Incretin-based therapies: Effects on plasma lipids and potential mechanisms

Incretin-based therapies have transformed the treatment of type-2 diabetes and obesity, yet their effects on lipid and lipoprotein metabolism are less appreciated than their glycemic and weight-related actions. This review examines evidence for the effects of glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, and dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonists on plasma lipids, with emphasis on triglyceride-rich lipoprotein metabolism in fasting and postprandial states. Across clinical studies, the most reproducible lipid-related effect is attenuation of postprandial lipemia, including reductions in triglycerides and apolipoprotein B48-containing lipoprotein (i.e., intestinally derived lipoprotein) measures, whereas effects on fasting lipid panels are generally less impressive and more heterogeneous across agents and populations. Acute studies reflect rapid effects on gastric emptying, intestinal lipid handling, and triglyceride-rich lipoprotein excursions, whereas chronic studies additionally incorporate the downstream influence of weight loss and improved glycemic control in those with diabetes. Human kinetic and stable isotope enrichment studies provide mechanistic insights that support contributions from both reduced intestinal lipoprotein particle output and enhanced clearance, with additional evidence for changes in hepatic apolipoprotein B100-containing lipoprotein metabolism. Complementary preclinical and biomarker data implicate adipose clearance pathways, the apolipoprotein C-III/lipoprotein lipase axis, neurohumoral regulation, and intestinal lymphatic transport as additional modulators. Taken together, the lipid effects of incretin-based therapies are directionally consistent with antiatherosclerotic benefit, but current evidence does not permit a clear estimate of how much they contribute to the established cardiovascular protection of glucagon-like peptide-1 receptor agonists.