Quarterly jab cut pancreatitis attacks in very high triglycerides

Plozasiran, an injection given once every three months, cut triglyceride levels by about 80% and lowered the rate of acute pancreatitis in adults with severe hypertriglyceridemia in two phase 3 trials published in the New England Journal of Medicine on 4 November 2026. In SHASTA-3 and SHASTA-4, more than nine in ten people on the drug got their triglycerides below 500 mg/dL, the level above which the risk of pancreatitis climbs. About half of those on placebo did.

The pancreatitis result is the part that could change care. Across both trials, people on plozasiran had attacks at a rate of about 1 per 100 patient-years, compared with 5 per 100 on placebo. That headline rests on a small number of events, though: 5 attacks on the drug and 13 on placebo. The trials lasted 12 months, mostly enrolled white men, and recorded more problems with blood sugar control in the plozasiran groups.

What is severe hypertriglyceridemia?

Triglycerides are the main type of fat carried in the blood. A normal fasting level is below 150 mg/dL, or about 1.7 mmol/L in the units used in UK laboratories. Severe hypertriglyceridemia (often shortened to sHTG) usually means a level of 500 mg/dL (about 5.6 mmol/L) or more.

At those levels the blood fills with large fat particles called chylomicrons and VLDL. They can trigger acute pancreatitis, a sudden and very painful inflammation of the pancreas. It often means a hospital stay, it can come back repeatedly, and severe attacks can be fatal.

The most extreme form is familial chylomicronemia syndrome (FCS), a rare genetic condition in which triglycerides typically exceed 880 mg/dL (about 9.9 mmol/L). Most people with sHTG do not have FCS. Their high levels come from a mix of genes, weight, diabetes, alcohol and some medicines. That much larger group is the one SHASTA-3 and SHASTA-4 set out to treat.

Standard care starts with diet, cutting alcohol and treating causes such as poorly controlled diabetes. Doctors may add fibrates or high-dose omega-3 fatty acids. Many people still stay above the danger threshold, which is why drug makers have been looking for something stronger.

How does plozasiran work?

Plozasiran is a small interfering RNA (siRNA), a type of medicine that silences one gene. It is built to reach liver cells, where it blocks production of apolipoprotein C-III (APOC3). APOC3 slows the breakdown and clearance of triglyceride-rich particles, so lowering it lets the body clear them faster.

The drug is made by Arrowhead Pharmaceuticals of Pasadena, California, and sold as Redemplo. It is already approved in the US, the EU, China, Canada and Australia as an add-on to diet for adults with FCS. The UK's medicines regulator, the MHRA, authorised it for FCS on 19 October 2026, and NICE recommended it for genetically confirmed FCS when diet and standard treatments have not worked well enough. People inject 25 mg under the skin once every three months.

The SHASTA trials were designed to support a much wider licence covering adults with sHTG who do not have FCS.

Who took part in SHASTA-3 and SHASTA-4?

The two trials (NCT06347003 and NCT06347016) had identical designs, endpoints and analysis plans. Together they randomly assigned 757 adults with severe hypertriglyceridemia: 446 in SHASTA-3 and 311 in SHASTA-4. Twice as many people got plozasiran as placebo, so 504 received the drug and 253 received dummy injections. Neither the patients nor their doctors knew who was on which.

Injections were given at the start and at months 3, 6 and 9. The main goal was the percentage change in fasting triglycerides from the start of the trial to month 12.

According to Rare Disease Advisor's summary of the paper, median starting triglycerides were 671 mg/dL in SHASTA-3 and 731 mg/dL in SHASTA-4. About 21% of participants had already had at least one episode of acute pancreatitis. Women made up only 17% of SHASTA-3 and 26% of SHASTA-4.

The paper's lead author is Gerald Watts of the University of Western Australia and Royal Perth Hospital. Investigators came from across Europe, North and South America, China, South Africa, Australia and New Zealand, including UK centres in Torbay and London. Arrowhead funded the trials, and several of its staff are co-authors.

