After many failed trials, novel therapeutics may finally tackle high triglycerides
Click Here to Manage Email Alerts
Key takeaways:
- Hypertriglyceridemia is common and associated with atherosclerotic cardiovascular disease risk.
- New agents in the pipeline may soon address the unmet need of therapies for high triglycerides.
BOSTON — After years of failed clinical trials with agents to lower severely elevated triglycerides, emerging therapeutics hold promise for effectively addressing hypertriglyceridemia and reducing associated CV risks, a speaker reported.
Hypertriglyceridemia is common, affects about one-third of the U.S. population and is associated with increased atherosclerotic CVD risk, yet studies show that despite statin therapy, ASCVD rates remain high in patients with elevated triglyceride levels, Michael D. Shapiro, DO, Fred M. Parrish Professor of Cardiology and Molecular Medicine and director of the Center for Prevention and Cardiovascular Disease at Wake Forest University School of Medicine, said during a presentation at the Cardiometabolic Health Congress. Elevated triglycerides are associated with an increase in remnant cholesterol, a decrease in HDL and an increase in LDL; however, large clinical trials with therapies to lower triglycerides and reduce residual risk have been mostly unsuccessful. Shapiro cited a “graveyard full of failed triglyceride-lowering therapies,” including niacin, fibrates and combination eicosapentaenoic acid and docosahexaenoic acid (EPA/DHA).
Image: Adobe Stock
“Despite the well-established link between elevated triglyceride levels and CVD, the numerous clinical trials aimed at lowering triglycerides have largely been unsuccessful,” Shapiro told Healio. “This enigma underscores the complexity of hypertriglyceridemia as a multifactorial condition and challenges the conventional wisdom of a linear relationship between triglyceride reduction and CV risk mitigation. Nevertheless, the unveiling of emerging therapies offers renewed hope and underscores the continued evolution of our understanding in this field.”
Lifestyle management, medication regimens
The American Heart Association and the American College of Cardiology define a normal triglyceride level as less than 150 mg/dL; borderline high as 150 mg/dL to 199 mg/dL; high as 200 mg/dL to 499 mg/dL and very high as 500 mg/dL or more. Clinicians should start by first evaluating patients for a variety of different lifestyle and comorbidity drivers of hypertriglyceridemia, Shapiro said, including poor diet, sedentary lifestyle, obesity, diabetes, chronic kidney disease and hypothyroidism. Only after addressing those underlying issues with lifestyle modifications should therapy be considered, Shapiro said.
Shapiro outlined several strategies to mitigate elevated triglyceride levels:
- In patients with elevated triglycerides at high CV risk despite statin therapy, data from the REDUCE-IT trial show icosapent ethyl (Vascepa, Amarin Pharmaceuticals), a pharmaceutical-grade omega-3 fatty acid containing EPA but not DHA, was superior to placebo for reducing risk for ischemic events. Shapiro said there has been ongoing controversy about the study findings due to the use of a mineral oil placebo, which a biomarker analysis demonstrated increased inflammatory, lipid and lipoprotein biomarkers among those who received it. “The question is, is there really benefit with icosapent ethyl, or is there detriment with the mineral oil placebo, or is it somewhere in between?” Shapiro said during the presentation. “Unfortunately, we do not know.”
- Olezarsen (Ionis) is an investigational ligand-conjugated antisense drug developed to inhibit the production of apolipoprotein C-III in patients with elevated triglyceride levels, including those with familial chylomicronemia syndrome (FCS). Data show olezarsen significantly reduced ApoC-III, triglycerides and atherogenic lipoproteins in patients with moderate hypertriglyceridemia and at high risk for or with established CVD. In February, FDA granted fast track designation for olezarsen in the treatment of FCS.
- Research in human genetics has shown the APOC3 and ANGPTL3 genes inhibit the lipoprotein lipase pathway and now several agents are in development, Shapiro said. Two novel RNA interference agents, one targeting ApoC-III and one targeting angiopoietin-like protein 3, improved various lipid parameters in early studies with healthy volunteers, Shapiro said. One agent targeting ApoC-III (ARO-APOC3, Arrowhead) was associated with reductions in serum APOC3 and improvements in other lipids, whereas another agent targeting ANGPTL3 (ARO-ANG3, Arrowhead) was associated with reductions in ANGPTL3 and improvements in other lipids.
More research needed
Shapiro said a deeper exploration into the genetic predispositions and molecular mechanisms underlying elevated triglyceride levels is essential.
“There is a pressing need to unravel the complexities of the interaction between triglycerides and other CV risk factors,” Shapiro told Healio. “On the clinical front, developing novel, effective and safe triglyceride-lowering therapies is a priority. This includes rigorous clinical trials to evaluate the efficacy and safety profiles of emerging drugs, as well as exploring innovative treatment modalities that go beyond traditional pharmacological approaches.”
References:
- Bhatt DL, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1812792.
- Clifton P, et al. Circulation. 2021;doi:10.1161/circ.144.suppl_1.10357.
- Tardif JC, et al. Eur Heart J. 2022;doi:10.1093/eurheartj/ehab820.
- Virani S, et al. J Am Coll Cardiol. 2021;doi:10.1016/j.jacc.2021.06.011.
Collapse
Shapiro MD. Hypertriglyceridemia: Trials, tribulations and transition to clinical practice. Presented at: Cardiometabolic Health Congress; Oct. 18-21, 2023; Boston.
Click Here to Manage Email Alerts