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Severe hypertriglyceridemia (sHTG) is when serum TGs are > 500mg/dL. 

The reason why managing severe hypertriglydemia is important is because it is associated with increased risk of 1) pancreatitis and 2) CV risk. 

The patients who get pancreatitis related to TG have a higher rates of organ failure and overall morbidity than other causes of pancreatitis. 

And how does TG lead to increased cardiovascular disease? Of course pts who have elevated TG have other reasons, like metabolic syndrome, that make them more susceptible to CV disease. But when triglycerides are high, you need more VLDL particles—more ‘trucks’—to carry all that fat and cholesterol around the body. More trucks means more traffic jam in the blood vessels. And on top of that, TGs and TG remnants are pro-inflammatory which we know plays a big factor into cardiovascular pathophysiology.

When you have a patient with elevated TG, first you should think about secondary causes or other driving factors:

1st ask them about their lifestyle

• Do they drink alcohol?
• What is their diet like?
• Do they have a sedentary lifestyle?

Next, look through their medication list 

• See if any of these medications might contribute?
  • atypical antipsychotic agents
  • glucocorticoids 
  •  oral estrogens 
  • HIV protease inhibitors 
  • Propofol 

Then look through their one-liner and see if they have the following conditions or need to be screened for it

• Nephrotic syndrome 
• Hypothyroidism 
• Cushing Syndrome 
• Inflammatory conditions 

Lastly think if genetics are play a role, which we will get to in a little bit

Next, we can consider management, including lifestyle factors and medications 

In terms of lifestyle, a very low-fat diet is key. It is also important to counsel a high fiber, low-carb diet, particularly limiting refined carbs. And of course, avoid alcohol consumption. Additionally, weight loss can lead to a significant TG reduction. 

These patients often needs medications too.  

• Statins: 
  1. the guidelines * (*2018 AHA/ACC cholesterol management guidelines) recommend a statin if they are 40–75 years old  and ≥7.5%  10 year-ASCVD risk  with persistent moderate (so fasting TG >150-499 mg/dl) 
     1. or severe HTG (≥500 mg/dL)
  2.  The benefit to starting a statin in these patients is that statins as we all know, reduce cardiovascular risk.
  3.  With a statin, we can expect patients to drop their triglycerides by 10-30%
• Omega 3-FA: These medications have both a significant TG reduction AND ASCVD risk reduction benefit. Notably, we should be using prescription strength, Eicosapentanoic (EPA) pre-dominant formulations and get up doses 3-4g/day
  1. You can expect about a 30% reduction in TG with omega-3s.
• Fibrates: These medications are first-line in preventing TG-related pancreatitis in patients with sHTG. Fibrates do not provide additional ASCVD benefits when added to statins.
  1. You can expect a 30-50% reduction in TG with fibrates

A genetic cause of sHTG worth knowing is familial chylomicronemia syndrome (aka FCS).  Chylomicrons are TG rich lipoproteins that are synthesized in enterocytes after a meal. 

We should suspect FCS when we see 1) fasting TG are ≥880-1,000 mg/dL 2) dont have significant secondary risk factors elevated TGs – they are usually thinner individual and 3) have maybe tried TG-lowering therapies in the past without a significant response. 

1. To date, there are 2 FDA-approved meds that target APOC-III, which is involved in the lipoprotein lipase activity to help clear triglycerides
   1. Olezarsan has been shown to decrease TG by ~40% compared to placebo
   2. Plozasiran has been shown to decrease TG by ~60% compared to placebo

So the summarize big takeaways, severe hypertriglyceridemia should signal to us search for secondary causes, act quickly to prevent pancreatitis, and reduce long-term cardiovascular risk. Really counsel the patient about their diet and activity. Start or intensify statin therapy and see if they may benefit from an additional medication, such as an prescription strength omega-3 or a fibate. And when levels are extreme or refractory, think genetics. The goal isn’t just to lower a number, but to change outcomes.

Full Podcast

Severe Hypertriglyceridemia: 5 Pearls Segment