When a blood test shows triglycerides above 500 mg/dL, the biggest short-term danger is no longer only the heart: it is acute pancreatitis, a sudden and sometimes life-threatening inflammation of the pancreas. On November 5, 2026, the New England Journal of Medicine published the full results of the SHASTA-3 and SHASTA-4 trials, and the pooled pancreatitis data were presented two days later at the American Heart Association Scientific Sessions in Chicago. A new drug, plozasiran, cut triglycerides by about 80% and lowered the rate of acute pancreatitis by roughly 78% in adults with severe hypertriglyceridemia.
Here is what the trials found, what they cannot tell us yet, and which blood tests show where you stand.
What counts as very high triglycerides?
Triglycerides are the fats that circulate in your blood after meals and are stored for energy. They are measured in a standard lipid panel. A fasting level below 150 mg/dL is considered normal. Severe hypertriglyceridemia starts at 500 mg/dL. Above roughly 880 to 1,000 mg/dL, the blood fills with large fat particles called chylomicrons: the plasma can look milky, and the risk of pancreatitis climbs sharply. For the full scale, see our guide to normal triglyceride levels and ranges.
Most people with very high triglycerides have a genetic tendency combined with aggravating factors: poorly controlled diabetes, heavy drinking, excess weight, an underactive thyroid, kidney disease, pregnancy or certain medicines. A rare inherited form, familial chylomicronemia syndrome (FCS), almost completely blocks the clearance of triglycerides. Our article on high triglyceride levels covers causes and everyday measures.
What the SHASTA-3 and SHASTA-4 trials tested
The two identical trials enrolled 757 adults whose fasting triglycerides were 500 mg/dL or higher. More than half had diabetes, and about one in five had already had pancreatitis. Participants were randomly assigned to plozasiran or a placebo, given as an injection under the skin every three months for one year, on top of diet and their usual lipid treatment.
Plozasiran is a small interfering RNA (siRNA). It switches off the liver's production of apolipoprotein C-III (apoC-III), a protein that acts as a brake on triglyceride clearance. Less apoC-III means fats are removed from the blood faster. The drug is already sold in the United States as Redemplo for FCS, approved in November 2025.
What the results show
| Outcome at 12 months | Plozasiran | Placebo |
|---|---|---|
| Median drop in triglycerides | 79% and 81% (by trial) | About 27% |
| Triglycerides back below 500 mg/dL | 91% and 93% of patients | 51% and 50% |
| Acute pancreatitis (pooled) | 1 per 100 patient-years | 5 per 100 patient-years |
| Any adverse event | 73% | 73% |
The benefit was largest in people who had had pancreatitis in the previous five years, with about a 91% reduction in new attacks according to the analysis presented at AHA. The most common side effect was worsening blood sugar control, mainly in people who already had diabetes (14% versus about 9% with placebo). Liver enzymes and platelet counts did not change in a clinically meaningful way.
What these trials cannot tell us yet
- The pancreatitis finding comes from a pooled analysis of both trials with a small number of events, so the estimate is imprecise.
- Follow-up lasted one year. Long-term benefit and safety still need to be established.
- The trials did not show fewer heart attacks or strokes: they were not designed to test that.
- Plozasiran is not yet approved for severe hypertriglyceridemia outside FCS. Its maker has said it plans to ask the FDA to expand the label by the end of 2026.
Plozasiran is not alone. Olezarsen (Tryngolza), which targets the same protein with a different technology, produced similar results in the CORE and CORE2 trials published in late 2025. In June 2026, the FDA approved it for adults with triglycerides of 500 mg/dL or higher to lower triglycerides and the risk of acute pancreatitis, the first drug with that label.
Which tests can monitor or screen for this?
- Lipid panel: triglycerides, total, LDL and HDL cholesterol, and non-HDL cholesterol. A high triglyceride result should be repeated after a 9 to 12 hour fast. See our triglycerides blood test guide.
- Fasting glucose and HbA1c: uncontrolled diabetes is one of the leading causes of very high triglycerides. See HbA1c normal range.
- Liver tests (ALT, AST, GGT): they point to alcohol or fatty liver and are used to monitor treatment.
- TSH and creatinine with eGFR: an underactive thyroid or kidney disease can raise triglycerides.
- Lipase and amylase: with abdominal pain, lipase is the key test to confirm pancreatitis. See amylase and lipase.
- ApoB: helps estimate heart risk when triglycerides make LDL cholesterol hard to calculate. See the ApoB blood test.
- Genetic testing: offered by lipid specialists when triglycerides stay very high despite treating the causes, to look for FCS.
