Cited by 377Diabetes Treatment and ManagementIon Transport and Channel RegulationMetabolism, Diabetes, and Cancer

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Development of SGLT1 and SGLT2 inhibitors

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Rieg, Timo, Vallon, Volker·2018·Diabetologia

DOI 10.1007/s00125-018-4654-7PMC PMC6124499

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Abstract

Sodium-glucose cotransporters SGLT1 (encoded by SGLT1, also known as SLC5A1) and SGLT2 (encoded by SGLT2, also known as SLC5A2) are important mediators of epithelial glucose transport. While SGLT1 accounts for most of the dietary glucose uptake in the intestine, SGLT2 is responsible for the majority of glucose reuptake in the tubular system of the kidney, with SGLT1 reabsorbing the remainder of the filtered glucose. As a consequence, mutations in the SLC5A1 gene cause glucose/galactose malabsorption, whereas mutations in SLC5A2 are associated with glucosuria. Since the cloning of SGLT1 more than 30 years ago, big strides have been made in our understanding of these transporters and their suitability as drug targets. Phlorizin, a naturally occurring competitive inhibitor of SGLT1 and SGLT2, provided the first insights into potential efficacy, but its use was hampered by intestinal side effects and a short half-life. Nevertheless, it was a starting point for the development of specific inhibitors of SGLT1 and SGLT2, as well as dual SGLT1/2 inhibitors. Since the approval of the first SGLT2 inhibitor in 2013 by the US Food and Drug Administration, SGLT2 inhibitors have become a new mainstay in the treatment of type 2 diabetes mellitus. They also have beneficial effects on the cardiovascular system (including heart failure) and the kidney. This review focuses on the rationale for the development of individual SGLT2 and SGLT1 inhibitors, as well as dual SGLT1/2 inhibition, including, but not limited to, aspects of genetics, genetically modified mouse models, mathematical modelling and general considerations of drug discovery in the field of metabolism.

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Background
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BackgroundInfluential
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“demonstrated clinical efficacy to non-diabetic populations [15,16].”
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“With the increasing number of diabetic patients worldwide [21,22], they are gaining attention as new therapeutic agents [23,24].”
Background
Cardiometabolic risk reductions in patients with type 2 diabetes mellitus newly treated with a sodium–glucose cotransporter 2 inhibitor versus a dipeptidyl peptidase‐4 inhibitor: A real‐world administrative database study in Japan
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“inhibitors became commercially available or are in the final phase of development [2].”
Background
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Background
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“SGLT2 inhibitors can inhibit proximal renal tubular sodium and glucose reabsorption to increase the urinary excretion of glucose, thereby reducing blood sugar [13].”
Background
Tolerability, Pharmacokinetic, and Pharmacodynamic Profiles of Henagliflozin, a Novel Selective Inhibitor of Sodium-Glucose Cotransporter 2, in Healthy Subjects following Single- and Multiple-dose Administration.
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“Glucose transporters GLUT-1 and GLUT-2 located on the basolateral membrane transport glucose from tubular cells into the circulation [19,91].”
Influential
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“…ﬂ ozin, and empagli ﬂ ozin were reported to have risks of DKA, UTI, and genital tract infections (Vasilakou et al., 2013; Rosenstock and Ferrannini, 2015; Rieg and Vallon, 2018), however, this study found that there was no signi ﬁ cant risk of DKA or UTI among all the included interventions.”
Result
d-allulose reduces postprandial glucose absorption in small intestine by competitive binding to glucose transport sites
Chen, K., Zhang, H., Jiang, B., Chen, J., & Zhang, T. (2023) · Food Bioscience · doi:10.1016/j.fbio.2023.103305 · Cited by 11
Saponins from Camellia sinensis Seeds Stimulate GIP Secretion in Mice and STC-1 Cells via SGLT1 and TGR5
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“Phlorizin, a dihydrochalcone from the bark of pears, apples, cherries and other fruits, is a known inhibitor of SGLT1 [17].”
