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SGLT2 Inhibitors and GLP/GIP/Glucagon Agonists: From Fundamental Mechanisms to Clinical Translation

A Special Issue of International Journal of Molecular Sciences (ISSN 1422-0067) belonging to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: 31 March 2027 | Viewed by 5427

Editor

Dr. Cosmin Mihai Vesa

E-Mail Website
Guest Editor
Preclinical Department, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
Interests: diabetes mellitus; obesity; nutrion; metabolic syndrome
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Rationale and Significance

Sodium–glucose cotransporter 2 (SGLT2) inhibitors and incretin-based multi-agonists targeting GLP-1, GIP and glucagon receptors have reshaped the therapeutic landscape of metabolic diseases. Initially developed as glucose-lowering agents, these drug classes have demonstrated broad benefits extending to cardiovascular, renal, hepatic and adipose tissue health, with implications for heart failure, chronic kidney disease, obesity and metabolic-dysfunction-associated steatotic liver disease (MASLD).

Despite remarkable clinical success, critical questions remain regarding their fundamental mechanisms of action, tissue-specific signaling pathways, long-term adaptations and pleiotropic effects beyond glycemic control. Parallel advances in medicinal chemistry, structural biology, systems metabolism and translational physiology now provide unprecedented opportunities to integrate mechanistic insights with clinical outcomes.

This Special Issue aims to bridge fundamental research and clinical investigation, providing a comprehensive and interdisciplinary forum to examine how SGLT2 inhibitors and GLP/GIP/glucagon receptor agonists work—from molecular and cellular mechanisms to human physiology and real-world clinical impacts.

Aims and Objectives

The objectives of this Special Issue are to

  1. Elucidate molecular, cellular and organ-level mechanisms underlying the actions of SGLT2 inhibitors and incretin-based multi-agonists;
  2. Integrate preclinical discoveries with clinical trial data and real-world evidence;
  3. Highlight emerging therapeutic indications and novel combination strategies;
  4. Identify unmet needs, controversies and future research directions in metabolic, cardiovascular and renal medicine.

Scope and Topics

We invite original research articles, reviews, mini-reviews and perspectives covering, but not limited to, the following topics:

Fundamental and Preclinical Research

  • Molecular mechanisms of SGLT2 inhibition in the kidney, heart, adipose tissue, liver and brain
  • Incretin receptor signaling, biased agonism and receptor crosstalk (GLP-1, GIP, glucagon)
  • Metabolic flexibility, mitochondrial function and energy expenditure
  • Role of glucagon signaling in obesity, diabetes and fatty liver disease
  • Inflammation, oxidative stress, autophagy and cellular stress responses
  • Systems biology, omics and integrative metabolic modeling
  • Sex differences and genetic determinants of drug response
  • Cardiovascular and renal protection: Mechanisms and clinical implications
  • Effects on heart failure phenotypes (HFrEF, HFpEF)
  • Chronic kidney disease progression and renal hemodynamics
  • Obesity, body composition and appetite regulation
  • MASLD/NASH and metabolic liver disease
  • Safety profiles, adverse effects and long-term outcomes
  • Biomarkers of response and precision medicine approaches
  • Dual and triple agonists: GLP-1/GIP, GLP-1/glucagon and GLP-1/GIP/glucagon
  • Combination therapies (e.g., SGLT2 inhibitors plus incretin agonists)
  • Novel drug delivery systems and next-generation molecules
  • Clinical trial design, endpoints and regulatory considerations
  • Real-world evidence and health economics

Dr. Cosmin Mihai Vesa
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • SGLT2 inhibitors
  • GLP-1 receptor agonists
  • GIP
  • glucagon
  • multi-agonists
  • cardiometabolic disease
  • renal protection
  • obesity
  • translational research

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Further information on MDPI's Special Issue policies can be found here.

Published Papers (3 papers)

