Sodium-glucose co-transporter (SGLT) inhibitors originated as simple C-aryl glucosides but have gradually evolved into clinically proven compounds benefiting metabolism, cardiovascular and kidney function. Between 2010 and 2025, substantial progress has been made in their medicinal chemistry, structural diversification, and mechanistic understanding. This review highlights major developments in structure-activity relationships (SAR), scaffold innovation, and structure-guided design that have shaped modern SGLT inhibitors. Early studies focused on establishing a metabolically stable C-aryl glucoside scaffold, revealing that the positioning of proximal and distal aryl groups, linker rigidity, and sugar-binding interactions critically influence activity. Subsequent efforts incorporated heteroaryl systems, fluorinated analogues, carba-sugars, and macrocyclic frameworks improved SGLT2 potency, SGLT2/SGLT1 selectivity, and overall drug-like properties. Further advances introduced N-glucosides, difluoro glycomimetics, l-xylose-based inhibitors, thioglucoside mimics, gut-restricted SGLT1 inhibitors, steroid-derived heterocycles, benzyl-modified C-glucosides, and dual-target designs like SGLT2-glycogen phosphorylase hybrids. More recent work has emphasized next-generation scaffolds, enhanced selectivity, oral bioavailability, multifunctional molecules, and cryo-EM-guided design based on high-resolution structures of SGLT1 and SGLT2-MAP17, clarifying sugar recognition, vestibule interactions, and isoform-specific inhibition. Taken together, these advances provide a coherent view of SGLT inhibitor evolution and offer a framework for designing the next-generation of SGLT-based therapies for diabetes and related cardiometabolic and renal disorders.

01 Oct 2025·PHYTOTHERAPY RESEARCH

Botanical Antinutrients as Natural Modulators of Postprandial Hyperglycemia and Hyperlipidemia: A Narrative Review

Review

Author: Borah, Anuj Kumar ; Nag, Sagnik ; Subramaniyan, Vetriselvan ; Talukdar, Amit ; Chetri, Megha ; Singh, Chongtham Sovachandra ; Das, Amlan ; Chutia, Hemanta

ABSTRACT:

Postprandial elevation in blood monosaccharide and lipid levels is recognized as a significant challenge to systemic homeostasis and physiology, which can be minimized by controlling and monitoring the use of antinutrients. Delve into the investigations made with botanical antinutrients towards modulating intestinal carbohydrate and lipid digestion and subsequent nutrient absorption. A literature search was performed utilizing Google Scholar, PubMed, and Scopus with search strings “antinutrients,” “antinutrients and obesity,” “pancreatic lipase inhibitors and obesity,” “alpha‐glucosidase inhibitors and obesity,” “amylase inhibitors and obesity,” “SGLT1 inhibitors”, “inhibitors of intestinal monosaccharide absorption,” and “inhibitors of intestinal lipid absorption.” Exclusion: (a) microorganism‐originated compounds and (b) botanical compounds demonstrating antihyperlipidemic and antihyperglycemic effects supported only by in silico studies. This literature enlightens documented shreds of evidence of natural plant‐derived antinutrients, the level of investigation, and the proposed mechanism of action. In vitro (enzymatic and cell‐based) and in vivo (obese and diabetic animals) studies have demonstrated that among the numerous botanical antinutrients noted for hyperlipidemia and hyperglycemia, Betulinic acid, Vaticanol A, Vaticanol E, and Berberine are supermolecules that tackle both conditions in animal models. Further, these compounds target the enzyme cyclooxygenase‐2 (COX2), a common culprit in metabolic disorders. The current state of the art sheds light on the potential use of botanical compounds, as monotherapy or in combination therapy, to be projected as a single solution for two problems, that is, hyperglycemia and hyperlipidemia. However, more robust experimentation, dose optimization, in vivo effectiveness, toxicological aspects, clinical safety and efficacy are to be validated.

01 Jun 2024·Advanced biology

Tas1R3 Dependent and Independent Recognition of Sugars in the Urethra and the Role of Tuft Cells in this Process

Article

Author: Bodenbenner‐Tuerich, Martin ; Briand, Loic ; Wiegand, Silke ; Deckmann, Klaus ; Perniss, Alexander ; Schmidt, Patricia

Abstract:

Increased sugar concentrations on mucosal surfaces display risk factors for infections. This study aims to clarify sugar monitoring in the urethra. Urethral tuft cells (UTC) are known sentinels monitoring the urethral lumen for potentially harmful substances and initiating protective mechanisms. Next‐generation sequencing (NGS), RT‐PCR, and immunohistochemistry show expression of the taste receptor Tas1R3 in murine UTC, a crucial component of the classical sweet detection pathway. Isolated UTC respond to various sugars with an increase of intracellular [Ca2+]. The Tas1R3 inhibitor gurmarin and Tas1R3 deletion reduces these responses. Utilizing mice lacking UTC, glibenclamide, a K+‐ATP channel antagonist, and phlorizin, a SGLT1 inhibitor, reveal an additional Tas1R3 independent sweet detection pathway. Inhibition of both pathways abrogates the sugar responses. Rat cystometry shows that intraurethral application of sucrose and glucose increases detrusor muscle activity Tas1R3 dependently. Sugar monitoring in the urethra occurs via two distinct pathways. A Tas1R3 dependent pathway, exclusive to UTC, and a Tas1R3 independent sweet detection pathway, which can be found both in UTC and in other urethral epithelial cells.

