Andrea Baragetti, Giuseppe Danilo Norata
Incretin-based therapies have gained momentum as a key strategy for reducing cardiovascular risk in individuals with obesity and/or type 2 diabetes (T2D). It remains unclear whether the cardiovascular benefits reflect a direct reduction in atherogenic lipoproteins-namely, low-density lipoproteins (LDL), very low-density lipoproteins (VLDL) and triglycerides-or broader effects mediated by weight loss, improved insulin sensitivity and reduced ectopic adiposity. This review examines these relationships in depth. We summarise molecular, cellular and physiological evidence describing how GLP-1, GIP, glucagon and amylin signalling regulate intestinal lipid absorption, hepatic apolipoprotein B (apoB)-lipoprotein assembly and peripheral lipoprotein catabolism. These mechanistic insights are integrated with the available clinical data on single or dual GIP/GLP-1 agonists and on related compounds that complement the modulation of either glucagon or amylin. Overall, these therapies predominantly reduce triglycerides and VLDL cholesterol, with these changes closely linked to reductions in hepatic ectopic adiposity and parallelled improvements in glycaemic control, insulin sensitivity and body weight. Agents that additionally activate glucagon or amylin pathways consistently produce greater lipid-lowering effects, supporting the concept that lipid benefits scale with global metabolic reprogramming rather than isolated receptor activation. Despite consistent lipid improvements, the short duration of most clinical trials limits assessment of long-term cardiovascular risk reduction. Moreover, the absence of data on apoB precludes definitive conclusions regarding changes in atherogenic lipoprotein burden. Uncertainty also remains regarding the preservation of lean mass during substantial weight loss. This review provides an up-to-date synthesis linking incretin pharmacology to lipid metabolism and identifies priorities for future cardiometabolic research.