Oral GLP-1 Therapeutics Advance for Obesity-Metabolic Syndrome, Facing Delivery Barriers and Emerging Strategies

The cardio-renal-metabolic continuum, encompassing chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and obesity, is driven by interconnected mechanisms like insulin resistance, glomerular hyperfiltration, and chronic inflammation. Current glucose-lowering and antihypertensive treatments leave substantial residual cardiovascular and renal risk, necessitating strategies that target multisystem disease biology. GLP-1 Receptor Agonists (GLP-1 RAs) have emerged as key agents due to their pleiotropic effects beyond glycemic control, including modulation of inflammatory pathways, reduction of oxidative stress, and promotion of satiety.

This comprehensive review analyzes the translational advances, clinical barriers, and emerging strategies for oral GLP-1-based therapeutics within the obesity-metabolic syndrome-diabetes continuum. The authors critically discuss the biological hurdles to oral peptide absorption, such as enzymatic degradation, low epithelial permeability, and pharmacokinetic variability. They also explore enabling technologies like SNAC-based gastric absorption, nanocarriers, and mucoadhesive systems designed to overcome these delivery challenges and improve therapeutic efficacy.

GLP-1 RAs exert pleiotropic effects, including glucose-dependent insulinotropic actions, modulation of inflammatory pathways, reduction of oxidative stress, and improved endothelial nitric oxide bioavailability. These actions contribute to weight reduction, decreased cardiovascular events, and slower renal disease progression. While injectable GLP-1 RAs offer consistent pharmacokinetic exposure, treatment burden and injection aversion limit long-term use. Oral delivery faces significant biological barriers, including enzymatic degradation, low epithelial permeability, and pharmacokinetic variability. Emerging strategies, such as SNAC-based gastric absorption, nanocarriers, and mucoadhesive systems, are being developed to enhance oral bioavailability. > Dedicated kidney studies now show semaglutide slows CKD progression and lowers mortality in diabetics with CKD, underscoring the relevance of new guidelines recommending GLP-1 RA therapy for specific populations. Future priorities include trials of GLP-1 RAs in non-diabetic patients with CKD.