Designing GLP-1 delivery: structural perspectives and formulation approaches for optimized therapy

Nutrition & Diabetes REVIEW ARTICLE www.nature.com/nutd OPEN Designing GLP-1 delivery: structural perspectives and formulation approaches for optimized therapy Ravi Vamsi Peri 1,2 ✉ , Harsh Anchan 1,2 , Kamal Jonnalagadda1, Ryan Varghese 1 and Pardeep Gupta1 ✉ 1234567890();,: © The Author(s) 2025 GLP-1 and its synthetic analogs have emerged as significant therapeutic agents for the management of metabolic disorders, merging glycemic control with weight loss through innovative structural and delivery breakthroughs. This review provides a meticulous exploration of GLP-1, elucidating its origin, secretion, and the challenges associated with its clinical application due to its fragility in the presence of DPP-IV, resulting in a short half-life. To overcome this limitation, various modifications and delivery strategies to enhance the pharmacokinetic properties and therapeutic efficacy of GLP-1 analogs have been studied. The review delves into the intricacies of different modification approaches, including N and C-terminal modifications, Fatty acid Side chain Modifications, and Large Molecule Conjugation Modifications, highlighting their rationale and resulting improvements in half-life, stability, receptor binding, and bioactivity. Additionally, the importance of optimized delivery strategies to ensure sustained and controlled release of GLP-1 analogs is discussed. The culmination of these scientific advancements provides valuable insights for the development of more effective treatments for metabolic disorders, ultimately paving the way for improved patient outcomes in the realm of metabolic health. Nutrition and Diabetes (2025)15:53 ; https://doi.org/10.1038/s41387-025-00397-4 INTRODUCTION Diabetes is a chronic metabolic disorder involving hyperglycemia and is characterized by defects in insulin secretion, insulin action, or both. If undiagnosed, diabetes can cause cardiovascular diseases, neuropathy (nerve damage), nephropathy (kidney damage), retinopathy (eye disorders), and even lower-limb amputation [1]. Diabetes has reached epidemic proportions globally, with an estimated 537 million adults affected in 2021. In the United States, the Centers for Disease Control and Prevention (CDC) reports that over 38.4 million individuals, approximately 11.6% of the population, are currently living with diabetes [2]. There are two types of diabetes: type 1 and type 2. Type 1 is an autoimmune disease in which insulin-producing β-cells are attacked by the host’s immune system, and is thought to be caused by a combination of viral infection, an environmental trigger, or gene malfunction [3, 4]. Type 1 diabetes mellitus (T1DM) patients typically need insulin injections for survival. Moreover, individuals with diabetes require continuous monitoring to prevent acute complications such as hypoglycemia and diabetic ketoacidosis. Type 2 diabetes mellitus (T2DM) is the predominant form, accounting for over 90% of all diabetes cases globally. It is characterized by insulin resistance, wherein peripheral tissues exhibit a diminished response to insulin, eventually resulting in impaired insulin utilization and relative insulin deficiency [3]. The current therapeutic paradigm for diabetes management entails a comprehensive, multi-modal strategy encompassing both lifestyle and pharmacological interventions. Foundational components include structured dietary modifications, regular physical activity, and weight management. Pharmacological treatment typically begins with non-insulin antihyperglycemic agents, either as monotherapy or in combination. These agents include thiazolidinediones (PPAR-γ agonists), dipeptidyl peptidase-4 (DPP-4) inhibitors, sulfonylureas, sodium-glucose cotransporter 2 (SGLT2) inhibitors, α-glucosidase inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists. Insulin therapy, delivered via subcutaneous (SC) injections or continuous subcutaneous insulin infusion (CSII) systems, remains indispensable, particularly in individuals with T1DM and those with progressive or inadequately controlled T2DM. GLP-1 and its analogs have emerged as significant therapeutic agents for managing metabolic disorders. GLP-1 is an endogenous incretin hormone produced by pancreatic L-cells through the proteolytic breakdown of the preproglucagon molecule. This breakdown generates two forms of GLP-1; a biologically active form GLP-1-(7–36) amide and an inactive form GLP-1-(1-37). The inactive form is considered a “precursor” as it gets converted into an active peptide GLP-1 (7-37) by cleaving a single arginine residue (Fig. 1) [5, 6]. Due to its insulinotropic action (stimulates insulin secretion), GLP-1-based treatments effectively prevent postprandial hyperglycemia (post-meal glucose spikes) in patients with T2DM. Additionally, its ability to suppress appetite contributes to weight loss and therefore offers synergistic benefits for managing T2DM. However, despite these advantages, the clinical use of native GLP-1 is significantly limited by its short plasma half-life (1–2 min), 1 Department of Pharmaceutical Sciences, Philadelphia College of Pharmacy, Saint Joseph’s University, Philadelphia, PA, USA. 2These authors contributed equally: Ravi Vamsi Peri, Harsh Anchan. ✉email: ; Received: 13 May 2025 Revised: 22 September 2025 Accepted: 29 September 2025 R.V. Peri et al. 2 Fig. 1 Origin of GLP-1, obtained from Li et al. 2021 [126], under the Creative Commons Attribution License (CC BY) License. A figure illustrating the intricate relationship between the synthesis, processing, and tissue-specific physiological handling of glucagon precursors. The preproglucagon gene encodes proglucagon, which undergoes tissue-dependent post-translational processing. In the intestinal and neural tissues, prohormone convertase PCSK1/3 mediates the cleavage of proglucagon, producing glicentin-related pancreatic polypeptide (GRPP), oxyntomodulin (OXM), glucagon-like peptide-1 (GLP-1), intervening peptide-2 (IP-2), and glucagon-like peptide-2 (GLP-2). Conversely, in pancreatic islet α-cells, PCSK2 serves as the primary processing enzyme, generating glucagon, GRPP, intervening peptide-1 (IP-1), and a distinct proglucagon fragment. owing to rapid enzymatic degradation by DPP-4 and renal clearance. These challenges necessitate frequent dosing or the use of modified analogs and innovative delivery systems to sustain therapeutic concentrations. The therapeutic potential of GLP-1 and its analogs extends beyond glycemic control and obesity management. Emerging evidence suggests their neuroprotective effects in neurodegenerative disorders, particularly Alzheimer’s disease, as well as potential anti-tumor properties in various malignancies [7]. SCOPE This review explores GLP-1 receptor agonists as an emerging therapeutic trend in the management of diabetes. Despite their significant clinical potential, they are associated with certain limitations, including suboptimal pharmacokinetics and patient adherence challeng (...truncated)