APOC3 and LDL-C Lowering: A Promising Strategy for Heart Disease Prevention, Study Finds

The findings, published in JAMA Cardiology, indicate that lower APOC3 levels are associated with a CHD risk reduction comparable to that observed with lower proprotein convertase subtilisin/kexin type 9 (PCSK9) per unit decrease in apolipoprotein B (ApoB). The study further highlights the potential of combining APOC3-lowering and low-density lipoprotein cholesterol (LDL-C)–-lowering genetic variants for an additive protective effect against CHD.

APOC3, a key regulator of triglyceride metabolism, has been increasingly recognized for its role in cardiovascular health. The researchers note that lower APOC3 levels have been linked to decreased plasma triglycerides and improved lipid profiles, contributing to a lower likelihood of CHD development. Similarly, LDL-C-lowering genetic variants, such as those influencing PCSK9 and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), have long been associated with cardiovascular protection.

Against the above background, Wenxiu Wang, Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China, and colleagues aimed to investigate if having genetically lower levels of APOC3 can reduce the risk of heart disease. It also explored whether a combination of lower APOC3 and LDL-C–lowering genetic variants provides additional protection against coronary heart disease.

For this purpose, the researchers conducted a population-based genetic association study using a 2×2 factorial Mendelian randomization approach. They analyzed data from the UK Biobank, including participants of European ancestry, between November 2023 and July 2024. Genetic scores were developed to simulate the effects of APOC3, HMGCR, and PCSK9 inhibitors.

The study assessed plasma lipid and lipoprotein levels, CHD, and type 2 diabetes (T2D) to determine whether genetically lower APOC3 levels reduce cardiovascular risk and whether the combined effect of APOC3 and LDL-C–lowering variants further decreases CHD risk.

The following were the key findings of the study:

• The study included 401,548 UK Biobank participants with a mean age of 56.9 years, of whom 54% were female.
• Genetically lower APOC3 was linked to a reduced risk of CHD (OR: 0.96) and T2D (OR: 0.97).
• Lower APOC3 and PCSK9 levels were associated with a similar reduction in CHD risk per 10 mg/dL decrease in ApoB (APOC3: OR 0.70; PCSK9: OR 0.71).
• Combining genetically lower APOC3 and PCSK9 showed an additive reduction in CHD risk (APOC3: OR 0.96; PCSK9: OR 0.93; combined: OR 0.90).
• Genetically lower HMGCR was also linked to a lower CHD risk, with an even greater reduction when combined with APOC3 (OR: 0.93).

The study suggests combining APOC3 inhibitors with LDL-C–lowering drugs may provide greater cardiovascular benefits than using either alone. Genetically lower APOC3 levels were linked to a CHD risk reduction similar to that seen with a lower PCSK9 per unit decrease in ApoB, and their combined effect further lowered CHD risk.

"These findings highlight the need for future research to evaluate APOC3-targeted therapies, particularly for high-risk individuals who do not achieve treatment goals with existing lipid-lowering options," the authors concluded.

Reference:

Wang W, Li R, Song Z, et al. Joint Associations of APOC3 and LDL-C–Lowering Variants With the Risk of Coronary Heart Disease. JAMA Cardiol. Published online March 19, 2025. doi:10.1001/jamacardio.2025.0195