Current and Emerging Therapies for Atherosclerotic Cardiovascular Disease Risk Reduction in Hypertriglyceridemia

Abstract

Hypertriglyceridemia (HTG) is a prevalent medical condition in patients with cardiometabolic risk factors and is associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), if left undiagnosed and undertreated. Current guidelines identify HTG as a risk-enhancing factor and, as a result, recommend clinical evaluation and lifestyle-based interventions to address potential secondary causes of elevated triglyceride (TG) levels. For individuals with mild to moderate HTG at risk of ASCVD, statin therapy alone or in combination with other lipid-lowering medications known to decrease ASCVD risk are guideline-endorsed. In addition to lifestyle modifications, patients with severe HTG at risk of acute pancreatitis may benefit from fibrates, mixed formulation omega-3 fatty acids, and niacin; however, evidence does not support their use for ASCVD risk reduction in the contemporary statin era. Novel therapeutics including those that target apoC-III and ANGPTL3 have shown to be safe, well-tolerated, and effective for lowering TG levels. Given the growing burden of cardiometabolic disease and risk factors, public health and health policy strategies are urgently needed to enhance access to effective pharmacotherapies, affordable and nutritious food options, and timely health care services.

Keywords: fibrates; lipids; lipoproteins; niacin; omega-3 fatty acids; statins; triglycerides.

Figure 1

Transport and metabolism of triglyceride-rich lipoproteins. TRL synthesis occurs in both the intestine and the liver. In the intestine, dietary lipids are packaged into chylomicrons (apoB48), and in the liver cholesterol and triglycerides, they are packaged into VLDL (apoB100). Lipoprotein lipase (LPL) releases the TG from TRL by catalyzing the hydrolysis of TG to free fatty acids (FFA). FFA cross the endothelium for oxidation or storage in the underlying tissue. Successive rounds of this process yield denser, triglyceride depleted particles. These particles are taken up by specialized receptors on the surface on hepatocytes, allowing the recycling of their lipid and protein contents. Inset: Several factors inhibit LPL activity, including APOC3 and ANGPTL3, which are novel targets for TG-lowering therapy. Insulin resistance (IR) likewise reduces LPL activity through pleiotropic mechanisms. Genetic variants in LPL or other factors required for its synthesis and functioning also modulate LPL activity. Created with biorender.com (accessed on 26 December 2022). Abbreviations: CM, chylomicron; FFA, free fatty acids; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; LDL, lipoprotein lipase; TG, triglyceride; TRL, triglyceride-rich lipoprotein; VLDL, very low-density lipoprotein.

Figure 2

Schematic representation of the proximal and distal factors related to the association between environmental, lifestyle, and social factors contributing to disparities in clinical risk factors and outcomes. Abbreviations: HTG, hypertriglyceridemia; SSB, sugar-sweetened beverages. * Niacin is not recommended for the clinical management of atherosclerotic cardiovascular disease.

Figure 3

Brief timeline and summary of key clinical trials focused on triglyceride lowering with statins and non-statin therapies (e.g., niacin, fibrates, and omega-3 fatty acids). Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CHD, coronary heart disease; CV, cardiovascular; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MACE, major adverse cardiovascular events; PUFA, poly-unsaturated fatty acids; RC, remnant cholesterol; T2D, type 2 diabetes; TG, triglycerides; VLDL-C, very low-density lipoprotein cholesterol.