CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurses: 1.00 Nursing contact hour
Physicians: maximum of 1.00 AMA PRA Category 1 Credit™
Released: January 28, 2024
Expiration: January 29, 2025
Using Guideline Recommendations
We have 2 sets of guidelines to help support us in our diagnosis and assessment of triglycerides: the 2018 American Heart Association (AHA) and American College of Cardiology (ACC) guidelines and the 2021 ACC Expert Consensus Decision Pathway (ECDP) for managing ASCVD in patients with persistent hypertriglyceridemia.3,4
In 2018, the AHA and ACC, with several other medical societies, published the 2018 AHA/ACC/multisociety guidelines on managing cholesterol, which identified groups of patients most likely to benefit from statin therapy to lower cholesterol and reduce risk of ASCVD. However, despite statin therapy, ASCVD event rates remained high in patients with elevated triglycerides. The 2021 ACC ECDP was written to address the need for consensus recommendations for treatment of patients with persistent hypertriglyceridemia.
Patient Populations and Considerations
The ACC ECDP classifies patients into 4 groups.3 On the slide, to the far left are adults with established cardiovascular disease and fasting triglycerides ≥150 mg/dL or nonfasting triglycerides ≥175 mg/dL, up to triglyceride levels of 500 mg/dL. The second group is adults with diabetes who do not have established atherosclerotic disease with triglycerides between 150 mg/dL and 499 mg/dL. The third group is adults who do not have cardiovascular disease or diabetes but who have high triglycerides, defined as levels between 150 mg/dL and 499 mg/dL. The fourth group is adults who have severe hypertriglyceridemia of ≥500 mg/dL.
The guidelines then present other factors to consider, such as some of the secondary causes of hypertriglyceridemia.3 Recommendations at this stage include optimizing diet and lifestyle interventions, such as implementing a low-carb diet and focusing on lower amounts of saturated fats; implementing guideline‑directed statin therapy; optimizing glycemic control in individuals with diabetes; monitoring response to therapy; and having important discussions with our patients on the benefits, preferences, potential harms of medications.
After doing all of this, if the patient continues to have persistent fasting hypertriglyceridemia, the next step is considering optional interventions, including referral to a registered dietitian and the addition of a triglyceride risk–based pharmacologic agent.3 These agents are considered risk based because there is not sufficient evidence at this time to definitively conclude that lowering triglycerides reduces cardiovascular events.
Patients Aged 20 Years and Older With Severe Hypertriglyceridemia
Next, we will take a closer look at patients with severe hypertriglyceridemia.3 We will divide them into 2 groups: those with triglycerides of 500-999 mg/dL and those with triglycerides of ≥1000 mg/dL.
For patients with triglycerides of 500-999 mg/dL, the initial process is the same: Rule out secondary causes, optimize their lifestyle, and implement glycemic control as necessary.3
Next, we have individuals 20-39 years of age or 40-75 years of age with triglycerides of 500-999 mg/dL and a 10‑year risk of cardiovascular disease of <5% based on the pooled cohorts equation, or with triglycerides of 500-999 mg/dL without diabetes or ASCVD.3 If patients in these categories experience persistent severe hypertriglyceridemia, the recommendations are to focus on lifestyle therapy and consider a very low–fat diet. To reduce the risk of pancreatitis, fibrate therapy or prescription omega‑3 fatty acids—specifically icosapent ethyl, which has been approved for patients with triglycerides of these levels—may be considered.
Then, in individuals who have the same triglyceride levels but a 10‑year ASCVD risk ≥5%, ASCVD, or diabetes, the recommendation is to be more proactive with statin therapy.3 If triglycerides remain elevated after initiating or increasing statin therapy, it is then recommended to begin a low-fat diet, further increase the intensity of statin therapy, and consider the addition of fibrates and icosapent ethyl or omega‑3 fatty acid ethyl esters, again to reduce the risk of pancreatitis.
For patients with the most severe hypertriglyceridemia—triglyceride levels ≥1000 mg/dL—the recommendations are as follows: rule out secondary causes, implement a very low–fat diet and optimize lifestyle interventions, optimize glycemic control as needed, and consider therapy with fibrates or prescription omega-3 fatty acids to reduce the risk of pancreatitis.3 Patients in this group also may consider statin initiation or intensification.
Standard Therapy and Medications for Severe Hypertriglyceridemia
As discussed, the standard medications and therapies for severe hypertriglyceridemia are diet and lifestyle changes, statins, and fibrates. Niacin was used in the past but largely has been removed from clinical practice because of an adverse event profile including hepatotoxicity and a lack of evidence that it reduces risk of pancreatitis or provides any cardiovascular benefit.19 Finally, we have the omega‑3 fatty acids, which can effectively lower triglyceride levels.
Common Medication Therapies for Severe Hypertriglyceridemia
Considering the potential triglyceride reductions with each medication in greater detail, fibrates are the most effective, with reductions of approximately 25% to 50%.20 The omega‑3 fatty acids provide a 20% to 50% reduction, and statins reduce triglycerides by 10% to 20%. Lastly, niacin is highly variable in its triglyceride‑lowering effect and, as mentioned, is not recommended for routine use.
