Hypertriglyceridemia is increasingly recognized as both a marker and mediator of residual cardiovascular risk, even in patients optimally treated with statins. The 2025 European Society of Cardiology (ESC) guidance emphasizes risk stratification and targeted therapy, particularly in high-risk and very high-risk patients.
Definition and Risk Stratification
Triglyceride (TG) levels are assessed in the fasting state.
• Mild to moderate hypertriglyceridemia: 135–499 mg/dL
• Severe hypertriglyceridemia: >750 mg/dL
Patients categorized as high-risk or very high-risk include those with established atherosclerotic cardiovascular disease (ASCVD), diabetes with target-organ damage, chronic kidney disease, or markedly elevated global CV risk.
Management of Fasting TG 135–499 mg/dL in High-Risk or Very High-Risk Patients
Statins as Foundation Therapy
Statins remain first-line therapy in patients with elevated triglycerides and high cardiovascular risk. Although primarily LDL-C–lowering agents, statins reduce triglycerides by 10–30% and significantly lower ASCVD events. ESC 2025 strongly recommends optimizing statin intensity before adding TG-specific agents.
Icosapent Ethyl for Residual Risk Reduction
For patients with fasting TG 135–499 mg/dL despite statin therapy, ESC 2025 recommends icosapent ethyl at a dose of 2 g twice daily.
Icosapent ethyl is a highly purified eicosapentaenoic acid (EPA) formulation. Its cardiovascular benefit extends beyond triglyceride lowering and includes anti-inflammatory, plaque-stabilizing, and antithrombotic effects. This recommendation is supported by robust outcome data demonstrating significant reduction in major adverse cardiovascular events in high-risk patients with elevated TG levels on statins.
Importantly, ESC guidance differentiates icosapent ethyl from mixed omega-3 fatty acid preparations, which have not consistently shown cardiovascular benefit.
Management of Severe Hypertriglyceridemia (>750 mg/dL)
Severe hypertriglyceridemia is clinically distinct due to the risk of acute pancreatitis and often reflects genetic disorders of triglyceride metabolism.
Familial Chylomicronaemia Syndrome (FCS)
When triglyceride levels exceed 750 mg/dL, particularly in the setting of recurrent pancreatitis, eruptive xanthomas, or lipemic serum, familial chylomicronaemia syndrome should be suspected. This rare condition is typically caused by impaired lipoprotein lipase (LPL) activity.
Volanesorsen in Familial Chylomicronaemia Syndrome
ESC 2025 recommends volanesorsen in patients with confirmed FCS and triglycerides persistently >750 mg/dL.
Volanesorsen is an antisense oligonucleotide that inhibits apolipoprotein C-III (ApoC-III), a key regulator that suppresses LPL activity. By reducing ApoC-III levels, volanesorsen markedly enhances triglyceride clearance and can reduce TG levels by up to 70–80%.
Recommended dose: • Volanesorsen 300 mg subcutaneously once weekly
Due to the risk of thrombocytopenia, patients on volanesorsen require regular platelet monitoring, and treatment should be supervised by lipid specialists.
What Is Not Recommended
ESC 2025 does not support routine use of fibrates or non-EPA omega-3 formulations for cardiovascular risk reduction in statin-treated patients with moderate hypertriglyceridemia. Their role remains limited to selected cases, mainly for pancreatitis prevention when TG levels are very high and other options are unsuitable.
Key Take-Home Messages
• Statins are first-line therapy for hypertriglyceridemia in high-risk patients
• Icosapent ethyl 2 g twice daily is recommended for fasting TG 135–499 mg/dL despite statins
• Severe hypertriglyceridemia (>750 mg/dL) warrants evaluation for familial chylomicronaemia syndrome
• Volanesorsen 300 mg weekly is reserved for confirmed FCS with very high TG levels
• Platelet monitoring is mandatory with volanesorsen therapy
Source: European Society of Cardiology (ESC) 2025 Guidelines
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