How far did triglycerides fall?

At month 12, median triglycerides had fallen from baseline by 79% in SHASTA-3 and 81% in SHASTA-4 in the plozasiran groups. Placebo groups also fell, by about 28% and 27%, a common pattern in trials where everyone gets extra attention to diet and where people often join when their levels happen to be at a peak.

The NEJM abstract gives the placebo-adjusted difference as minus 45 percentage points (95% confidence interval, minus 51 to minus 38) in SHASTA-3 and minus 47 points (minus 54 to minus 39) in SHASTA-4. Those figures are smaller than a simple subtraction of the two medians would give. That is because the trials estimated the median difference between individual patients in the two groups, which is a different calculation from subtracting one group's median from the other's.

Figures from the NEJM abstract, Arrowhead's ESC release and Rare Disease Advisor's report of the full paper. Placebo changes come from the secondary report.

Among people who started with triglycerides of 880 mg/dL or higher, levels fell by a median of 85% in both trials. More than half of those on the drug reached a normal level below 150 mg/dL, something that very few people on placebo managed.

Plozasiran also lowered other fats linked to clogged arteries. Remnant cholesterol fell by 53 and 56 percentage points more than placebo, and non-HDL cholesterol by 21 and 28 points. The trials did not test whether this cuts heart attacks or strokes, so those changes are a lab finding for now.

Did plozasiran prevent pancreatitis?

This was tested in a pooled analysis of both trials that was planned before the results were known. An independent committee reviewed each suspected attack.

In the plozasiran groups there were 5 attacks in 5 people over 504 patient-years of follow-up. In the placebo groups there were 13 attacks in 9 people over 253 patient-years. By our own arithmetic, that works out to about 1.0 and 5.1 attacks per 100 patient-years, which matches the rates of 1 and 5 in the paper.

The rate ratio was 0.22 (95% CI, 0.07 to 0.67; p=0.008), which Arrowhead describes as a 78% reduction. The company puts the absolute risk reduction at 4.1 percentage points over a year. That means about 24 people would need treatment for a year to prevent one attack. The risk of a first attack was also lower (hazard ratio 0.26; 95% CI, 0.09 to 0.78), and the time to a first attack was 283 days on the drug, against 182 days on placebo.

The benefit looked largest in people who had already had pancreatitis. In those with a prior attack, Arrowhead reports a 91% lower attack rate (rate ratio 0.09) and an absolute reduction of 34 percentage points. That implies treating about three such people for a year to prevent one attack. At the American Heart Association meeting in Chicago on 7 November, the company added that none of the 35 plozasiran patients with both a past attack and triglycerides of 880 mg/dL or more had an attack, compared with 5 attacks among 17 similar patients on placebo.

Those subgroup numbers are small, and the confidence intervals around them are wide. The whole pancreatitis analysis involves 18 attacks. A few events going the other way would have changed the percentages a lot. Still, the direction fits what doctors expect, since getting triglycerides below 500 mg/dL is the main thing that protects the pancreas.

For more on reading this kind of result, our guide to absolute and relative risk explains why a 78% reduction and a 4 percentage point reduction can describe the same trial.

What were the side effects?

Adverse events of any kind were reported in 73% of people in both the plozasiran and placebo groups. Serious adverse events were slightly less common with the drug, at 8.3% against 10%. Few people stopped treatment because of side effects: 1.4% on plozasiran and 0.8% on placebo.

The clearest signal was blood sugar. Worsening glycemic control was reported in 14.3% of people on plozasiran and 8.7% on placebo, according to Arrowhead. The NEJM paper, as summarised by Rare Disease Advisor, describes a modest rise in HbA1c, the blood test that tracks average sugar levels. Arrowhead says mean HbA1c did not keep rising over time. Raised blood sugar is also the most common side effect listed by the MHRA for the FCS licence, so people with diabetes or prediabetes may need closer checks.

