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Lipid Metabolism and Emerging Targets for Lipid-Lowering Therapy
Daniel Gaudet1, Jean-Philippe Drouin-Chartier2, Patrick Couture3
1Clinical Lipidology and Rare Lipid Disorders Unit, Department of Medicine, Université de Montréal Community Gene Medicine Center, Chicoutimi, Québec, Canada.
Insights
Novel therapies for dyslipidemia aim to reduce cardiovascular disease risk beyond statins. Future challenges include accessibility and cost, impacting the era of precision medicine.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Biochemistry
Background:
- Cardiovascular disease (CVD) is a leading cause of death globally.
- Dyslipidemia is a major risk factor for CVD and atherosclerosis.
- Current lipid-lowering drugs like statins and ezetimibe do not fully protect all patients.
Purpose of the Study:
- To review novel therapeutic strategies for managing dyslipidemia and associated cardiovascular risks.
- To discuss emerging treatments targeting atherogenic lipoproteins and high-density lipoprotein (HDL) metabolism.
- To highlight potential challenges, such as cost and accessibility, for next-generation lipid-lowering agents.
Main Methods:
- Review of ongoing clinical trials and emerging therapies for lipid-related disorders.
- Analysis of novel drug targets including PCSK9 inhibitors, Apo(a) inhibitors, MTP inhibitors, and gene therapies.
- Examination of therapies targeting HDL and reverse cholesterol transport.
Main Results:
- Several novel therapies are in clinical development to reduce atherogenic lipoproteins and manage triglyceride-rich lipoproteins.
- Emerging treatments also focus on enhancing high-density lipoprotein (HDL) function and reverse cholesterol transport.
- Current clinical trials are evaluating the efficacy and safety of these advanced lipid-modulating agents.
Conclusions:
- Novel therapies offer promising avenues for CVD prevention by addressing unmet needs in dyslipidemia management.
- The cost and reimbursement of these advanced treatments may significantly limit their accessibility.
- Accessibility, rather than efficacy, is likely to be the primary challenge for next-generation lipid-lowering agents in precision medicine.
Abstract:
Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality worldwide, and dyslipidemia constitutes a major risk factor for CVD and premature atherosclerosis. Therapies to reduce the plasma levels of atherogenic lipoproteins are well established interventions that decrease CVD risk. However, treatment of dyslipidemia with the most widely used lipid-lowering drugs (ie, statins and ezetimibe) often fails to protect a significant proportion of patients from cardiovascular risk. The development of several novel therapies to treat lipid-related disorders and their associated risks is ongoing and includes the following: (1) reducing plasma levels of atherogenic lipoproteins using proprotein convertase subtilisin/kexin type 9 inhibitors, antisense inhibitors of Apolipoprotein (Apo)(a), microsomal triglyceride transfer protein inhibitors, antisense oligonucleotides of ApoB for inhibiting very low-density lipoprotein production, and inhibitors of angiopoietin-like protein 3 or ApoC-III for triglyceride-rich lipoprotein management upstream of low-density lipoprotein production as well as gene replacement therapy to improve low-density lipoprotein and triglyceride-rich lipoprotein clearance; and (2) emerging therapies that target high-density lipoprotein (HDL) and reverse cholesterol transport using cholesteryl ester transfer protein inhibitors, HDL peptide mimetics, and autologous infusion of pre-β HDLs. Clinical trials of several of these emerging therapies are currently being conducted. Despite the potential efficacy of these new therapies in CVD prevention, their costs might limit their use because of limited reimbursement funds. Therefore, the real challenge facing the next generation of lipid-lowering agents will most likely be accessibility, reflecting a new paradigm that applies to almost all emerging therapies for any disease in the era of precision medicine.