This article was created with Dr. Vera Bittner, Section Head of General Cardiology, Prevention, and Imaging and Medical Director of the Coronary Care Unit at University of Alabama at Birmingham.
Hypertriglyceridemia, characterized by elevated triglyceride (TG) levels, is increasingly recognized as a significant cardiovascular risk enhancer. Despite statin therapy, patients with atherosclerotic cardiovascular disease (ASCVD) often experience residual risks, partly attributed to remnant lipoprotein particles, which are highly atherogenic.
Persistent TG elevation is defined as TG >150 mg/dL, and a more concerning threshold is TG >175 mg/dL after three months of healthy lifestyle modifications. Identifying and addressing secondary causes, such as uncontrolled diabetes mellitus and medication-induced hypertriglyceridemia (e.g., beta-blockers, diuretics, steroids, tamoxifen, cyclophosphamide), is crucial in patient management.
Hypertriglyceridemia can also be a manifestation of metabolic syndrome and is associated with any combination of 2 other abnormalities: abdominal obesity, hypertension, impaired fasting blood glucose (HbA1c between 5.5 and 6.4%), and low HDL.
Lifestyle Modifications
The foundation of hypertriglyceridemia management begins with lifestyle interventions, particularly dietary modifications. Patients should prioritize reducing refined sugars, such as sucrose and fructose, and limit alcohol intake.
A heart-healthy dietary pattern can significantly improve triglyceride levels, including increased fiber, healthy fats (monounsaturated and polyunsaturated fats), and omega-3 fatty acids. Moreover, achieving optimal low-density lipoprotein (LDL) cholesterol levels remains paramount in reducing cardiovascular risk.
Triglyceride-Lowering Pharmacotherapy
Omega-3 Fatty Acids
Omega-3 fatty acid therapy has been extensively studied in hypertriglyceridemia. The JELIS and REDUCE-IT trials provided evidence supporting the cardiovascular benefits of high-dose eicosapentaenoic acid (EPA).
- The REDUCE-IT trial included 8,000 patients, with 70% in secondary prevention and 29% in primary prevention (diabetes mellitus patients). Those receiving icosapent ethyl (4 g daily) vs. placebo (mineral oil) demonstrated a 25% reduction in major adverse cardiovascular events (MACE). However, risks included an increased incidence of atrial fibrillation (5.3% vs. 3.9%) and a trend toward an increased risk of bleeding.
- The EVAPORATE study showed that EPA reduced plaque burden as seen via coronary CT angiography (CTA), though a small sample size limited the study.
- The STRENGTH trial, involving 13,000 patients, evaluated a combination of EPA and docosahexaenoic acid (DHA) vs. a corn oil placebo. It found no cardiovascular benefits, and the trial was stopped early for futility.
Fibrates
Fibrates, once considered a primary option for TG reduction, have shown no significant cardiovascular benefit when combined with statins. Their role remains limited to patients with severe hypertriglyceridemia (>500 mg/dL) at risk for pancreatitis rather than ASCVD risk reduction.
Future Therapies
Plozasiran, a novel small interfering RNA (siRNA) therapy, is emerging as a promising agent targeting apolipoprotein C3 (APOC3), a key regulator of triglyceride metabolism. Phase 2b trials have demonstrated a 90% reduction in APOC3, a 70% reduction in TG levels, and a substantial increase in HDL levels without a significant rise in LDL. Ongoing Phase 3 multicenter, randomized, placebo-controlled trials aim to determine its long-term cardiovascular outcomes and potential as a breakthrough therapy in hypertriglyceridemia management.
Angiopoietin-like protein 3 (ANGPT3) inhibits the activity of lipoprotein lipase and endothelial lipase, increasing serum LDL cholesterol and TG levels. In early clinical trials, Solbinsiran, another small interfering RNA developed to inhibit the hepatic translation of ANGPLT3 messenger RNA, lowers ANGPLT3 levels by up to 86%, TGs by up to 73%, LDL by up to 30%, and apo B by 36%.
GIP/GLP1 Receptor Agonists
Tirzepatide – a dual GIP/GLP1 receptor agonist – affects cardiometabolic health. A meta-analysis pooling data from 7 phase 3 randomized clinical trials of 7,805 patients with type 2 diabetes mellitus revealed that compared to placebo, Tirzepatide reduced the prevalence of metabolic syndrome from 82% to 51%, particularly in patients <65, with a significant dose-response association, with higher doses being more effective in resolving metabolic syndrome. Compared to placebo, Tirzepatide decreased the waist circumference by 16%, TG by 47%, systolic blood pressure by 33%, fasting blood sugar by 28%, and prevented HDL reduction by 66%.
The Future of Hypertriglyceridemia
Hypertriglyceridemia is a marker of remnant cholesterol and triglyceride-rich lipoprotein, which remains a significant cardiovascular risk factor, particularly in patients with ASCVD and residual risk despite statin therapy. Lifestyle modifications are the cornerstone of treatment, with omega-3 fatty acids (specifically icosapent ethyl) providing some clinical benefits. The future of triglyceride-lowering therapy lies in emerging RNA-based treatments such as Plozasiran or Solbinsiran and the GIP/GLP1 receptor agonists for the treatment of obesity and diabetes, which may revolutionize hypertriglyceridemia management in high-risk populations.
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