Therapeutic Innovations for Lowering Triglycerides

CardioNerds co-founders Dr. Daniel Ambinder and Dr. Amit Goyal are joined by Dr. Spencer Weintraub, Chief Resident of Internal Medicine at Northwell Health, Dr. Michael Albosta, third-year Internal Medicine resident at the University of Miami, and Anna Biggins, Registered Dietitian Nutritionist at the Georgia Heart Institute. Expert commentary is provided by Dr. Zahid Ahmad, Associate Professor in the Division of Endocrinology at the University of Texas Southwestern. Together, they discuss a fascinating case involving a patient with a new diagnosis of hypertriglyceridemia. Episode audio was edited by CardioNerds Intern Student Dr. Pacey Wetstein.

A woman in her 30s with type 2 diabetes, HIV, and polycystic ovarian syndrome presented with one day of sharp epigastric pain, non-bloody vomiting, and a new lower extremity rash. She was diagnosed with hypertriglyceridemia-induced pancreatitis, necessitating insulin infusion and plasmapheresis.  

The CardioNerds discuss the pathophysiology of hypertriglyceridemia-induced pancreatitis, potential organic and iatrogenic causes, and the cardiovascular implications of triglyceride disorders. We explore differential diagnoses for cardiac and non-cardiac causes of epigastric pain, review acute and long-term management of hypertriglyceridemia, and discuss strategies for the management of the chylomicronemia syndrome, focusing on lifestyle changes and pharmacotherapy. 

This episode is part of a case reports series developed in collaboration with the National Lipid Association and their Lipid Scholarship Program, with mentorship from Dr. Daniel Soffer and Dr. Eugenia Gianos.

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Pearls – Hypertriglyceridemia

1. Cardiac sarcoidosis can present with a variety of symptoms, including arrhythmias, heart block, heart failure, or sudden cardiac death. The acute management of hypertriglyceridemia-induced pancreatitis involves prompt recognition and initiation of therapy to lower triglyceride levels using either plasmapheresis or intravenous insulin infusion +/- heparin infusion. Insulin infusion is used more commonly, while plasmapheresis is preferred in pregnancy.  
2. Medications such as fibrates and omega-3 fatty acids can be used to maintain long-term triglyceride reduction to prevent the recurrence of pancreatitis, especially in patients with persistent triglyceride elevation despite lifestyle modifications. Statins can be used in patients for ASCVD reduction in patients with a 10-year ASCVD risk > 5%, age > 40 years old, and diabetes or diabetes with end-organ damage or known atherosclerosis. Consider preferential use of icosapent ethyl as an omega-3 fatty acid for triglyceride lowering if the patients fit the populations that appeared to benefit in the REDUCE IT trial.  
3. Apply targeted dietary interventions within the context of an overall healthy dietary pattern, such as a Mediterranean or DASH diet. Limit full-fat dairy, fatty meats, refined starches, added sugars, and alcohol. Encourage high-fiber vegetables, whole fruits, low-fat or fat-free dairy, plant proteins, lean poultry, and fish. Pay special attention to the cooking oils to ensure the patient is not using palm oil, coconut oil, or butter when cooking. Instead, use liquid non-tropical plant oils. Initiate a very low-fat diet (< 5% of total daily calories from fat) for 1-4 weeks when TG levels are > 750 mg/dL. 
4. Recommend and encourage patients to exercise regularly, with a minimum goal of 150 minutes/week of moderate-intensity aerobic activity. If weight loss is required, aim for more than >225 – 250 minutes/week.  
5. Develop patient-centered and multidisciplinary strategies for preventing hypertriglyceridemia-induced pancreatitis by incorporating patient education on the importance of medication adherence, specialist follow-up, regular monitoring of triglyceride levels, and lifestyle modifications to maintain optimal lipid profiles and reduce the future risk of pancreatitis. 

Notes – Hypertriglyceridemia

1. Who is at risk for hypertriglyceridemia and what are the key pathophysiological mechanisms by which elevated triglycerides may lead to pancreatitis?  

