Plozasiran (Redemplo) is approved for an inherited triglyceride disorder, but its use in common dyslipidemia is still unproven

Table of Contents

1.0 Summary

Plozasiran, sold as Redemplo, is an injection given every three months that switches off the liver’s production of apolipoprotein C-III, a protein that slows the clearance of triglycerides from the blood. The US Food and Drug Administration approved it on November 18, 2025, as an addition to diet for adults with familial chylomicronemia syndrome (FCS), an inherited condition in which triglycerides run in the thousands and attacks of acute pancreatitis keep coming back [1]. In the PALISADE trial of 75 people with persistent chylomicronemia, whose median starting triglyceride level was 2,044 mg/dL, plozasiran cut triglycerides by about 80% and lowered the odds of pancreatitis compared with placebo [2]. Trials in severe hypertriglyceridemia from other causes point the same way, but those results have so far come out only as conference news [4]. In the much more common mixed dyslipidemia, where triglycerides are moderately raised alongside LDL cholesterol, plozasiran lowers triglycerides, yet no trial has shown that it prevents heart attacks or strokes [7]. For now it treats pancreatitis risk in FCS and has no established place in routine cholesterol care.

2.0 Key Points

  1. The FDA approved plozasiran (Redemplo) on November 18, 2025, as an adjunct to diet to reduce triglycerides in adults with familial chylomicronemia syndrome [1].
  2. In PALISADE, 75 patients with persistent chylomicronemia, with or without a genetic diagnosis, received plozasiran 25 mg or 50 mg or placebo every three months; at 10 months median triglycerides fell 80% and 78% on the two doses against 17% on placebo, and the odds of acute pancreatitis were lower (odds ratio 0.17; 95% CI 0.03 to 0.94) [2].
  3. In people with severe hypertriglyceridemia from other causes, the phase 3 SHASTA-3 and SHASTA-4 trials reported a triglyceride reduction of roughly 80% at one year and fewer pancreatitis events than placebo, but only conference news coverage is available so far [4].
  4. In mixed dyslipidemia (triglycerides 150 to 499 mg/dL), the phase 2b MUIR trial of 353 people found placebo-adjusted triglyceride reductions of 44 to 62 percentage points at 24 weeks, and its authors concluded that a cardiovascular outcomes trial is still needed [7].
  5. Worsening blood sugar control appeared in some patients, most often at the 50 mg doses in MUIR (20% and 21% against 10% on placebo), and LDL cholesterol rose at the highest dose in SHASTA-2 even though apolipoprotein B did not [6, 7].

3.0 What the drug does

Triglycerides travel in the blood inside particles called chylomicrons, which carry fat absorbed from food, and VLDL, which the liver makes. An enzyme called lipoprotein lipase breaks these particles down. Apolipoprotein C-III (apoC-III) blocks that enzyme, so the more apoC-III a person has, the more slowly triglyceride-rich particles are cleared [7].

Plozasiran is a small interfering RNA (siRNA). It is sugar-tagged so that it is taken up by liver cells, where it destroys the genetic message the cell uses to build apoC-III. Less apoC-III is made, and triglycerides are cleared faster [1]. It is given as an injection under the skin every three months [2]. It is the first approved drug of this kind for this target [1].

4.0 The evidence in familial chylomicronemia syndrome

FCS is a recessive genetic disorder in which chylomicrons build up in the blood, and its main danger is acute pancreatitis, often in repeated attacks [2]. The same picture, called persistent chylomicronemia, can also arise from several causes acting together rather than a single gene [2].

PALISADE was a phase 3, placebo-controlled trial of 75 patients with persistent chylomicronemia, with or without a confirmed genetic diagnosis. Patients received plozasiran 25 mg, plozasiran 50 mg, or placebo every three months for 12 months. Their median triglyceride level at the start was 2,044 mg/dL. At 10 months, median triglycerides had fallen 80% on 25 mg and 78% on 50 mg, compared with 17% on placebo. Acute pancreatitis was less common with plozasiran (odds ratio 0.17; 95% CI 0.03 to 0.94) [2].

Overall adverse event rates were similar across the groups. The most common were abdominal pain, nasopharyngitis, headache, and nausea, and severe and serious adverse events were less common with plozasiran than with placebo. Some patients who already had prediabetes or diabetes developed high blood sugar on plozasiran [2].