Background
Renoprotective effects of empagliflozin in type 1 and type 2 models of diabetic nephropathy superimposed with hypertension
Williams, J. M., Murphy, S., Wu, W., Border, J. J., Fan, F., & Roman, R. J. (2022) · GeroScience · doi:10.1007/s11357-022-00610-7 · Cited by 16
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Canagliflozin attenuates post-resuscitation myocardial dysfunction in diabetic rats by inhibiting autophagy through the PI3K/Akt/mTOR pathway
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“34,35 The administration of canagliﬂozin offers some protection against diabetic myocardial I/RI, however, the exact mechanisms underlying its protective effects remain incompletely understood.”
Background
Unfavorable effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on the skeletal system of nondiabetic rats.
Londzin, P., Brudnowska, A., Kurkowska, K., Wilk, K., Olszewska, K., Ziembiński, Ł., Janas, A., Cegieła, U., & Folwarczna, J. (2022) · Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · doi:10.1016/j.biopha.2022.113679 · Cited by 10
Ginsenoside Rd protects cerebral endothelial cells from oxygen-glucose deprivation/reoxygenation induced pyroptosis via inhibiting SLC5A1 mediated sodium influx
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“SLC5A2 is almost exclusively expressed in the kidney and is responsible for glucose reabsorption from the tubular system, while SLC5A1 mediates glucose absorption in the small intestine [36].”
Background
Phloridzin Acts as an Inhibitor of Protein-Tyrosine Phosphatase MEG2 Relevant to Insulin Resistance
Yoon, S., Yu, J. S., Hwang, J.-Y., So, H., Seo, S., Kim, J. K., Jang, T., Chung, S. J., & Kim, K. H. (2021) · Molecules · doi:10.3390/molecules26061612 · Cited by 10
Real-World Clinical Outcomes Associated with Canagliflozin in Patients with Type 2 Diabetes Mellitus in Spain: The Real-Wecan Study
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Bioactive peptides PIISVYWK and FSVVPSPK improve glucose homeostasis by targeting DPP-IV and glucose transport in type 2 diabetic mice
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Profiling of Antidiabetic Bioactive Flavonoid Compounds from an Edible Plant Kudzu (Pueraria lobata).
Wang, W., Liu, Y.-F., Liu, D., Zhou, H., Li, Y., Yuan, W., Xu, S.-W., Wang, J.-X., Liang, X.-M., & Weng, J.-P. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.4c02564 · Cited by 9
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“In the intestines, SGLT1 inhibition inhibits intestinal glucose absorption and increases glucose delivery to the distal gut, stimulating GLP-1 secretion and further reducing postprandial hyperglycemia [92].”
Background
Importance of intensive blood pressure control in type 2 diabetes: Mechanisms, treatments and current guidelines
Marre, M. (2020) · Diabetes Obesity and Metabolism · doi:10.1111/dom.13975 · Cited by 9
“The SGLT2s are located principally in the proximal tubular cells.(91)”
Background
Oral Defense: How Oral Rehydration Solutions Revolutionized the Treatment of Toxigenic Diarrhea
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Anthocyanins and Metabolic Disease: A New Frontier in Precision Nutrition
Patanè, G. T., Moreira, R., Almeida-Santos, M., Putaggio, S., Barreca, D., Oliveira, P. F., & Alves, M. G. (2026) · Antioxidants · doi:10.3390/antiox15010061 · Cited by 8
“In the small intestine, SGLT1, GLUT2, and OATP2B1, respectively, encoded by the SLC5A1 [173], SLC2A2 [174], and SLCO2B1 [175] genes, are involved in intestinal absorption of ACNs.”
A Human Engineered Heart Tissue‐Derived Lipotoxic Diabetic Cardiomyopathy Model Revealed Early Benefits of Empagliflozin
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Sodium‐glucose cotransporter 1/2 inhibition and risk of neurodegenerative disorders: A Mendelian randomization study
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“Sodium–glucose cotransporters 1 (SGLT1, encoded by SLC5A1 gene) and sodium–glucose cotransporters 2 (SGLT2, encoded by SLC5A2 gene) play key roles in epithelial glucose reabsorption, with SGLT2 retrieving most glucose in the tubular system of the kidney and SGLT1intheintestinereabsorbingtheremainder(Rieg&Vallon,2018).”