• The exact mechanism is not clear. The proposed mechanism is that when serum triglycerides exceed 1000 mg/dL, blood flow is impaired through the capillary beds supplying the pancreas, resulting in ischemia. The ischemic injury resulting from this disruption of microcirculation disrupts the acinar structure of pancreatic cells and exposes pancreatic enzymes to triglyceride-rich particles. This results in activation of enzymatic activity with degradation of the chylomicron-triglycerides particles, which causes inflammation, subsequently leading to hemorrhage, edema, and necrosis of the pancreatic tissue.  

• Chylomicronemia syndrome can be multifactorial or familial. Familial chylomicronemia syndrome (FCS) is often discovered very early in life, and patients have a loss of function in one of the several genes involved in regulating triglyceride metabolism. These genes include LPL, APOC2, APOA5, LMF1, and GPIHBP1. 

• Multifactorial chylomicronemia syndrome is the most common cause of chylomicronemia syndrome. It is usually the result of a clustering of genetic variants, including heterozygosity of one of the five genes previously mentioned, as well as more frequent variants with small effects in more than 40 additional genes that have been implicated. Having a genetic variant plus an aggravating factor will often exacerbate the metabolic defect and lead to chylomicronemia syndrome. There are many potential aggravating factors, but some of the more common ones include a diet high in refined sugars, heavy alcohol consumption, obesity with or without metabolic syndrome, medications, renal disease, HIV, and pregnancy.  

2. What are the acute treatment strategies for hypertriglyceridemia-induced pancreatitis, and how are they similar and different to treating pancreatitis from other etiologies?  

• All patients should be assessed for hemodynamic compromise, the severity of illness with or without scoring systems, and end-organ damage to determine the need for intensive care resources. Initially, patients usually require aggressive fluid resuscitation and pain management, which are standard across all types of acute pancreatitis. Delayed fluid resuscitation has been associated with worse outcomes. Multiple trials have been performed evaluating the best amount of fluid. Although there is not an exact answer to this, as all patients are different, all patients should be resuscitated until euvolemic. The WATERFALL trial showed that administration of 10 mL/kg bolus followed by 1.5 mL/kg maintenance until the patient reaches euvolemia was a superior approach to more aggressive fluid resuscitation. A patient’s volume status should be reassessed every 6 hours for 24 – 48 hours, and fluids should be discontinued once euvolemia has been achieved. There is no guideline consensus on the preferred analgesic management, but it is generally recommended to administer medication to mitigate symptoms of pain and nausea for all patients.  

• For hypertriglyceridemia-induced pancreatitis, it is key to initiate fasting to decrease chylomicron production and further increasing triglyceride levels. Although historically, this was the same approach for other causes of pancreatitis, more recent data shows that early enteral feeding reduces the risk of complications such as pancreatic necrosis. However, these studies were not performed in patients with pancreatitis from hypertriglyceridemia and should not be extrapolated to this distinct population. Currently, it is recommended that patients be kept NPO until triglycerides are below 500 mg/dL, which is the point at which LPL activity becomes saturated. When feeding is initiated, it should be with a very low-fat diet with no refined carbohydrates.  

• Hypertriglyceridemia differs from other causes of pancreatitis as the management is centered around the rapid reduction of triglyceride content in the blood. Generally, these patients are admitted to the intensive care unit to undergo either insulin infusion +/- heparin drip or plasmapheresis. Although there has never been a clinical trial comparing these two approaches, a recent comprehensive meta-analysis showed no significant difference in mortality or clinical outcomes. Insulin infusion had a lower number of deaths, but a higher rate of acute renal failure, hypoglycemia, and hypotension, neither of which reached statistical significance. Insulin is more commonly used and generally preferred given that it is more cost-effective, less invasive, and can have utility in treating underlying diabetes exacerbation, which is common amongst these patients. Insulin infusion works by increasing the activity of lipoprotein lipase (LPL), resulting in increased clearance of chylomicron particles. Although in some countries, insulin is combined with heparin, given heparin’s ability to increase LPL release, this is rarely done as heparin can deplete endothelial LPL, increase bleeding events, and potentially cause heparin-induced thrombocytopenia. Plasmapheresis, on the other hand, works by removing the triglycerides directly from the bloodstream, which can rapidly reduce levels. It does require central venous access, which is more invasive. Plasmapheresis is preferred in pregnancy as data in case series supports it reduces the risk of a systemic inflammatory response.  

