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Published on: October 12, 2017
From Lipids to Inflammation: New Approaches to Reducing Atherosclerotic Risk
Michael D Shapiro1, Sergio Fazio2
1From the Knight Cardiovascular Institute, Center for Preventive Cardiology, Oregon Health & Science University, Portland, OR.
Insights
New lipid-lowering therapies offer hope for reducing atherosclerotic cardiovascular disease risk beyond statins. Research explores novel drugs targeting cholesterol, triglycerides, and inflammation to address residual risk and statin intolerance.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Atherosclerosis Research
Background:
- Statins revolutionized atherosclerotic cardiovascular disease (ASCVD) risk reduction, but residual risk and statin intolerance persist.
- Recent advancements have revitalized lipid-lowering therapeutics, offering new hope for managing hypercholesterolemia and ASCVD.
- The cholesterol hypothesis is re-energized by positive results from combination therapies like ezetimibe with statins.
Purpose of the Study:
- To review the current landscape and emerging therapies for lipid management in ASCVD.
- To highlight novel drug classes and pathways being investigated for cardiovascular risk reduction.
- To discuss the ongoing evaluation of triglyceride-lowering strategies and the inflammatory hypothesis of atherosclerosis.
Main Methods:
- Review of recent clinical trial outcomes and drug development in lipid-lowering and atherosclerosis.
- Analysis of novel therapeutic targets including proprotein convertase subtilisin kexin-9 (PCSK9) inhibitors, antisense therapies, and anti-inflammatory agents.
- Examination of evidence for triglyceride-lowering agents and their impact on cardiovascular events.
Main Results:
- PCSK9 inhibitors represent a new class of cholesterol-lowering drugs with demonstrated efficacy.
- Niacin and cholesteryl ester transfer protein inhibitors have shown limited cardiovascular benefits.
- Emerging therapies like antisense oligonucleotides targeting apolipoprotein C-III and apo(a) show promise.
- Ongoing trials are investigating omega-3 fatty acids for hypertriglyceridemia and anti-inflammatory approaches for atherosclerosis.
Conclusions:
- Despite statin advancements, significant unmet needs remain in ASCVD risk reduction.
- A new era of lipid-lowering therapies is emerging, offering diverse mechanisms to address residual risk.
- Future research will clarify the roles of novel lipid-modulating and anti-inflammatory agents in preventing cardiovascular events.
Abstract:
The introduction of statins ≈ 30 years ago ushered in the era of lipid lowering as the most effective way to reduce risk of atherosclerotic cardiovascular disease. Nonetheless, residual risk remains high, and statin intolerance is frequently encountered in clinical practice. After a long dry period, the field of therapeutics targeted to lipids and atherosclerosis has entered a renaissance. Moreover, the demonstration of clinical benefits from the addition of ezetimibe to statin therapy in subjects with acute coronary syndromes has renewed the enthusiasm for the cholesterol hypothesis and the hope that additional agents that lower low-density lipoprotein will decrease risk of atherosclerotic cardiovascular disease. Drugs in the orphan disease category are now available for patients with the most extreme hypercholesterolemia. Furthermore, discovery and rapid translation of a novel biological pathway has given rise to a new class of cholesterol-lowering drugs, the proprotein convertase subtilisin kexin-9 inhibitors. Trials of niacin added to statin have failed to demonstrate cardiac benefits, and 3 cholesterol ester transfer protein inhibitors have also failed to reduce atherosclerotic cardiovascular disease risk, despite producing substantial increases in HDL levels. Although the utility of triglyceride-lowering therapies remains uncertain, 2 large clinical trials are testing the influence of omega-3 polyunsaturated fatty acids on atherosclerotic events in hypertriglyceridemia. Novel antisense therapies targeting apolipoprotein C-III (for triglyceride reduction) and apo(a) (for lipoprotein(a) reduction) are showing a promising trajectory. Finally, 2 large clinical trials are formally putting the inflammatory hypothesis of atherosclerosis to the test and may open a new avenue for cardiovascular disease risk reduction.
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