Background
Conjugated linoleic acid from Suaeda salsa improves the intestinal health in T2DM mice by regulating colonic barrier function, intestinal glycolipid transporters and intestinal flora
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SGLT2 Inhibitors: Paradigm Shift from Diabetes Care to Metabolic Care—An Indian Perspective
KUMAR, K. M. P., Unnikrishnan, A., Jariwala, P. V., Mehta, A., Chaturvedi, R., Panchal, S., Lakhani, P., Acharya, R., & Dixit, J. (2024) · Indian Journal of Endocrinology and Metabolism · doi:10.4103/ijem.ijem_377_23 · Cited by 10
“[26] SGLT2i including canagliflozin (CANA), empagliflozin (EMPA), dapagliflozin (DAPA) and ertugliflozin (ERTU) are approved by the United States Food and Drug Administration (USFDA) and the European Medicines Agency (EMA); [27] of these, CANA (100 mg and 300 mg), DAPA (5 mg and 10 mg), and EMPA…”
Background
Sodium‐glucose cotransporter‐2 inhibitors and the risk of gout in patients with type 2 diabetes mellitus: A propensity‐score‐matched, new‐user design study with an active comparator using the IQVIA Medical Research Data UK database
Subramanian, A., Gokhale, K., Sainsbury, C., Nirantharakumar, K., & Toulis, K. (2022) · Diabetes, obesity and metabolism · doi:10.1111/dom.14858 · Cited by 8
“Their main site of action is a high-capacity, low-affinity glucose transporter, SGLT2, located in the proximal convoluted renal tubule.(2) Inhibition of tubular glucose reuptake results in a consistent increase in urinary glucose and, thus, calorie excretion, leading to a relatively modest decrease (in the order of 0.”
Background
Pharmacological mechanisms of sodium-glucose co-transporter 2 inhibitors in heart failure with preserved ejection fraction
Liang, B., Liang, Y., & Gu, N. (2022) · BMC Cardiovascular Disorders · doi:10.1186/s12872-022-02693-8 · Cited by 8
“SGLT1 and SGLT2, encoded by SLC5A1 and SLC5A2 respectively, are important mediators of epithelial glucose transport, and together with SI are SGLT2is targets [44].”
Background
The Impact of Novel Anti-Diabetic Medications on CV Outcomes: A New Therapeutic Horizon for Diabetic and Non-Diabetic Cardiac Patients
Mazin, I., Chernomordik, F., Fefer, P., Matetzky, S., & Beigel, R. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11071904 · Cited by 8
“However, a thorough understanding of the mechanism of action inhibiting glucose secretion and transport from the kidney through inhibition in SGLT-2 and SGLT-1 was established only in the 1990s [40], leading to the development of Phlorizin-like molecules.”
Background
Pharmacological Management of Diabetes Mellitus: A Century of Expert Opinions in Cecil Textbook of Medicine
Manu, P., Rogozea, L. M., & Cernea, S. (2021) · American Journal of Therapeutics · doi:10.1097/mjt.0000000000001401 · Cited by 12
Using adult stem cells to monitor endothelial dysfunction in diabetes mellitus
Jain, R., Awal, H. B., & Sen, S. (2020) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2020.107588 · Cited by 13
Intestinal Gastrin/CCKBR Axis Protects against Type 2 Diabetes by Reducing Intestinal Glucose Absorption through the PI3K/Akt/eIF4B Signaling Pathway
Liu, X., Liu, X., Liu, Y., Long, A., Liu, W., Sun, S., Lu, S.-B., Wu, X., Jia, X.-Y., Jose, P. A., et al. (2025) · Advancement of science · doi:10.1002/advs.202410032 · Cited by 7
The cellular and molecular mechanisms mediating the protective effects of sodium–glucose linked transporter 2 inhibitors against metabolic dysfunction‐associated fatty liver disease
Ao, N., Du, J., Jin, S., Suo, L., & Yang, J. (2024) · Diabetes Obesity and Metabolism · doi:10.1111/dom.16043 · Cited by 7
“20 In clinical practice, some SGLT2 inhibitors have been used to help manage chronic kidney disease (CKD) and heart failure in patients with and without DM thanks to their cardioprotective and renoprotective benefits.”
