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 

Plozasiran and Severe Hypertriglyceridemia in SHASTA 3/4, With Christie Ballantyne, MD

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

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/

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

Videos

Christie Ballantyne, MD, unpacks SHASTA-3/4 results on plozasiran for severe hypertriglyceridemia, from triglyceride reduction to pancreatitis prevention.

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

Closing Thoughts on ASCVD Management

In the final episode, 'Closing Thoughts on ASCVD Management,' the panelists explore what meaningful, systemic change would look like in cardiovascular prevention, opening with the observation that early and consistent attention to lifestyle, blood pressure, and cholesterol management could reduce cardiovascular disease mortality by as much as 75%. The discussion identifies several interconnected levers for closing the treatment gap, including the integration of automated risk assessment tools within electronic medical records in primary care settings, structured wellness touchpoints that remove the burden of prevention from overstretched practitioners, and algorithmic treatment pathways that allow clinicians to anticipate the combination therapy intensity needed to reach a patient's LDL goal from the outset rather than waiting through sequential adjustments. One panelist notes that with currently available tools and a streamlined approach, it is theoretically possible to get virtually all patients to their LDL goal within approximately three months using eight clearly defined steps. The panel also reflects on the misalignment between healthcare reimbursement structures and preventive care, with one panelist noting that procedural and diagnostic services continue to be rewarded far more generously than prevention-focused practice, representing a fundamental systemic barrier to implementation.

The episode closes with final thoughts from each panelist, converging on a shared message of urgency and optimism. The panel emphasizes that the tools to achieve guideline-recommended LDL targets already exist, and that the primary remaining challenges are consistent measurement, diligent follow-up, and sustained patient engagement. Panelists stress the importance of establishing a baseline lipid panel before initiating therapy and repeating testing regularly to confirm both efficacy and adherence, proactively inviting patients to share concerns that might otherwise lead to silent discontinuation. The series concludes with a call to action grounded in the principles of personalized medicine, reminding clinicians that assessing individual risk, setting clear LDL targets, combining lifestyle and pharmacotherapy appropriately, and maintaining an ongoing partnership with each patient are the cornerstones of meaningful ASCVD prevention and treatment.

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Experts reveal how risk assessment, LDL-C targets, and smarter follow-up boost adherence—turning guidelines into real cardiovascular prevention.

Navigating Access, Shared Decision-Making, and Long-Term Adherence in ASCVD

In 'Navigating Access, Shared Decision-Making, and Long-Term Adherence in ASCVD,' our experts delve into the practical realities of accessing advanced lipid-lowering therapies in the United States, where insurance coverage for PCSK9 inhibitors varies considerably across commercial plans, Medicaid, and Medicare. The panel distinguishes between Medicare Part B and Part D coverage structures, noting that inclisiran tends to fare better under Part B while monoclonal antibodies such as evolocumab and alirocumab are subject to the more variable Part D formulary landscape, often requiring prior authorization and generating significant administrative burden for clinical practices. One panelist describes training a dedicated staff member to manage insurance denials and appeals, reflecting the reality that securing guideline-directed therapy for high-risk patients frequently demands substantial practice resources. The panel also highlights an emerging third pathway for access, noting that some manufacturers are beginning to offer direct-to-patient programs at reduced prices, with monoclonal antibody costs dropping to approximately half of retail price in some cases, though even these reduced costs remain out of reach for many patients.

The conversation then shifts to shared decision-making as a cornerstone of long-term adherence, with the panel referencing survey data from studies of 5,000 and 10,000 statin-prescribed patients showing that a key predictor of self-reported adherence was whether patients felt genuinely consulted and included in the treatment decision by their prescriber. The panelists acknowledge that time constraints in clinical practice can make thorough shared decision-making difficult, but argue that the investment pays dividends in long-term patient buy-in and persistence with therapy. The episode closes with a candid discussion about the challenge of health misinformation, with the panel encouraging clinicians to proactively acknowledge that much of what patients encounter online about medications is unreliable, and to position themselves as trusted partners in the patient's health journey, emphasizing that the personal connection between prescriber and patient remains one of the most powerful tools available in supporting adherence and achieving lasting ASCVD risk reduction.

Our last episode, 'Closing Thoughts on ASCVD Management,' further explores ASCVD, highlighting the critical steps needed to bridge the persistent gap between guideline-recommended LDL goals and real-world clinical outcomes, with panelists offering forward-looking recommendations spanning healthcare system reform, risk assessment tools, treatment algorithms, patient engagement, and the foundational importance of long-term follow-up and adherence.

Learn how clinicians reach ultra-low LDL targets in high-risk patients using ezetimibe, PCSK9s, and smarter insurance documentation.

Personalizing Therapy Across High-Risk Conditions and Comorbidities in ASCVD

In this episode, 'Personalizing Therapy Across High-Risk Conditions and Comorbidities in ASCVD,' the panelists explore the practical integration of non-statin lipid-lowering therapies for high and very high-risk patients who remain above guideline-recommended LDL targets despite background statin therapy. The discussion opens with the importance of patient education around evolving LDL goals, noting that many patients were previously counseled to targets of less than 100 or less than 70 mg/dL and now need to understand why a more aggressive goal of less than 55 mg/dL, with an optimal range of 30 to 40 mg/dL, is being pursued. The panel emphasizes that since doubling a statin dose yields only an additional 5 to 6% LDL reduction, combination therapy is the necessary strategy for the vast majority of patients requiring further lowering. The conversation addresses the role of ezetimibe as an accessible first add-on, with PCSK9 inhibitors including monoclonal antibodies such as evolocumab and alirocumab, as well as inclisiran, reserved for patients who remain significantly above goal. The panelists also highlight the practical importance of precise clinical documentation, with one noting that clearly stating in the medical record that PCSK9 inhibitor initiation represents guideline-directed therapy is essential to navigating insurance and prior authorization barriers in the United States.

The discussion then turns to how specific comorbidities shape therapy selection, with the panel examining type 2 diabetes, chronic kidney disease, and established cardiovascular disease as conditions that can shift a patient from high to very high risk, thereby lowering the LDL goal and necessitating earlier combination therapy. For patients with type 2 diabetes, the panel notes a preference for directing more of the LDL lowering burden toward PCSK9 inhibitors rather than maximizing statin intensity, in order to avoid worsening glycemic control. The potential of early combination therapy in lipid-lowering naive patients presenting with myocardial infarction is also highlighted, with registry data suggesting superior outcomes compared to a stepwise escalation approach. The episode closes with a discussion of pioglitazone as an underutilized agent in type 2 diabetes that offers particular benefits for stroke prevention and cardiovascular risk reduction alongside its glucose-lowering properties, reinforcing the panel's broader message that comorbidities should be addressed directly with the therapies best suited to each condition while simultaneously pursuing the lowest achievable LDL goal.

The next episode in this series, 'Navigating Access, Shared Decision-Making, and Long-Term Adherence in ASCVD,' features the panelists advancing their conversation on ASCVD and focusing on the complex insurance and prior authorization landscape surrounding PCSK9 inhibitor access in the United States, while examining how shared decision-making, patient education, and strong prescriber-patient relationships drive long-term medication adherence in high-risk patients.

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Christie Ballantyne, MD

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