Diarrhoea affected 5.6% on plozasiran and 3.2% on placebo. Injection site reactions were uncommon (3.2% against 2.0%), and there were no cases of anaphylaxis. The company reported no meaningful changes in platelet counts or liver enzymes. In a small subgroup who had liver MRI scans, liver fat did not rise.

Three people on plozasiran died during the trials. Two deaths were cardiovascular and one was from a blood cancer, chronic myelomonocytic leukaemia. The investigators judged all three to be caused by disease the patients already had and unrelated to the drug.

How does plozasiran compare with olezarsen?

Plozasiran is not the first APOC3 drug to show it can prevent pancreatitis in sHTG. On 24 June 2026 the US Food and Drug Administration approved olezarsen (Tryngolza), made by Ionis, to reduce triglycerides and the risk of acute pancreatitis in adults with sHTG. Olezarsen is an antisense drug injected once a month. Its approval rested on the CORE and CORE2 trials in 1,061 adults.

Comparing the two directly is not possible. No trial has put them head to head, and the studies enrolled different people. The olezarsen trials had higher average starting triglycerides, above 1,100 mg/dL, and measured the main result at six months. The main practical differences are dosing, every three months for plozasiran against monthly for olezarsen, and safety labelling. The FDA's olezarsen label includes a warning about liver enzyme abnormalities.

For patients, a second option could matter. The two companies will also compete on price and insurance coverage, which this kind of trial does not address.

What happens next?

Arrowhead says it will file a supplemental application with the FDA before the end of 2026 to extend the Redemplo licence to sHTG. It bought a priority review voucher in August, which can shorten the FDA's review clock. The company plans to apply in other regions as well, using SHASTA-3, SHASTA-4 and a third trial, MUIR-3.

People who finished 12 months could join an open-label extension, where everyone gets the drug. That study should show whether the effect holds and whether the blood sugar signal grows or fades with longer use.

The trials leave three big questions open:

• Does plozasiran prevent heart attacks and strokes, given that it lowers remnant and non-HDL cholesterol?
• How safe is it over many years, especially for people with diabetes?
• Will the pancreatitis benefit look as strong in a larger and more diverse group of patients?

Can people in the UK get plozasiran for high triglycerides?

Not yet, unless they have FCS. The MHRA licence and the NICE recommendation cover only adults with FCS, and NICE's guidance applies to those whose condition is genetically confirmed. We found no UK application for the wider sHTG use. Olezarsen's sHTG approval is also US-only for now.

If you have very high triglycerides, the usual steps still apply. Your GP or lipid clinic can check for causes such as diabetes, kidney or thyroid problems, alcohol and medicines that raise triglycerides. Some people with very high levels may be eligible for clinical trials, and our guide on how to find and join a clinical trial explains where to look.

Questions to ask your doctor

If you have been told your triglycerides are very high, these questions may help at your next appointment:

• What was my last fasting triglyceride level, and how does it compare with 5.6 mmol/L?
• Have I had pancreatitis, or symptoms that might have been pancreatitis?
• Could anything I take, or another condition, be pushing my levels up?
• Would a referral to a lipid clinic make sense for me?
• If newer treatments such as plozasiran become available here, would I be likely to qualify?

This article is for general information and is not medical advice. Talk to your own doctor before changing any treatment or diet.

What remains uncertain?

SHASTA-3 and SHASTA-4 show that a quarterly injection can bring triglycerides down to safer levels in nearly everyone who takes it, with side effects similar to placebo apart from blood sugar. The pancreatitis reduction is encouraging, and it matches what was seen with olezarsen. It is based on 18 attacks over one year, mostly in white men, which leaves real uncertainty about its size.

The FDA filing expected by the end of 2026 will be the next marker. Our cardiology section will follow whether regulators accept the evidence and how the two APOC3 drugs end up being used.