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New Triglyceride-Lowering Drug

Possibly a new option for reducing triglyceride levels and risk of developing insulin resistance….

Elevated triglyceride levels are often associated with insulin resistance, metabolic syndrome, diabetes, cardiovascular events, and pancreatitis. Triglycerides can be elevated due to many factors such as genetics, smoking, obesity, and overconsumption of alcohol and carbohydrates. Normal levels should be less than 150 mg/dl. However, many patients present with much higher levels. Current treatment of hypertriglyceridemia includes niacin, fibrates, and diets high in fish oil, but not all patients respond to treatments.

ISIS 304801 is a new experimental drug in its second of three required trials for approval in the United States. ISIS 304801 is a second-generation antisense inhibitor of apolipoprotein C-III (APOC3) synthesis, which is an important regulator of plasma triglyceride levels that slows the breakdown of triglycerides. The inhibition of APOC3 will speed up the breakdown of triglycerides and allow it to leave the body quickly, resulting in lower triglyceride levels and possibly reducing the risk of developing insulin resistance and metabolic syndrome.

The study was a randomized, double-blinded, placebo-controlled trial, which included a total of 57 patients who were either treated with the drug or a placebo to evaluate ISIS 304801 in untreated patients with fasting triglyceride levels between 350 mg/dl and 2,000 mg/dl. The study also included 28 patients who were treated with stable fibrate therapy that had fasting triglyceride levels between 225 mg/dl and 2,000 mg/dl. Patients received weekly doses for over a course of 13 weeks. The primary outcome was the percentage change in APOC3 from baseline.

ISIS 304801 resulted in a dose-dependent and prolonged decrease in plasma APOC3 levels (decreases of 40.0±32.0% in the 100-mg group, 63.8±22.3% in the 200-mg group, and 79.6±9.3% in the 300-mg group, vs. an increase of 4.2±41.7% in the placebo group). When administered as an add-on to fibrates, there was a 60.2±12.5% decrease in the 200-mg group and 70.9±13.0% decrease in the 300-mg group, vs. a decrease of 2.2±25.2% in the placebo group. Treatment with ISIS 304801 was shown to reduce triglyceride levels 31 to 71 percent without any reported unpleasant side effects.

Practice Pearls:

  • Elevated triglyceride levels are often associated with insulin resistance, metabolic syndrome, diabetes, cardiovascular events, and pancreatitis.
  • ISIS 304801 is a second-generation antisense inhibitor of apolipoprotein C-III (APOC3) synthesis, which slows the breakdown of triglycerides.
  • ISIS 304801 was shown to reduce triglyceride levels 31 to 71 percent without any reported unpleasant side effects.

Gaudet D, Alexander VJ, Baker BF, et al. “Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia.” N Engl J Med. 2015;373(5):438-47.