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Research

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27 pages, 1112 KB  
Article
Disproportionality Analysis of Tirzepatide vs. Semaglutide and Liraglutide: System Organ Class-Level Post-Marketing Reporting Patterns in EudraVigilance
by Ruxandra Cristina Marin, Cosmin Mihai Vesa, Delia Mirela Tit, Andrei-Flavius Radu and Gabriela S. Bungau
Int. J. Mol. Sci. 2026, 27(7), 2988; https://doi.org/10.3390/ijms27072988 - 25 Mar 2026
Viewed by 1729
Abstract
Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, introduces a mechanistically distinct approach within incretin-based therapies. While its efficacy is established, real-world data comparing post-marketing safety with established GLP-1 receptor agonists remain limited. This study assessed System [...] Read more.
Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, introduces a mechanistically distinct approach within incretin-based therapies. While its efficacy is established, real-world data comparing post-marketing safety with established GLP-1 receptor agonists remain limited. This study assessed System Organ Class (SOC)-level reporting patterns for tirzepatide versus semaglutide and liraglutide using EudraVigilance data. Aggregated individual case safety reports (ICSRs) were analyzed using pairwise disproportionality analyses based on a case/non-case approach. Reporting odds ratios (RORs) with 95% confidence intervals were calculated. False discovery rate (FDR) correction using the Benjamini–Hochberg procedure and sensitivity analyses restricted to serious and healthcare professional–reported cases were performed to assess robustness. After FDR adjustment, 20 SOCs were significant in tirzepatide–semaglutide and 23 in tirzepatide–liraglutide comparisons; eight SOCs remained significant across all analytical conditions. Compared with semaglutide, tirzepatide showed higher reporting for immune (ROR 1.97, 95% CI 1.75–2.21) and hepatobiliary disorders (ROR 1.71, 95% CI 1.61–1.82). Versus liraglutide, higher odds occurred for musculoskeletal (ROR 2.02, 95% CI 1.85–2.21) and psychiatric disorders (ROR 2.14, 95% CI 1.99–2.30), and lower odds for neoplasms (ROR 0.28, 95% CI 0.26–0.31). Tirzepatide shows heterogeneous reporting patterns compared with GLP-1 receptor agonists, with consistent excess reporting for hepatobiliary, immune, and musculoskeletal disorders. These findings are hypothesis-generating and warrant confirmation in exposure-adjusted studies. Full article
(This article belongs to the Special Issue SGLT2 Inhibitors and GLP/GIP/Glucagon Agonists: From Fundamental Mechanisms to Clinical Translation)
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14 pages, 2858 KB  
Article
SOCS1 Mimetic Peptide Enhances Empagliflozin Improvement on Kidney Damage in the Type 2 Diabetes Mouse Model BTBR ob/ob
by Marcelo Aguilar-Cartes, Lucas Opazo-Ríos, Alejandra Droguett, Sebastian Mas-Fontao, Juan Antonio Moreno, Carmen Gómez-Guerrero, Jesús Egido and Sergio Mezzano
Int. J. Mol. Sci. 2026, 27(5), 2466; https://doi.org/10.3390/ijms27052466 - 8 Mar 2026
Cited by 1 | Viewed by 1094
Abstract
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. During the last few years, remarkable advances have been made in the treatment of DN. Sodium–glucose cotransporter type 2 inhibitors (SGLT2i) consistently prevent or delay albuminuria and renal failure in patients [...] Read more.
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. During the last few years, remarkable advances have been made in the treatment of DN. Sodium–glucose cotransporter type 2 inhibitors (SGLT2i) consistently prevent or delay albuminuria and renal failure in patients with DN. Prior research from our group highlights the Janus kinase/signal transducers and activators of transcription axis as a critical target in DN. Specifically, the administration of suppression of cytokine signaling 1 (SOCS1) mimetic peptides (MiS1) modulates aberrant signaling, resulting in profound beneficial effects on renal function and structural integrity in experimental DN. The aim of this study was to evaluate the effect of empagliflozin and MiS1 on kidney damage and its associated inflammatory, oxidative stress and lipotoxic mechanisms in an advanced type 2 DN mouse model BTBR ob/ob. Mice were treated for 7 weeks with empagliflozin and MiS1, alone or in combination, and monitored for glycemia, body weight, albuminuria, histopathological damage, podocyte loss, and gene expression related to inflammation, redox balance, and lipid metabolism. Empagliflozin or MiS1 monotherapies significantly reduced albuminuria and structural renal injury, preserved podocyte number, and downregulated genes involved in inflammatory, oxidative, and mitochondrial–lipid metabolic dysregulation, with empagliflozin additionally improving metabolic parameters. Notably, the combined therapy achieved the greatest reduction in albuminuria and histological damage with enhanced suppression of pathogenic inflammatory and metabolic pathways, resulting in superior renoprotection compared with monotherapy. These findings suggested that add-on therapy with SOCS1 peptidomimetics and SGLT2i may help mitigate residual albuminuria and renal damage in type 2 DN. Full article
(This article belongs to the Special Issue SGLT2 Inhibitors and GLP/GIP/Glucagon Agonists: From Fundamental Mechanisms to Clinical Translation)
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Review

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27 pages, 4450 KB  
Review
Molecular Mechanisms and Clinical Evidence Supporting the Four Pillars of Therapy in Diabetic Kidney Disease: Emerging Therapeutic Perspectives
by Hidekatsu Yanai, Hiroki Adachi, Mariko Hakoshima and Hisayuki Katsuyama
Int. J. Mol. Sci. 2026, 27(6), 2757; https://doi.org/10.3390/ijms27062757 - 18 Mar 2026
Cited by 1 | Viewed by 1941
Abstract
Diabetic kidney disease (DKD) is one of the most serious complications of diabetes and the leading cause of end-stage renal disease worldwide. Recently, renin-angiotensin system inhibitors, non-steroidal mineralocorticoid receptor antagonists, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists were proposed as the [...] Read more.
Diabetic kidney disease (DKD) is one of the most serious complications of diabetes and the leading cause of end-stage renal disease worldwide. Recently, renin-angiotensin system inhibitors, non-steroidal mineralocorticoid receptor antagonists, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists were proposed as the four pillars for treating DKD. To understand the molecular mechanisms by which these drugs improve DKD, we described the histological and molecular changes due to diabetes. Based on our understanding of the molecular changes in DKD, we present evidence on the efficacy of these drugs in improving DKD and discuss why such drugs improve the prognosis of DKD. In addition to diabetes and hypertension, insulin resistance, dyslipidemia and hyperuricemia are risk factors for DKD. Metformin, fibrates, and febuxostat have been reported to improve DKD; however, caution is required when administering these drugs to patients with renal impairment due to concerns about the onset of lactic acidosis, rhabdomyolysis, and deterioration of renal function, respectively. Imeglimin, pemafibrate, and dotinurad have similar chemical structures or effects to metformin, fibrates, and febuxostat, respectively, but are safer in patients with renal impairment. Furthermore, they have specific mechanisms to improve DKD and may offer new options for its treatment. This article is a narrative review. Regarding emerging therapies for DKD, no high-evidence-level research has yet been published, and further progress in this area is warranted. Full article
(This article belongs to the Special Issue SGLT2 Inhibitors and GLP/GIP/Glucagon Agonists: From Fundamental Mechanisms to Clinical Translation)
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