations of established drugs, such as statins with ezetimibe, are being utilized to improve adherence and enhance lipid-modifying effects [4].
Novel Targets: Research is focusing on new therapeutic targets, including angiopoietin-like protein 3 (ANGPTL3) and lipoprotein(a), which have shown promise in reducing LDL-C and triglyceride levels independently of LDL receptors [5].
Gene Silencing Approaches: RNA silencing techniques, such as inclisiran (siRNA against PCSK9), are being explored for their potential to lower lipid levels effectively [4].
Antisense Oligonucleotides: These therapies, such as mipomersen, target specific proteins involved in lipid metabolism, offering new avenues for treatment in patients with familial hypercholesterolemia [1].
Conclusion
The landscape of lipid-lowering therapies is evolving with innovative treatments that extend beyond traditional statin therapy, aiming to reduce cardiovascular risk more effectively.
This response is for informational purposes and should not replace personalized medical advice from a licensed professional.
How do the new therapies compare in efficacy to traditional statins?
Current and Emerging Uses of Statins in Clinical Therapeutics: A Review. Statins, a class of cholesterol-lowering medications that inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, are commonly administered to treat atherosclerotic cardiovascular disease. Statin use may expand considerably given its potential for treating an array of cholesterol-independent diseases. However, the lack of conclusive evidence supporting these emerging therapeutic uses of statins brings to the fore a number of unanswered questions including uncertainties regarding patient-to-patient variability in response to statins, the most appropriate statin to be used for the desired effect, and the efficacy of statins in treating cholesterol-independent diseases. In this review, the adverse effects, costs, and drug-drug and drug-food interactions associated with statin use are presented.
Furthermore, we discuss the pleiotropic effects associated with statins with regard to the onset and progression of autoimmune and inflammatory diseases, cancer, neurodegenerative disorders, strokes, bacterial infections, and human immunodeficiency virus. Understanding these issues will improve the prognosis of patients who are administered statins and potentially expand our ability to treat a wide variety of diseases. Use of statins for reducing the risk of ASCVD: Recently, the ACC and AHA approved the revision of existing guidelines designed to reduce the risk of ASCVD that were based on evidence generated from a series of randomized controlled trials. While previous recommendations focused on specific target levels of LDL-C, the new recommendations defined patient groups who would most likely benefit from moderate- or high-intensity statin therapy. These groups have been identified as follows: clinical ASCVD, ie, acute coronary syndromes, or a history of myocardial infarction, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease of atherosclerotic origin; primary elevations of LDL-C ≥190 mg/dL; age 40–75 years with diabetes and LDL-C 70–189 mg/dL; age 40–75 years with LDL-C 70–189 mg/dL and estimated 10-year ASCVD risk ≥7.5%.
As these guidelines are clinically implemented, it is predicted that 12.8 million additional individuals will now qualify for statin therapy. As statin use continues to increase, a concern is raised that patients, as well as physicians, may become over-reliant on pharmacological methods of controlling high cholesterol levels and disregard approaches such as lifestyle changes that are beneficial for not only improving cardiovascular health but also overall well-being. Lifestyle changes such as the elimination of tobacco products, dietary modifications, weight management, exercise, and yoga have been shown to be effective in reducing the risk of CVD. Thus, it is recommended that patients who qualify for statin therapy would benefit the most from intervention strategies that would include statin therapy coupled with a healthy lifestyle. Type 2 diabetes: The question of whether statin use significantly raises blood glucose levels and contributes to the development of T2DM is complicated by the fact that high LDL-C, ASCVD, and T2DM share common risk factors. Other contributing risk factors are socioeconomic and include race/ethnicity, culture, and geographical location. Thus, the likely use of statins by patients with T2DM may be deleterious with respect to their T2DM-related conditions. The diabetogenic effects of statins are thought to arise from several mechanisms that converge on glucose regulation and pancreatic beta cells. A thorough review of the literature reveals the following three key themes that are important for understanding the relationship that may exist between statin therapy and T2DM. Because of the mechanisms discussed earlier, statins may raise blood sugar levels. Numerous population-based studies have consistently reported that compared to patients in the placebo group, a greater number of patients receiving statin therapy were subsequently diagnosed with T2DM. However, it has become widely accepted that this relationship is dependent on statin type and dose. It is thought that “statin therapy is associated with a slightly increased risk of developing diabetes.” However, the risk is low, and when compared to the reduction in coronary events, the benefits of statin therapy outweigh the risk of developing diabetes. Statins may have a diabetogenic potential through the various mechanisms discussed earlier.
While new-onset T2DM is observed with all statins, and associations coupled from those observations, a causal relationship cannot be implicated as numerous patients of the control group (receiving a placebo) also in fact developed T2DM. However, it is evident that further research should be conducted in specific patient populations, with tightly controlled variables. Retrospective data can be skewed by recall bias; therefore, prospective data should be obtained through closely monitored randomized control trials in order to compare specific AEs (such as SAMS) that may result from the use of various statins in defined patient populations.
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