Physician Perceptions of Medication Prescribing in Heart Failure: A Scoping Review
Vasudevan, S., Thayaparan, A., Teng, L., Lammoza, N., Aung, A., Edwards, G., Gibbs, H., & Hopper, I. (2024) · The Cardiology · doi:10.1159/000539524 · Cited by 7
“…class 1 GDMT, SGLT2 inhibitors can be used across the entire spectrum of EF [5, 6] and have been used for type 2 diabetes for over a decade [47]; thus, the familiarity that non-cardiologist prescribers have with SGLT2i may instil greater con ﬁ dence in these groups to initiate new…”
Inverted U‐shaped associations between serum uric acid and fasting ‐ plasma glucose level in non‐diabetic, pre‐diabetic, and diabetic adults: A population‐based study in China
Shi, H., Liu, Y.-N., Yang, D., Liang, P.-F., Chen, C., Luan, H., & Shi, C. (2023) · Journal of Diabetes Investigation · doi:10.1111/jdi.14132 · Cited by 7
“This inhibition is potentially mediated by the actions of sodium dependent anion transporters, such as sodium-glucose co-transporter 2 (SGLT2) 38 and sodium-glucose co-transporter 1 (SGLT1) 39 .”
Background
Overlapping risk factors for diabetic ketoacidosis in patients with type 1 diabetes on ipragliflozin: case analysis of spontaneous reports in Japan from a pharmacovigilance safety database
Abiru, N., Nakatsuji, Y., Noguchi, M., & Tsuboi, K. (2023) · Expert Opinion on Drug Safety · doi:10.1080/14740338.2023.2193393 · Cited by 7
Obesity-associated cardiometabolic complications in polycystic ovary syndrome: The potential role of sodium-glucose cotransporter-2 inhibitors
Pruett, J. E., Romero, D. G., & Cardozo, L. L. Y. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.951099 · Cited by 10
“However, there were multiple drawbacks to using phlorizin, an early SGLT2 inhibitor naturally found in apple trees (33, 34), such as poor absorption in the gut and its concurrent inhibition of SGLT1 (35).”
Background
Correlation between albuminuria and interstitial injury marker reductions associated with SGLT2 inhibitor treatment in diabetic patients with renal dysfunction
Sato, S., Takayanagi, K., Shimizu, T., Kanozawa, K., Iwashita, T., & Hasegawa, H. (2022) · European Journal of Medical Research · doi:10.1186/s40001-022-00737-5 · Cited by 7
In Vivo Functional Assessment of Sodium-Glucose Cotransporters (SGLTs) Using [18F]Me4FDG PET in Rats
Matsusaka, Y., Chen, X.-Y., Arias-Loza, P., Werner, R., Nose, N., Sasaki, T., Rowe, S. P., Pomper, M., Lapa, C., & Higuchi, T. (2022) · Molecular Imaging · doi:10.1155/2022/4635171 · Cited by 7
“Recently, inhibition of sodium glucose cotransporters (SGLTs) has emerged as a therapeutic strategy for type 2 diabetes mellitus (T2DM) to increase urinary glucose excretion and/or decrease glucose absorption in the small intestine [1].”
BackgroundMethod
No apparent pharmacokinetic interactions were found between henagliflozin: A novel sodium‐glucose co‐transporter 2 inhibitor and glimepiride in healthy Chinese male subjects
Que, L., Huang, K., Xiang, X., Ding, Y., Chu, N.-N., & He, Q. (2022) · Journal of Clinical Pharmacy and Therapeutics · doi:10.1111/jcpt.13659 · Cited by 7
Using adjuvant pharmacotherapy in the treatment of type 1 diabetes
Sjöholm, Å. (2021) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2021.1939679 · Cited by 7
Cardiorenal protection with SGLT2: Lessons from the cardiovascular outcome trials
Silva‐Cardoso, J., Sheikh, O., Nashawi, M., Pham, S. V., Gallegos, K. M., Dinkha, L. R., & CHILTON, R. J. (2019) · Journal of Diabetes · doi:10.1111/1753-0407.13007 · Cited by 10
“SGLT2 inhibitors (-gliflozins) act by inhibiting renal tubular reabsorption of glucose by inhibition of the SGLT2 protein, which decreases blood glucose, decreases blood pressure, increases water and sodium excretion, and promotes urinary loss of calories in the form of glucose.(6) It has been shown that therapy with…”
Background
Cardiorenal protection with dapagliflozin in patients with type 2 diabetes mellitus and chronic coronary syndrome undergoing percutaneous coronary intervention: a registry cross-sectional study