Emerging Severe Hypertriglyceridemia Therapies
There also are emerging therapies for severe hypertriglyceridemia, including evinacumab, an ANGPTL3 inhibitor; pegozafermin, an analogue of human fibroblast growth factor 21; and volanesorsen and olezarsen, antisense oligonucleotides that target APOC3.19,21,22 The oligonucleotides work by blocking APOC3, which inhibits lipoprotein lipase, so inhibition of APOC3 allows lipoprotein lipase to be activated. These therapies are at various stages in the clinical investigation process.
Evinacumab in Severe Hypertriglyceridemia With or Without Lipoprotein Lipase Pathway Mutations: A Phase II Randomized Trial
A recent phase II clinical trial assessed evinacumab for patients with severe hypertriglyceridemia with or without mutations in lipoprotein lipase.23 The data showed that for patients with multifactorial chylomicronemia (MCM), there was still evidence of triglyceride reductions, regardless of whether the patients had loss of function lipoprotein lipase mutations. However, for patients with FCS, there was no significant decrease in triglycerides. Further trials for this drug on preventing pancreatitis were halted by the drug company, so it is unlikely that it will be moved on for further evaluation for severe hypertriglyceridemia treatment.
Pegozafermin in Severe Hypertriglyceridemia: A Phase II Randomized Trial of a FGF21 Analogue
Data from a recent phase II trial of 4 different doses of pegozafermin in patients with severe hypertriglyceridemia showed that weekly injections of pegozafermin induced significant reductions in triglycerides—in the range of 50% to 60%.24 Biweekly injections also reduced triglyceride levels, although not to the same degree. Another benefit was reduction in hepatic fat, which has led to some interesting investigations in its use for metabolic dysfunction–associated steatohepatitis.
COMPASS: Volanesorsen in Patients With MCM
Volanesorsen is a single-stranded ASO that decreases the mRNA of APOC3. The COMPASS trial of volanesorsen in patients with MCM demonstrated significant efficacy.25 At 3 months, there was an approximately 70% reduction in triglyceride concentration—close to 10 mmol/L. Unfortunately, thrombocytopenia, defined as platelet counts <140,000 per microliter, was a common adverse event of volanesorsen. So, although volanesorsen was approved for use in Europe, it was not approved by the FDA in the United States because of increased risk of thrombocytopenia.
Effect of Olezarsen in Lowering Triglyceride Levels in Patients With High Risk of Established Cardiovascular Disease: A Phase II Randomized Trial
To address this, a similar medication is poised to come to market. Olezarsen is a next-generation, ligand-conjugated apoC-III ASO, differing from volanesorsen in its GalNAc moiety.26 A phase II trial of olezarsen in patients with moderate hypertriglyceridemia demonstrated significant lowering of triglyceride levels, even at the lowest dose of 10 mg every 4 weeks.
Ongoing: Olezarsen Phase III Trial for Severe Hypertriglyceridemia
Based on the promising results from the phase II trial in individuals with elevated triglycerides and high risk of or established ASCVD, a phase III trial is ongoing to evaluate the efficacy of olezarsen. The trial will look at the percent change in fasting triglycerides compared with placebo using an 80-mg monthly dose (NCT05079919). This offers the potential to have a new agent for the treatment of severe hypertriglyceridemia in the United States for the first time in many years.
Selecting Optimal Medical Therapy
When we think about selecting optimal medical therapy for our patients with hypertriglyceridemia, we need to balance lowering ASCVD risk with reducing the risk of pancreatitis, as there is not sufficient evidence that lowering triglycerides alone reduces ASCVD risk.
To date, the only study in patients with hypertriglyceridemia that has demonstrated a link between reducing triglycerides and lowering risk of cardiovascular events is REDUCE-IT, which showed that treatment with icosapent ethyl was associated with lower triglyceride levels and a reduced risk of cardiovascular events.27 However, there was only an approximately 20% reduction in triglyceride levels, so it is thought that this compound has other effects that may mitigate cardiovascular risk in patients with hypertriglyceridemia and the benefit seen in the trial was not due to triglyceride reduction alone.
With respect to risk of pancreatitis, the idea is that if you reduce triglyceride levels, that should reduce the risk of pancreatitis in a patient with hypertriglyceridemia. However, this theory must be proven in clinical trials. Therefore, it can be difficult to strike a balance between percent triglyceride reduction and reduction in the risk of pancreatitis, as often a 20% reduction in triglycerides will not allow individuals to meet the previously stated targets.
Monitoring Recommendations
Frequent triglyceride monitoring in patients with hypertriglyceridemia is important, and repeated testing depends on the severity of their hypertriglyceridemia. Once patients have started on lifestyle interventions or medication and gotten their glucose under control, we can monitor their triglyceride levels anywhere from every 2-3 months to every 4-6 months. This is balanced with monitoring their safety with medications or the lifestyle they are leading. With the exception of niacin, which has the potential to lead to some hepatotoxicity, minimal monitoring is needed from a therapy standpoint, other than to assess triglyceride reduction and ensure that individuals are adherent to therapy.
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