A later post hoc analysis looked only at the 67 PALISADE participants who had already had at least one attack of pancreatitis. Over the year, a new attack occurred in 2 of 45 patients on plozasiran and 5 of 22 on placebo (hazard ratio 0.17; 95% CI 0.03 to 0.87) [3]. That is a large relative difference, but it rests on seven events in total and a question asked after the trial was finished [3].

The FDA approval, dated November 18, 2025, covers adults with FCS, with plozasiran used alongside diet [1]. It has since also been approved in Canada and China [8].

5.0 The evidence in other kinds of high triglycerides

Most people with triglycerides above 500 mg/dL do not have FCS. Their levels reflect a mix of genes, weight, diabetes, alcohol, medicines, and other factors. This group, usually called severe hypertriglyceridemia, is where the next decision about plozasiran lies.

SHASTA-2 was a phase 2b dose-finding trial in 229 adults with fasting triglycerides between 500 and 4,000 mg/dL who were already on stable lipid treatment. Their mean starting level was 897 mg/dL. At 24 weeks the highest dose lowered triglycerides by 57% more than placebo, and 144 of the 159 patients on plozasiran (90.6%) got below 500 mg/dL [6]. The trial measured blood lipids, not pancreatitis or heart events [6].

The larger phase 3 trials, SHASTA-3 and SHASTA-4, ran in 24 countries and were presented at ESC Congress 2026. According to American College of Cardiology news coverage, plozasiran every three months lowered triglycerides by roughly 80% at one year compared with placebo, with significantly fewer episodes of acute pancreatitis [4]. The news report did not include event counts, confidence intervals, or detailed safety data, and the full paper has not yet been reviewed here [4]. A separate phase 3 trial is now recruiting about 288 adults with severe hypertriglyceridemia who have had at least two attacks of pancreatitis, one of them in the past year, to test plozasiran 25 mg every three months against placebo [5].

Mixed dyslipidemia is a different and far more common problem. Triglycerides are moderately raised and LDL cholesterol or non-HDL cholesterol is also high, and the worry is heart attack and stroke rather than pancreatitis. In the MUIR trial, 353 people with triglycerides of 150 to 499 mg/dL plus an LDL cholesterol of at least 70 mg/dL or a non-HDL cholesterol of at least 100 mg/dL received plozasiran or placebo. At 24 weeks, triglycerides fell by 49.8 percentage points more than placebo on 10 mg every three months, 56.0 on 25 mg, 62.4 on 50 mg, and 44.2 on 50 mg every six months [7]. Worsening blood sugar control was reported in 10% of the placebo group and in 12%, 7%, 20%, and 21% of the four plozasiran groups [7]. The investigators concluded that a clinical outcomes trial is warranted [7].

In the open-label extensions of SHASTA-2 and MUIR, where everyone eventually received 25 mg every three months, triglyceride reductions held for two years: 77% and 79% below baseline at 12 and 24 months in SHASTA-2, and 62% and 63% in MUIR. Remnant cholesterol, non-HDL cholesterol, and apolipoprotein B also moved in a favorable direction, and HbA1c stayed stable [8]. There was no placebo group in this phase, and the abstract did not give exact figures for those secondary measures [8].

6.0 Where it fits in the Sandusky model

The Sandusky model separates two reasons for treating triglycerides. When fasting triglycerides are 500 mg/dL or higher, the aim is to prevent pancreatitis, and that is one of the listed reasons for referral to the clinic (/clinical/02-patient-eligibility.html). When triglycerides are 135 to 499 mg/dL, the aim is to lower the risk of heart disease, and treatment rests on statins, LDL lowering, and icosapent ethyl in selected patients (/clinical/05-treatment-pathways.html).

Plozasiran belongs to the first group only. For an adult with FCS whose triglycerides stay very high on a strict low-fat diet, it is an approved treatment backed by a randomized trial that showed fewer pancreatitis episodes [1, 2]. In the model it would sit next to fibrates in the pancreatitis-prevention part of the pathway, as a specialist drug for a confirmed or strongly suspected FCS diagnosis rather than a routine next step.

For severe hypertriglyceridemia without FCS, the phase 3 results look similar [4], but in the United States the drug is currently approved only for FCS [1]. Until the full SHASTA-3 and SHASTA-4 data are published and regulators decide on a wider approval, using it in this group would be off-label.