Zhao, Z., Zheng, N., Zhang, T., Zhang, C., Li, Y., Lan, M., Zhang, N., Li, H., Ai, H., & Liu, D. (2025) · Cardiovascular Diabetology · doi:10.1186/s12933-025-02678-9 · Cited by 11
Effect of empagliflozin on plasma lipids and lipoproteins in type 2 diabetes and heart failure – Empire HF and SIMPLE
Emanuelsson, F., Jensen, J., Omar, M., Jürgens, M., Kistorp, C., Brandt, N., Møller, J. E., Schou, M., Bechmann, L. E., Larsen, E. L., et al. (2024) · Journal of clinical lipidology · doi:10.1016/j.jacl.2024.12.015 · Cited by 8
The Impact of SGLT1 Inhibition on Frailty and Sarcopenia: A Mediation Mendelian Randomization Study
Huang, B., Zhang, Y., Ruan, G., Yu, X., Liu, Q., Zhang, M., Yu, M., Chen, A., Liang, Y. Z., Xie, L., et al. (2024) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.13614 · Cited by 6
Integrating traditional and modern medicines to treat heart failure
Tian, Z., & Zhang, S.-Y. (2024) · Nature Medicine · doi:10.1038/s41591-024-03135-y · Cited by 6
Synthetic approaches and clinical application of small-molecule inhibitors of sodium-dependent glucose transporters 2 for the treatment of type 2 diabetes mellitus
Xie, T., & Zhao, L.-J. (2024) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2024.116343 · Cited by 5
Impact of SGLT2 Inhibitors on Corneal Nerve Morphology and Dendritic Cell Density in Type 2 Diabetes
Asiedu, K., Tummanapalli, S. S., Alotaibi, S., Wang, L. L., Dhanapalaratnam, R., Kwai, N. C. G., Poynten, A. M., Markoulli, M. P., & Krishnan, A. V. (2023) · Ocular Immunology and Inflammation · doi:10.1080/09273948.2023.2263789 · Cited by 6
“13,14 In addition to their effects on glucose metabolism, they also possess anti-inflammatory effects.”
BackgroundResult
Circ_0003028 enhances the proliferation and glycolytic capacity and suppresses apoptosis in non-small cell lung cancer cells via the miR-1305/miR-1322-SLC5A1 axis
Shi, L., Huang, Y., Chen, S., Wang, S. L., Yan, C., Chen, X., Zhang, B., & Ke, B. (2023) · Annals of Translational Medicine · doi:10.21037/atm-23-178 · Cited by 6
“Among them, SGLT1 and SGLT2, which are encoded by SLC5A1 and SLC5A2, respectively, are GLUT proteins across the cell membrane (42).”
Renal Metabolome in Obese Mice Treated with Empagliflozin Suggests a Reduction in Cellular Respiration
Bangarbale, S., Shepard, B. D., Bansal, S., Jayatilake, M. M., Kurtz, R., Levi, M., & Ecelbarger, C. M. (2022) · Biomolecules · doi:10.3390/biom12091176 · Cited by 6
“The modern class of sodium glucose cotransporter, type 2 inhibitors (SGLT2i), including Empagliflozin (EMPA), were developed in the first decade of the 2000′s as a refinement of the original drug, Phlorizin (found in root bark, leaves, and apples), and shown to induce glycosuria [1].”
Background
Considerations and possibilities for sodium-glucose cotransporter 2 inhibitors in pediatric CKD
Kula, A. J. (2022) · Pediatric Nephrology · doi:10.1007/s00467-022-05456-x · Cited by 7
“Soon after their discovery and classification, SGLT1 and SGLT2 were both identified as therapeutic targets for patients with diabetes [8].”
Background
Sodium Glucose Transporter, Type 2 (SGLT2) Inhibitors (SGLT2i) and Glucagon-Like Peptide 1-Receptor Agonists: Newer Therapies in Whole-Body Glucose Stabilization
Shepard, B. D., & ECELBARGER, C. A. (2021) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2021.06.005 · Cited by 7
SGLT2 Inhibitors and nephroprotection in diabetic kidney disease: From mechanisms of action to the latest evidence in the literature
Rico-Fontalvo, J. E., Daza-Arnedo, R., Cardona-Blanco, M., Leal-Martínez, V., Abuabara-Franco, E., Pájaro-Galvis, N., Cabrales, J., Correa, J., Cueto, M., Amable, D., et al. (2020) · Journal of Clinical Nephrology · doi:10.29328/journal.jcn.1001058 · Cited by 12
“Dapaglifozin was approved for use in the market for the irst time in Europe in 2012; the Food and Drug Administration (FDA) approved the medication for the treatment of T2D in January 2014 [17].”