News (Medical) associated with SGLT1 inhibitors(China Medical University)

22 Aug 2023

·www.prnewswire.com

Post-bariatric Hypoglycemia in the 7MM: Navigating the Challenges, Opportunities, and Emerging Therapies (2023-2032)

DUBLIN, Aug. 22, 2023 /PRNewswire/ -- The "Post-Bariatric Hypoglycemia Market Insights, Epidemiology and Forecast to 2032" report has been added to ResearchAndMarkets.com's offering. The postbariatric hypoglycemia landscape is marked by both challenges and opportunities. While the US dominates the market, gaps in diagnostic criteria and standardized treatments persist. Emerging therapies like mizagliflozin and AVEXITIDE hold promise in reshaping the treatment paradigm. Future efforts should focus on developing effective treatments tailored to individual needs, considering the variability in patients' responses to current therapies. As the field evolves, innovative solutions are expected to drive significant transformations in the postbariatric hypoglycemia market. Epidemiology and Market Trends In 2022, the United States contributed to about 79% of postbariatric hypoglycemia cases across the 7MM (United States, EU4 countries, and Japan). The US also dominated the market, constituting approximately 89% of the total 7MM market share. Nevertheless, due to the lack of standardized diagnostic criteria, research findings comparison, prevalence rate determination, and uniform treatment approaches remain challenging. The present management landscape involves off-label therapies, which show varying effectiveness. Hence, there's a need for targeted and efficient treatments. Market Dynamics and Players The report delves into the market's future growth potential, encompassing diagnosis rates, disease progression, and treatment guidelines. Furthermore, it comprehensively covers management techniques and emerging therapies, including profiles of late-stage and significant therapies that could reshape the market. Notable players in the postbariatric hypoglycemia treatment arena include Vogenx and Eiger Biopharmaceuticals. The market shares among countries indicate that the US, EU4, the UK, and Japan hold varying sizes, with the US leading significantly. Emerging Therapies The report spotlights two emerging therapies: Mizagliflozin (Vogenx): An orally administered SGLT1 inhibitor, mizagliflozin, targets elevated SGLT1 levels in the gut of postbariatric hypoglycemia patients. This inhibits excessive insulin secretion triggered by elevated blood glucose levels. The drug is in Phase II clinical development. AVEXITIDE (Eiger BioPharmaceuticals): AVEXITIDE is a peptide blocking GLP-1 receptors, curbing dysregulated insulin secretion and reducing fasting and postprandial hypoglycemia. It has earned breakthrough designation for postbariatric hypoglycemia treatment and is progressing towards Phase III trials. Epidemiology and Expert Insights The report offers a comprehensive epidemiological outlook, segregating data by specific bariatric surgery cases, severity-specific PBH cases, and total treated PBH cases. The forecast shows rising cases in the US, EU4, the UK, and Japan. Insights from Key Opinion Leaders (KOLs) and Subject Matter Experts (SMEs) across prestigious institutions worldwide contribute to a robust understanding of the current and emerging treatment patterns. Qualitative Analysis and Market Access Through techniques like SWOT analysis and Conjoint Analysis, the report assesses various facets, such as disease diagnosis, patient awareness, cost-effectiveness, and therapy accessibility. It also addresses market access and reimbursement issues, exploring factors influencing the entry of innovative treatments into the market. Reimbursement plays a pivotal role in determining the adoption of expensive new drugs. Key Topics Covered 1. Key Insights 2. Report Introduction 3. Postbariatric Hypoglycemia (PBH) Market Overview at a Glance 4. Executive Summary of Postbariatric Hypoglycemia 5. Disease Background and Overview 6. Methodology 7. Epidemiology and Patient Population 8. Patient Journey 9. Emerging Therapies 10. Postbariatric Hypoglycemia (PBH): Seven Major Market Analysis 11. KOL Views 12. SWOT Analysis 13. Unmet Needs 14. Market Access and Reimbursement 15. Appendix A selection of companies mentioned in this report includes: Vogenx Eiger BioPharmaceuticals For more information about this report visit About ResearchAndMarkets.com ResearchAndMarkets.com is the world's leading source for international market research reports and market data. We provide you with the latest data on international and regional markets, key industries, the top companies, new products and the latest trends. Media Contact: Research and Markets Laura Wood, Senior Manager [email protected] For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900 U.S. Fax: 646-607-1907 Fax (outside U.S.): +353-1-481-1716 Logo: SOURCE Research and Markets

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus	Preclinical	Taiwan Province	China Medical University (Taiwan)	01 Dec 2015

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