3. What are the proposed mechanisms by which high triglycerides may contribute to atherosclerosis? 

• There are several proposed mechanisms for the association between elevated triglyceride levels and ASCVD. First, elevated triglyceride levels correspond with high circulating triglyceride-rich lipoprotein particles, also known as remnant cholesterol. This includes VLDL, IDL, and chylomicron remnants. These particles are thought to be at least as, if not more, atherogenic than LDL-C. Remnant particles readily penetrate the arterial wall, similar to LDL, but do not require oxidative modification for macrophage uptake and can be taken up unregulated, leading to foam cells and atherosclerosis.  

• Second, having elevated levels of triglyceride-rich lipoproteins is pro-inflammatory. When triglyceride-rich lipoproteins are hydrolyzed by lipoprotein and endothelial lipases, the release of oxidized free fatty acids along the endothelial wall leads to the activation of pro-inflammatory signaling pathways that can increase vascular permeability and promote the migration of leukocytes and atherogenic lipoprotein particles into the arterial wall. This is mediated by cytokines and chemoattractant proteins.  

4. What long-term pharmacologic management strategies should be considered in patients with hypertriglyceridemia-induced pancreatitis?  

• Fibrates are the first line pharmacotherapy when the goal of treatment is to prevent acute pancreatitis, especially when triglyceride levels are >1000. The ability of lipoprotein lipase to clear triglyceride-rich lipoproteins becomes saturated at TG levels of approximately 500-700 mg/dL. When the ability to clear TRL is impaired, dietary fat intake can lead to large increases in blood TG levels. Those with TG >1000 are at particularly high risk of acute pancreatitis. Fibrates stimulate PPAR alpha and primarily decrease TGs via the upregulation of LPL. The reduction of TGs from fibrates ranges from 25-50%. Some data suggests fenofibrate may be more effective at lowering TG then gemfibrozil. Gemfibrozil is the only Fibrate therapy that has shown a reduction in cardiovascular events in the VA-HIT and HHS trials. However, it is worth noting these trials were not performed on background statin therapy, which is now contraindicated in patients taking Gemfibrozil due to the increased risk of rhabdomyolysis. 

• Prescription Omega-3 fatty acids lower TGs, possibly via decreased activity of SREBP1c. These are less potent reducers of triglycerides with reductions between 10-50%. While Icosapent Ethyl, a purified form of EPA, does have TG-lowering effects, it is primarily used for ASCVD risk reduction in individuals >age 50 with TG >150 and a history of ASCVD or those without ASCVD but with diabetes mellitus and multiple risk factors. This is based on the aforementioned REDUCE-IT trial. Briefly, REDUCE-IT randomized patients having moderate hypertriglyceridemia and a history of ASCVD or diabetes and other risk factors on background statin therapy to receive icosapent ethyl (pure EPA) or placebo. Patients in the icosapent ethyl group experienced an 18.3% reduction in triglyceride level compared to a 2.2% increase in the placebo group, as well as a 4.8% absolute risk reduction and 25% relative risk reduction in the primary endpoint, a composite of CV death, non-fatal MI, non-fatal stroke, coronary revascularization, or unstable angina with an NNT of 21. The therapy was associated with a slight, although significant, increase in risk of atrial fibrillation, which occurred in 5.3% of patients receiving IPE compared to 3.9% in the placebo group. There was also an increased risk of bleeding, which approached statistical significance. The use of biologically active mineral oil as the placebo has led to some controversy regarding the validity of REDUCE-IT results. In this case, our patient does not exactly fit this study population investigated in that clinical trial. Other Omega-3 fatty acids include mixtures of EPA/DHA such as Omega-3-acid ethyl esters and Omega-3-carboxylic acids, which are often used to reduce the risk of pancreatitis in those with triglyceride levels >500 mg/dL. Combined EPA/DHA products have been investigated in several trials, including but not limited to STRENGTH, VITAL, ASCEND, and OMEMI. However, none of these trials have shown any significant reduction in cardiovascular endpoints.  

