The New England Journal of MedicinePlozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia

Effective Reduction of Triglyceride Levels through APOC3 Inhibition in Mixed Hyperlipidemia

This study examines the safety and efficacy of plozasiran, a small interfering RNA targeting APOC3, in patients with mixed hyperlipidemia. The phase 2b, double-blind, randomized, placebo-controlled trial reveals significant reductions in fasting triglyceride levels among participants receiving various dosages of plozasiran, highlighting its potential as a therapeutic option for managing atherosclerotic cardiovascular disease risk due to elevated non-HDL cholesterol levels.

Study Design:

• Participants: 353 patients with mixed hyperlipidemia (triglyceride level of 150 to 499 mg/dL and either LDL cholesterol level ≥70 mg/dL or non-HDL cholesterol level ≥100 mg/dL).
• Randomization: Participants assigned in a 3:1 ratio to receive plozasiran or placebo within four cohorts.
  • Cohorts 1-3: Received 10 mg, 25 mg, or 50 mg of plozasiran or placebo quarterly.
  • Cohort 4: Received 50 mg of plozasiran or placebo half-yearly.
• Primary Endpoint: Percent change in fasting triglyceride level at week 24.

Key Findings:

• Triglyceride Reduction at Week 24:
  • 10 mg quarterly: -49.8 percentage points (95% CI, -59.0 to -40.6)
  • 25 mg quarterly: -56.0 percentage points (95% CI, -65.1 to -46.8)
  • 50 mg quarterly: -62.4 percentage points (95% CI, -71.5 to -53.2)
  • 50 mg half-yearly: -44.2 percentage points (95% CI, -53.4 to -35.0)
• Glycemic Control Worsening:
  • Placebo: 10%
  • 10 mg quarterly: 12%
  • 25 mg quarterly: 7%
  • 50 mg quarterly: 20%
  • 50 mg half-yearly: 21%

HCN Medical Memo
Plozasiran has demonstrated a significant capacity to reduce triglyceride levels in patients with mixed hyperlipidemia, suggesting it could be an effective therapeutic option. Physicians should consider the potential benefits and monitor glycemic control when prescribing this treatment.

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