SHASTA-3/4: What an 80% Triglyceride Cut Means, With Christie Ballantyne, MD

Plozasiran, an RNA interference (RNAi) therapeutic targeting apolipoprotein C-III (APOC3), reduced triglyceride levels by approximately 80% at 1 year in patients with severe hypertriglyceridemia, according to results from the phase 3 SHASTA-3 and SHASTA-4 trials presented at the European Society of Cardiology (ESC) Congress 2026.¹

Christie Ballantyne, MD, Baylor College of Medicine, discussed what these results mean in practice with HCPLive.

What An 80% Triglyceride Reduction Means in Practice

Ballantyne noted SHASTA-3 and SHASTA-4 enrolled patients with sustained severe hypertriglyceridemia despite existing treatment: "These are people who had what we'd call sustained severe high triglycerides. They'd already been treated. So, these were people who were mostly on 2 drugs or more.

Ballantyne also said about a third of participants had baseline triglycerides above 880 mg/dL (10 mmol/L), averaging around 650 mg/dL overall, a level well beyond what conventional therapies typically achieve. "Lowering triglycerides is great, but that's just a number. The main issue is pancreatitis," Ballantyne said.

For the primary endpoint, treatment with plozasiran led to median triglyceride reductions at month 12 of 79% in SHASTA-3 and 81% in SHASTA-4, compared with a placebo reduction of approximately 27% in each trial. Across the trial populations, cumulative acute pancreatitis events were reduced by 78% with plozasiran versus placebo, and in the subset with triglycerides > 880 mg/dL, pancreatitis was reduced by 100%.¹

Pancreatitis Prevention as Secondary Prevention

Ballantyne said the number needed to treat (NNT) findings were the most striking part of the results.

"There was also a very significant reduction in the people who had SHTG over 500, but not over 880... the people who had a prior history of pancreatitis, the number needed to treat was 3. I mean, you're talking about almost a 90% reduction in the episodes of pancreatitis," Ballantyne said. "It wasn't only if you had over 880. If you had a pancreatitis and over 500, they were still at a high risk for getting it again, and there was great benefit."

Ballantyne pointed to a prior trial of an antisense oligonucleotide targeting the same pathway, showing concordant benefit in a similar population: patients with sustained chylomicronemia above 880 mg/dL, particularly those with a pancreatitis history, saw substantial benefit from treatment in both studies.²

He framed a history of pancreatitis with persistent severe hypertriglyceridemia as its own secondary-prevention scenario. "It's a little bit like everyone's pretty convinced secondary prevention, you've had a heart attack. Yeah, you got to lipids, blood pressure, treat them aggressively. It's the same thing for triglycerides and pancreatitis. Once they've had an event, they're at high risk for another event," Ballantyne said. "The NNT for preventing the second event was 3. We don't ever see that in a trial."

Dosing, Adherence, and the Placebo Group's Improvement

Asked about the clinical importance of quarterly dosing compared with daily oral therapies, Ballantyne pointed to how easily severe hypertriglyceridemia can spike outside the clinic. He described patients whose fasting triglycerides might run 600 to 650 mg/dL even on treatment, and how a single high-fat, high-alcohol weekend, a scenario he said he sees regularly in his practice, could send levels from 600 to 3000 mg/dL. A therapy persisting for months, he said, provides buffering against exactly this kind of lapse, whereas missed doses or poor adherence with daily therapies leave patients more exposed.

Ballantyne attributed the placebo group's roughly 27% triglyceride reduction to the effect of trial participation itself, including reinforced attention to alcohol, diet, exercise, and background medications, noting this can often bring patients out of the chylomicronemia range and below 500 mg/dL, even without study drug. On treatment interruption, he said plozasiran's long half-life offers some protection, with benefit persisting out to about 6 months even if a dose is delayed, though he emphasized continued adherence to background therapies, including fibrates and omega-3 agents, remains important.

Ballantyne said plozasiran has genuinely changed the standard of care, particularly for patients with a pancreatitis history and persistent severe hypertriglyceridemia, calling the consistency between plozasiran and the prior antisense oligonucleotide trial reassuring evidence for the field.²

References

1. European Society of Cardiology. Plozasiran significantly reduces triglyceride levels in patients with severe hypertriglyceridaemia. Published August 30, 2026. Accessed August 30, 2026. https://www.escardio.org/news/press/press-releases/plozasiran-significantly-reduces-triglyceride-levels-in-patients-with-severe-hypertriglyceridaemia/

2. Marston NA, Bergmark BA, Alexander VJ, et al; for the CORE-TIMI 72a and CORE2-TIMI 72b Investigators. Olezarsen for managing severe hypertriglyceridemia and pancreatitis risk. N Engl J Med. 2026;394(5):429-441. doi:10.1056/NEJMoa2512761