ApoC-III Inhibitors Like Olezarsen Dramatically Cut Acute Pancreatitis Risk
- Nov 10
- 3 min read
New data presented at recent scientific sessions confirms a major shift in how clinicians can manage Severe Hypertriglyceridemia (SHTG), a condition defined by plasma triglyceride levels generally above 500 mg/dL and associated with extreme risk of Acute Pancreatitis. Conventional triglyceride-lowering drugs like fibrates and omega-3 fatty acids often have limited efficacy, providing only modest reductions. However, novel nucleic acid therapies targeting apolipoprotein C-III (apoC-III) are providing unprecedented results in reducing triglycerides and protecting patients from life-threatening pancreatitis.
Apolipoprotein C-III (ApoC-III) is identified as a central regulator of triglyceride metabolism that inhibits lipoprotein lipase (LPL) and impairs the clearance of triglyceride-rich lipoproteins (TRLs). Highly effective new treatments are designed to target the APOC3 mRNA, reducing apoC-III protein production. These include antisense oligonucleotides (ASOs) like volanesorsen and olezarsen, and small interfering RNAs (siRNAs) such as plozasiran.
The efficacy of these treatments in reducing pancreatitis risk is now well-documented. The drug olezarsen, a GalNAc-conjugated ASO, was evaluated in the Phase 3 CORE-TIMI 72a and CORE2-TIMI 72b trials involving 1,061 patients with SHTG (triglyceride levels ≥ 500 mg/dL). Researchers found that olezarsen significantly reduced triglyceride levels, achieving a placebo-adjusted reduction of up to 72.2 percentage points in CORE-TIMI 72a. Importantly, more than 85% of patients taking olezarsen saw their triglyceride levels drop below 500 mg/dL, compared with just 35% in the placebo group.
Crucially, olezarsen significantly decreased the incidence of Acute Pancreatitis. The incidence rate in the pooled olezarsen groups was 1.1 per 100 patient years, compared with 6.2 per 100 patient years in the placebo group—translating to an impressive 85% relative risk reduction. These findings underscore olezarsen's potential as a cornerstone therapy for preventing this serious complication.
Similarly, other apoC-III inhibitors demonstrated success. Plozasiran, an siRNA, reduced the incidence of acute pancreatitis in the PALISADE trial, with 2 events in the treatment group compared to 7 events in the placebo group. Furthermore, a meta-analysis pooling data from three volanesorsen trials showed that acute pancreatitis occurred in 2% of the treatment group versus 10% in the placebo group.
Beyond the ApoC-III pathway, other new treatments are emerging. The medication DR10624, which activates FGF21, glucagon, and GLP-1 receptors, was shown in a Phase 2 trial to reduce triglyceride levels by up to 74.5% and liver fat by 63.5% in patients with SHTG.
Finally, new retrospective data offered reassurance regarding another class of widely used metabolic medications: GLP-1 receptor agonists (often referred to as weight loss drugs). Despite initial hesitation from clinicians due to the interaction with the pancreas and the patients' high risk of pancreatitis, a large study found no increased risk of Acute Pancreatitis in SHTG patients taking GLP-1 RAs. Even better, for patients with high triglycerides who had never had pancreatitis, being on a GLP-1RA medication led to a four times lower risk of developing the condition compared to those not taking the drug.
While the evidence is mounting for the effectiveness of ApoC-III inhibition in preventing pancreatitis, its role in reducing atherosclerotic cardiovascular disease (ASCVD) risk remains unproven, awaiting further imaging and outcomes studies. However, the immediate benefit of curbing Acute Pancreatitis risk marks a definitive step forward.
In essence, if managing high triglycerides was like trying to drain a flooded room with a leaky bucket (conventional therapy), the new ApoC-III inhibitors, especially potent agents like Olezarsen, act as a powerful pump, capable of clearing the high floodwaters and preventing the associated disaster of Acute Pancreatitis.
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Keywords: Acute Pancreatitis Risk
Acute Pancreatitis Risk
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