Method
Sugar Transport Across Epithelia
Loo, D. D. F., & Wright, E. M. (2020) · Physiology in health and disease · doi:10.1007/978-3-030-55454-5_6 · Cited by 6
Improving the catalytic activity of glycosyltransferase UGT88F1 for highly efficient biosynthesis of phlorizin through structure-guided engineering
Guo, X., Deng, Z., Yang, Y.-Z., Zhang, B., Zhang, Y., Yuan, Z., Liu, C., Rao, Y., & Luo, Z. (2025) · Food Bioscience · doi:10.1016/j.fbio.2025.107617 · Cited by 5
Inhibitory Effect of Boesenbergia rotunda and Its Major Flavonoids, Pinostrobin and Pinocembrin on Carbohydrate Digestive Enzymes and Intestinal Glucose Transport in Caco-2 Cells
Aimjongjun, S., Khamto, N., Buangamdee, V., Sornda, T., Srivilai, J., & Limpeanchob, N. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262010158 · Cited by 5
“The results confirmed that phlorizin consistently demonstrated the strongest binding affinity, particularly toward SGLT1 and SGLT2, aligning with its known role as a selective inhibitor for these transporters [14].”
Identification of Resistance Loci to Avian Leukosis via Genome-Wide Association Analysis in Chengkou Mountain Chickens
Li, Y., Tan, M., Yang, G., Xu, Q., Wang, Q.-G., Wang, H.-W., & Lan, X. (2025) · Animals · doi:10.3390/ani15101365 · Cited by 5
“Enrichment of these genes in pathways related to ion transport and cancer metabolism suggests that their dysfunction may alter membrane permeability, facilitating viral invasion and disease progression [48–57].”
Disparities in heart failure deaths among people with diabetes in the United States: 1999–2020
Grobman, B., Mansur, A., & Lu, C. Y. (2025) · Diabetes, obesity and metabolism · doi:10.1111/dom.16301 · Cited by 5
“41,42 For heart failure, previous research has shown that isosorbide dinitrate and hydralazine significantly lower heart failure mortality among Black patients.”
SGLT2 Inhibition in Heart Failure: Clues to Cardiac Effects?
Savage, P., Dixon, L., Grieve, D., & Watson, C. J. (2024) · Cardiology in Review · doi:10.1097/crd.0000000000000637 · Cited by 7
Comparison of the Pharmacokinetics, Safety, and Tolerability of Two Empagliflozin Formulations in Healthy Korean Subjects
Jiang, X., Bae, S., Yoon, D. Y., Park, S. J., Oh, J., Cho, J., & Yu, K. (2023) · Drug Design Development and Therapy · doi:10.2147/dddt.s409368 · Cited by 6
Exploring the Pleiotropic Genes and Therapeutic Targets Associated with Heart Failure and Chronic Kidney Disease by Integrating metaCCA and SGLT2 Inhibitors’ Target Prediction
Li, H., Mai, Z., Yu, S., Wang, B., Lai, W., Chen, G., Zhou, C., Liu, J., Yang, Y., Chen, S., et al. (2021) · BioMed Research International · doi:10.1155/2021/4229194 · Cited by 5
Function Trumps Form in Two Sugar Symporters, LacY and vSGLT
Abramson, J., & Wright, E. M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073572 · Cited by 5
“The inhibition of human SGLTs by phlorizin has been exploited by the pharmaceutical industry to develop high affinity phlorizin analogs for the treatment of Type 2 Diabetes Mellitus [18,19].”
