Target Populations for Novel Triglyceride-Lowering Therapies

Area of Science:

• Biochemistry
• Pharmacology
• Cardiovascular Medicine

Background:

• Lipoprotein lipase (LPL) is crucial for triglyceride hydrolysis and remnant lipoprotein clearance.
• Dysregulation of LPL activity is implicated in hypertriglyceridemia, acute pancreatitis, cardiovascular disease, and metabolic dysfunction-associated steatohepatitis (MASH).
• Novel therapeutic strategies aim to enhance LPL activity to mitigate these conditions.

Purpose of the Study:

• To review emerging drug classes that increase LPL activity for treating dyslipidemias.
• To examine the evidence supporting apolipoprotein C-III (APOCIII) and angiopoietin-like protein (ANGPTL) 3, 3/8, and 4 inhibitors.
• To discuss fibroblast growth factor-21 (FGF21) analogues as a related therapeutic approach.

Main Methods:

• Review of clinical trials and epidemiological/genetic studies on triglyceride- and remnant cholesterol-lowering agents.
• Analysis of drug development pipelines targeting APOCIII and ANGPTLs.
• Evaluation of FGF21 analogues for metabolic and cardiovascular indications.

Main Results:

• APOCIII inhibitors are approved for reducing acute pancreatitis risk in severe hypertriglyceridemia.
• ANGPTL inhibitors demonstrate significant triglyceride and remnant cholesterol reduction.
• FGF21 analogues show efficacy in reducing hepatic steatosis and fibrosis in MASH patients.

Conclusions:

• APOCIII inhibitors and ANGPTL inhibitors offer potent triglyceride- and remnant cholesterol-lowering effects.
• These novel agents are valuable for managing severe hypertriglyceridemia and MASH.
• Further research is needed to confirm their role in preventing atherosclerotic cardiovascular disease.