• Statins are primarily used for reducing ASCVD risk, although they do lower triglycerides primarily through increased clearance of VLDL via upregulation of the remnant receptor. The 2021 ACC Expert Consensus Decision Pathway for hypertriglyceridemia recommends initiating or intensifying statin therapy for patients aged 40-75 years, with triglycerides of 500-999 mg/dL and with either a 10-year ASCVD risk of ≥5% or diabetes mellitus. The 2018 ACC/AHA multisociety Guideline on the Management of Blood Cholesterol provides key groups that qualify for primary prevention of statin therapy, including those with ASCVD risk >7.5%, age between 40-75 with diabetes mellitus type 1 or 2, and low-density lipoprotein cholesterol (LDL-c) >190 mg/dL. These guidelines further elaborate that in adults 20 to 39 years of age with diabetes mellitus type 2, statin therapy can be considered if they have type 2 diabetes mellitus ≥10 years, albuminuria (≥30 mcg of albumin/mg creatinine), eGFR < 60 mL/min/1.73 m2, retinopathy, neuropathy, or ABI <0.9.  

5. What dietary management approaches are effective in preventing recurrent episodes of hypertriglyceridemia-induced pancreatitis, and how do they impact triglyceride levels?  

• There are many ways to approach dietary interventions in the clinic. The National Lipid Association created a 2023 guideline called “Nutrition interventions for adults with dyslipidemia: A Clinical Perspective from the National Lipid Association,” which can be helpful in guiding clinical care. Always use a patient-centered approach and incorporate patients’ preferences, cultural backgrounds, financial resources, and food availability when applying the dietary guidelines. 

• Start by identifying the food sources in a patient’s diet that can dramatically raise triglycerides: foods rich in added sugars, refined starches, saturated fats, and alcohol. Identifying and minimizing or eliminating these foods upfront (depending on the severity of the hypertriglyceridemia) will lead to substantial improvements in a patient’s lipid profile. 

• The NLA guidelines created four categories based on the severity of hypertriglyceridemia and whether patients have FCS. These categories include patients with triglycerides >= 750 mg/dL with FCS, >= 750mg/dL with suspected MCS, >= 500 mg/dL and < 500 mg/dL.  

• All patients with elevated triglycerides should be advised to strive for an overall healthy dietary pattern such as a Mediterranean or DASH Diet, maximize plant sources of protein, limit or eliminate beverages and foods with added sugars, limit full-fat dairy products, maximize intake of fibrous vegetables, and are encouraged to perform at least 150 minutes/week of moderate-intensity exercise or 75 minutes/week of vigorous exercise but increasing the exercise past this threshold will continue to have added benefits as recommended by the American College of Sports Medicine.  

• The NLA recommends completely abstaining from alcohol for patients with triglycerides >500 mg/dL. For those below 500 mg/dL the recommendation is that men do not exceed two drinks/day and women do not exceed one drink/day. However, in general, it’s best to advise all patients to limit their alcohol as much as possible because it increases the secretion of VLDL, impairs lipolysis, and increases free fatty acid fluxes from adipose tissue to the liver. 

• Dietary saturated fats can also raise both triglycerides and LDL-C and should be replaced with unsaturated fatty acids. Foods rich in saturated fats include those such as butter, beef, and tropical oils such as coconut oil, palm, and palm kernel oil. A thorough review of how patients prepare their food should be performed because making simple changes, such as cooking with olive oil rather than butter or tropical oils, can improve triglycerides and LDL-C.  

• For those with TG levels > 750mg/dL: the goal should be initially to maintain a very low-fat diet with <5%, but after 4 weeks and improvement of triglyceride elevations, there can be liberalization of the patient’s diet. Depending on the patient’s risk profile, including whether they have FCS and current triglyceride levels, cautious relaxation of dietary restrictions can be allowed to improve quality of life and allow for more flexibility in food intake. Patients with FCS must maintain a very low-fat diet for life and should be referred to a registered dietitian specializing in lipid management. 

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