Recent research advances
For decades, treatment of severe hypertriglyceridemia relied on a very low-fat diet, cutting alcohol, fibrates and omega-3 fatty acids, with uneven results in the people at highest risk. Drugs that silence apoC-III work directly on the brake that keeps fats in the blood, and they are the first to show, in rigorous trials, fewer episodes of pancreatitis.
Reviews published in 2026 see their most immediate role in people at very high risk of pancreatitis. They also stress that a heart benefit has not been shown: an imaging study with olezarsen found no change in coronary plaque. Another analysis found that olezarsen's effect adds to that of fibrates, which many patients already take. For you, the practical message is twofold: get a very high result rechecked promptly, and look for the cause, because controlling diabetes and cutting alcohol remain the first steps.
When to see a doctor
- If your triglycerides are above 500 mg/dL: talk to your primary care clinician soon to repeat the test and look for a cause.
- If they are above 1,000 mg/dL, or you have had pancreatitis before: ask for a referral to a lipid specialist or endocrinologist.
- If you have severe pain in the upper abdomen spreading to the back, with vomiting: call 911 or go to the emergency room.
Glossary
- Triglycerides: blood fats used for energy storage, measured in the lipid panel.
- Severe hypertriglyceridemia: fasting triglycerides of 500 mg/dL or higher.
- Chylomicrons: large particles that carry fat from meals; in excess they make plasma look milky.
- Apolipoprotein C-III (apoC-III): a liver protein that slows the clearance of triglycerides.
- Small interfering RNA (siRNA): a molecule that switches off the production of one specific protein.
- Acute pancreatitis: sudden inflammation of the pancreas that causes severe abdominal pain.
- Lipase: a pancreatic enzyme whose blood level rises sharply during pancreatitis.
Frequently asked questions
What triglyceride level causes pancreatitis?
The risk becomes real above 500 mg/dL and rises sharply above about 1,000 mg/dL, especially in people who have had pancreatitis before. It also depends on the cause and on day-to-day swings.
Is plozasiran FDA approved for high triglycerides?
It is approved as Redemplo for familial chylomicronemia syndrome only. Its maker plans to seek approval for severe hypertriglyceridemia. Olezarsen (Tryngolza) is already approved for that use.
Do I need to fast for a triglyceride test?
Fasting is not required for a routine lipid panel, but a high triglyceride result should be confirmed after fasting, because a recent meal raises the level.
What does milky blood plasma mean?
Milky (lipemic) plasma usually means triglycerides are very high. Labs often flag it, and it should prompt a quick conversation with your clinician.
Can very high triglycerides come down without medication?
Stopping alcohol, sharply cutting fat and added sugars, losing weight and controlling diabetes often lower triglycerides a lot. Above 500 mg/dL, medical follow-up is still needed.
Sources
- Watts GF, Ballantyne CM, Blanco Echevarria A, et al. Plozasiran for severe hypertriglyceridemia and risk of pancreatitis. N Engl J Med. 2026;395:1805-1817. DOI: 10.1056/NEJMoa2610014
- Marston NA, Bergmark BA, Alexander VJ, et al. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med. 2025;394:429-441. DOI: 10.1056/NEJMoa2512761
- Zimerman A, Marston NA. Targeting apolipoprotein C-III in hypertriglyceridemia: implications for pancreatitis and cardiovascular risk. Curr Atheroscler Rep. 2026;28. DOI: 10.1007/s11883-026-01472-6
- Kelly MS, Lewis J, Zuch D, et al. Olezarsen and plozasiran: novel apoC-III targeting medications for the treatment of hypertriglyceridemia. J Cardiovasc Pharmacol. 2026;88:337-351. DOI: 10.1097/FJC.0000000000001854
- Wang AZ, Alexander VJ, Prohaska TA, et al. Efficacy and safety of olezarsen in patients with vs without baseline fibrate use. J Clin Lipidol. 2026;20:2119-2127. DOI: 10.1016/j.jacl.2026.08.001
- HCPLive. SHASTA-3/4: plozasiran could cut acute pancreatitis risk by 78% across sHTG spectrum. November 8, 2026
- American Gastroenterological Association. FDA approves olezarsen to reduce acute pancreatitis risk in severe hypertriglyceridemia. June 2026
- National Heart, Lung, and Blood Institute. High blood triglycerides
- ClinicalTrials.gov. SHASTA-3, NCT06347003
- ClinicalTrials.gov. SHASTA-4, NCT06347016
Further reading
- High triglyceride levels: causes, risks and management
- Pancreatitis: symptoms, causes and when to worry
- Lipid panel: what each result means
- Pelacarsen and Lp(a): the HORIZON trial results
- Lipase levels: causes and risks
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