Background
Glucosuric, renal and haemodynamic effects of licogliflozin, a dual inhibitor of sodium‐glucose co‐transporter‐1 and sodium‐glucose co‐transporter‐2, in patients with chronic kidney disease: A randomized trial
He, Y., Pachori, A. S., Chen, P., Ma, S., Mendonza, A. E., Amer, A., Marbury, T. C., & Hinder, M. (2021) · Diabetes Obesity and Metabolism · doi:10.1111/dom.14327 · Cited by 5
Pharmacomicrobiomics of Non-Antibiotic Drugs: Mechanisms and Clinical Consequences of Gut Microbiota Alterations
Dumitru, C. N., Dumitru, A. O., Goroftei, L., Niculet, E., Ignat, M. D., Baroiu, L., Nechita, A., & Balan, G. (2026) · Pharmaceutics · doi:10.3390/pharmaceutics18060651 · Cited by 4
“…expressed in the intestine; however, the related transporter SGLT1 is highly expressed in the proximal small intestine, and compensatory SGLT1 upregulation during SGLT2 inhibition has been demonstrated, potentially altering small intestinal glucose availability for bacterial fermentation [28,89].”
Comparison of the Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Cardiac Fibroblast Properties
Baufays, C., Cumps, J., Dufeys, C., Ginion, A., Bertrand, L., Horman, S., Beauloye, C., & Marino, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262010098 · Cited by 4
“Several SGLT2i, including canagliflozin, empagliflozin, and dapagliflozin, derive from phlorizin, an early non-selective SGLT inhibitor isolated in 1835 from the root bark of the apple tree [2,3].”
Safety and efficacy of adjuvant Sotagliflozin therapy in patients with T1D - an update and systematic review and meta-analysis
Lei, Y., Yao, S., Wang, Z., Tu, Q., Yuan, Z., & Jiang, Q. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1506652 · Cited by 4
Reshaping the Treatment Landscape of a Galactose Metabolism Disorder
Rubio-Gozalbo, M., Vos, E., Rivera, I., Lai, K., & Berry, G. (2025) · Journal of Inherited Metabolic Disease · doi:10.1002/jimd.70013 · Cited by 4
“Inhibition of these transporters has already been studied mainly for type 2 diabetes mellitus (OMIM 125853) treatment [64].”
Cardioprotection of Canagliflozin, Dapagliflozin, and Empagliflozin: Lessons from preclinical studies
Soares, R. R., Viggiani, L. F., Filho, J. M. R., & Joviano‐Santos, J. V. (2024) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2024.111229 · Cited by 5
Emphysematous Pyelonephritis in a Patient on SGLT2 Inhibitor Therapy: A Rare Clinical Case Report
Artinyan, E., Dimov, N., & Vaysilova, M. (2024) · Case Reports in Nephrology and Dialysis · doi:10.1159/000539390 · Cited by 4
“These molecules block the sodium-dependent glucose cotransporter in the proximal tubule, leading to increased glucose excretion in the urine [4].”
Background

Authors: Rieg, T., & Vallon, V.
Affiliations: University of South Florida (US)
University of California San Diego (US)
Corresponding author: Rieg, Timo
Vallon, Volker
ORCID: Rieg, Timo
Vallon, Volker
Venue: Diabetologia
Publisher: Springer Science and Business Media LLC
Published: 2018-08-22
Volume: 61
Issue: 10
Pages: 2079-2086
ISSN: 0012-186X (ISSN-L)
1432-0428
DOI: 10.1007/s00125-018-4654-7
PMC: PMC6124499
OpenAlex: W2883581800
Cited by: 377
References: 71
Citations by year: 2026: 39 · 2025: 53 · 2024: 49 · 2023: 66 · 2022: 58 · 2021: 50 · 2020: 36 · 2019: 24 · 2018: 2
FWCI: 4.35
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Diabetologia (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (R01DK112042)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords: SGLT1 inhibitors, SGLT2 inhibitors, sodium-glucose cotransporter, SGLT1, SLC5A2, phloridzin, glucose-galactose malabsorption, glycosuria, type 2 diabetes, heart failure, renal protection, drug discovery, mathematical modeling, genetically engineered mouse models, intestinal glucose absorption, renal glucose reabsorption
MeSH terms: Sodium-Glucose Transporter 2 Inhibitors, Animals, Blood Glucose, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Disease Models, Animal, Glucose, Humans, Intestinal Mucosa, Kidney, Mutation, Phlorhizin, Drug Design, Diabetic Ketoacidosis, Sodium-Glucose Transporter 1, Sodium-Glucose Transporter 2, Mice

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