While statins have revolutionized the treatment of high LDL cholesterol, cutting heart attack and stroke risk by up to 50%, cardiovascular disease remains the leading cause of death worldwide, indicating a need to look beyond traditional targets. Researchers are now focusing on other lipids like lipoprotein(a), HDL cholesterol, triglycerides, and remnant cholesterol to further reduce cardiovascular risk.
Targeting Lipoprotein(a)
Lipoprotein(a), a form of LDL cholesterol with an additional protein, apolipoprotein(a), is genetically determined and largely unresponsive to statins, exercise, or diet. About one in five people have elevated levels, increasing their risk of cardiovascular disease. Scientists are developing therapies using genetic technology to silence the apolipoprotein(a) gene. Early studies have shown significant reductions in lipoprotein(a) levels, up to 92% in some cases. However, the critical question remains whether lowering lipoprotein(a) will translate into reduced cardiovascular events. The HORIZON study, involving over 8,300 participants with high lipoprotein(a) and a history of heart problems, is expected to provide results in 2025. Another trial, OCEAN(a)-Outcomes, is also underway, with completion expected by the end of 2026.
Rethinking HDL Cholesterol
For years, HDL cholesterol was considered beneficial, removing cholesterol from plaques and transporting it to the liver. However, attempts to raise HDL levels with medication have been disappointing. Research now suggests that simply increasing HDL quantity may not be enough; improving its functionality is key. CSL112, composed of the main protein component of HDL particles, aims to enhance cholesterol removal. A preliminary study showed CSL112 was safe and increased the blood's ability to absorb cholesterol. However, the AEGIS-II trial, involving over 18,200 people who had recently suffered a heart attack, did not meet its primary endpoint of reducing major cardiac events. Researchers are still analyzing the data for more insights.
The Triglyceride Conundrum
High triglyceride levels have been linked to increased cardiovascular risk, but studies aimed at lowering triglycerides have produced conflicting results. The REDUCE-IT trial, using a purified EPA derivative, showed a 25% reduction in major cardiovascular events. However, the STRENGTH trial, using EPA plus DHA, failed to demonstrate any benefit. Discrepancies may be due to the mineral oil placebo used in REDUCE-IT, which may have skewed the results. A more recent trial, PROMINENT, tested pemafibrate in over 10,000 participants with type 2 diabetes, high triglycerides, and low HDL. Despite a 26% reduction in triglyceride levels, there was no difference in cardiovascular event rates, suggesting that triglycerides may be indicators of poor cardiovascular health rather than direct causes.
Emerging Target: Remnant Cholesterol
Remnant cholesterol, encompassing cholesterol that isn't HDL or LDL, is now recognized as a potential risk factor. These fatty remnants, if not cleared efficiently, can accumulate in atherosclerotic plaques. High levels of remnant cholesterol have been linked to cardiovascular disease, independent of LDL cholesterol levels. Researchers are exploring treatments like olezarsen to promote the clearance of these particles, but further studies are needed to determine their impact on cardiovascular outcomes.
Ultimately, the evolving understanding of cholesterol emphasizes the importance of minimizing all non-HDL cholesterol through lifestyle modifications and, potentially, novel therapies. As Dr. Feingold stated, "If it's not HDL, we should minimize it. The lower, the better."
