Pharmacometabolomics for the Study of Lipid-Lowering Therapies: Opportunities and Challenges

Abstract

Lipid-lowering therapies are widely used to prevent the development of atherosclerotic cardiovascular disease (ASCVD) and related mortality worldwide. "Omics" technologies have been successfully applied in recent decades to investigate the mechanisms of action of these drugs, their pleiotropic effects, and their side effects, aiming to identify novel targets for future personalized medicine with an improvement of the efficacy and safety associated with the treatment. Pharmacometabolomics is a branch of metabolomics that is focused on the study of drug effects on metabolic pathways that are implicated in the variation of response to the treatment considering also the influences from a specific disease, environment, and concomitant pharmacological therapies. In this review, we summarized the most significant metabolomic studies on the effects of lipid-lowering therapies, including the most commonly used statins and fibrates to novel drugs or nutraceutical approaches. The integration of pharmacometabolomics data with the information obtained from the other "omics" approaches could help in the comprehension of the biological mechanisms underlying the use of lipid-lowering drugs in view of defining a precision medicine to improve the efficacy and reduce the side effects associated with the treatment.

Keywords: atherosclerotic cardiovascular disease; lipid-lowering drugs; metabolomics; statins.

Figure 1

Schematic workflow of metabolomic studies. Several steps are involved from experimental design and biological sample preparation to data analysis, processing, and interpretation. Nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) are the main analytical technologies used in metabolomics research. GC-MS, gas chromatography-MS; LC-MS, liquid chromatography-MS.

Figure 2

Sites and targets of lipid-lowering therapies. Diagram of the mechanisms of action of the principal lipid-lowering drugs including those drug classes that have not yet been the object of pharmacometabolomic studies. Drug classes analyzed in metabolomic studies are highlighted by yellow boxes. Statins reduce cholesterol synthesis through 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibition. Fibrates are peroxisome proliferator-activated receptor alpha (PPARα) activators, able to increase Lipoprotein lipase activity and globally reduce triglycerides (TG) levels. Reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9), responsible for the degradation of low-density lipoprotein receptor (LDLR), can be achieved with monoclonal antibodies or Inclisiran, a siRNA specific for PCSK9 that prevents translation of PCSK9 messenger RNA. Other drug classes without pharmacometabolomic studies are reported in green boxes. Bempedoic acid is a potent inhibitor of adenosine triphosphate (ATP) citrate lyase (ACL), a cellular enzyme responsible for the production of precursors for fatty acid and cholesterol synthesis. Lomitapide is an inhibitor of microsomal triglyceride transfer protein (MTP), an enzyme responsible for the synthesis of very low-density lipoproteins in the liver and chylomicrons in the intestine. Anionic exchange resins are bile acids sequestrants. The depletion of the bile acid pool stimulates the conversion of cholesterol to bile acid, reducing intracellular cholesterol in hepatocytes. Ezetimibe selectively inhibits intestinal cholesterol absorption, inhibiting the cholesterol transport protein Nieman Pick C1-like 1 protein (NPC1L1) in the intestine. ApoB100, apolipoprotein B100; LDL, low-density lipoprotein; LDL-r, LDL receptor; mab, monoclonal antibody; CoA, coenzyme A.