For mixed dyslipidemia, plozasiran has no place in the model today. Lowering triglycerides has not yet been shown to prevent cardiovascular events with this drug [7]. The model’s first priority in these patients remains LDL cholesterol and apolipoprotein B, and SHASTA-2 is a reminder of why: at the highest dose LDL cholesterol rose by a placebo-adjusted 60% while apolipoprotein B did not change and non-HDL cholesterol fell by 20% [6]. A falling triglyceride number is not the same as fewer atherogenic particles, which is why the model leans on apolipoprotein B (/clinical/06-advanced-tools.html). Plozasiran does not replace a statin or other LDL-lowering treatment.

7.0 Open questions

The pancreatitis benefit in FCS comes from a 75-patient trial followed for 12 months, with wide confidence intervals [2]. The recurrent-pancreatitis finding is a post hoc analysis resting on seven events [3]. Longer follow-up in larger numbers would make the size of the benefit clearer.

The SHASTA-3 and SHASTA-4 results have so far been available only as conference news, without event counts or full safety data [4]. The full publication will show how large the pancreatitis reduction was and in whom.

Blood sugar needs watching. High blood sugar appeared in some PALISADE patients who already had prediabetes or diabetes [2], and worsening glycemic control was more frequent on the 50 mg doses in MUIR [7]. The open-label extension reported stable HbA1c [8], but it had no comparison group.

The biggest question is whether plozasiran lowers heart attacks and strokes in people with moderately raised triglycerides. MUIR measured blood lipids over 48 weeks, and its authors called for an outcomes trial [7]. Until one reports, the drug is a treatment for pancreatitis risk, not for cardiovascular risk.

PALISADE, MUIR, and the extension study were all funded by the manufacturer, Arrowhead Pharmaceuticals [2, 7, 8].

This summary is provided for clinical decision support only and does not replace individualized clinical judgment. Findings are summarized from the cited primary sources; consult those sources before changing practice.

Version History

Version Date Description
1.0.0 2026-09-17 Initial release

References

  1. Syed YY.. Plozasiran: First Approval. Drugs. 2026-03-06. doi:10.1007/s40265-026-02293-2. Available at: https://doi.org/10.1007/s40265-026-02293-2
  2. Watts GF et al. Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk. The New England journal of medicine. 2024-09-02. doi:10.1056/nejmoa2409368. Available at: https://doi.org/10.1056/nejmoa2409368
  3. Loomba R et al. Clinical Trial: Plozasiran Prevents Recurrent Pancreatitis in Adults With Very Severe Hypertriglyceridemia-Results of a Post Hoc Analysis of the Phase 3 PALISADE Study. Alimentary pharmacology & therapeutics. 2026-04-01. doi:10.1111/apt.70623. Available at: https://doi.org/10.1111/apt.70623
  4. CRHCP, SHASTA-3/4: Advances in Dementia and Triglyceride Management. https://www.acc.org/Latest-in-Cardiology/Articles/2026/08/29/08/48/sun-1215pm-prevention-esc-2026.
  5. Study of Plozasiran in Adults With Severe Hypertriglyceridemia at Risk of Acute Pancreatitis. ClinicalTrials.gov. 2026-09-02. https://clinicaltrials.gov/study/NCT06880770.
  6. Gaudet D et al. Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia: The SHASTA-2 Randomized Clinical Trial. JAMA cardiology. 2024-07-01. doi:10.1001/jamacardio.2024.0959. Available at: https://doi.org/10.1001/jamacardio.2024.0959
  7. Ballantyne CM et al. Plozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia. The New England journal of medicine. 2024-05-28. doi:10.1056/nejmoa2404143. Available at: https://doi.org/10.1056/nejmoa2404143
  8. Ballantyne CM et al. Use of plozasiran across a spectrum of hypertriglyceridemia: Long-term efficacy and safety data from the open-label extension period of SHASTA-2 and MUIR Trials. American journal of preventive cardiology. 2026-03-24. doi:10.1016/j.ajpc.2026.101523. Available at: https://doi.org/10.1016/j.ajpc.2026.101523

© 2026 The Sandusky Dyslipidemia Model. For clinical decision support only. Not a substitute for clinical judgment.