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Development of SGLT1 and SGLT2 inhibitors
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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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“For type 2 diabetes, complementary disease-modifying therapies that may reduce or eliminate the need for insulin administration have also represented a rapidly expanding field of interest130–132.”
From 100 years of insulin: celebrating the past, present and future of diabetes therapy (2021) · cites this paper as [131]
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“79 Despite the benefits of simultaneous inhibition of intestinal SGLT1 and renal SGLT2, there is a potential for bloating, gastro-intestinal (GI) discomfort, and diarrhea afterward the malabsorption of intestinal glucose/galactose.”
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“The sodium-dependent glucose transporters 2 (SGLT2) located in the proximal tubule are responsible for reabsorbing 90% of the glucose that is fi ltered through the glomerulus (105).”
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“…regulate EGFR activity in TNBC. Sodium/glucose cotransporter 1, encoded by the SLC5A1 gene in humans, is an active glucose transporter, which utilizes sodium gradients to transport glucose into cells independent of extracellular glucose concentration (Rieg and Vallon, 2018; Wright et al., 2011).”
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“As a precautionary measure, it could be of great importance to evaluate the ability of these molecules to inhibit the activity of intestinal glucose transporters in order to avoid the risk of inducing a hypoglycemic condition [70].”
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A risk model of gene signatures for predicting platinum response and survival in ovarian cancer
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“When SGLT-2 is dysfunctional—as a result of mutations in the SLC5A2 gene—the renal capacity for absorbing glucose decreases to the residual capacity of SGLT-1 (80 g/d).(10)”
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“However, some of these inhibitors are in clinical trials, so further studies are necessary before their possible therapeutic application (Rieg and Vallon 2018).”
BackgroundDisruption of energy utilization in diabetic cardiomyopathy; a mini review
Nirengi, S., da Silva, C. P. V., & Stanford, K. I. (2020) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2020.08.015 · Cited by 35
“SGLT2 inhibitors such as empagliflozin and sotagliflozin (a SGLT1/SGLT2 dual inhibitor) are the newest class of oral hypoglycemic agents approved by the Food and Drug Administration [74] and commercially available for T2D treatment.”
BackgroundInfluentialBridging the gap: glucose transporters, Alzheimer’s, and future therapeutic prospects
Albaik, M., Saleh, D. S., Kauther, D., Mohammed, H., Alfarra, S., Alghamdi, A., Ghaboura, N., & Sindi, I. A. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1344039 · Cited by 34
“SGLT2 inhibitors have demonstrated great success in the treatment of type 2 diabetes mellitus, in addition to having been found to have advantageous effects on the cardiovascular system, kidneys, and Alzheimer ’ s disease (Rieg and Vallon, 2018; Esterline et al., 2020; Nishimura et al., 2022).”
Montalbano, G., Maugeri, A., Guerrera, M. C., Miceli, N., Navarra, M., Barreca, D., Cirmi, S., & Germanà, A. (2021) · Molecules · doi:10.3390/molecules26041119 · Cited by 29
“, dihydrochalcones) can influence carbohydrate uptake [55] or inhibit the enzymes involved in the metabolization of polysaccharides into monomers [56], hence inducing caloric restriction with remarkable anti-obesity effects.”
BackgroundDavid-Silva, A., Esteves, J. V. D. C., Morais, M., Freitas, H. S., Zorn, T. M. T., Corrêa‐Giannella, M. L., & Machado, U. F. (2020) · Diabetes Metabolic Syndrome and Obesity · doi:10.2147/dmso.s242282 · Cited by 37
Ion channels and transporters in diabetic kidney disease
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“Its discovery traces back over 150 years to research on glucosuria (22).”
Unveiling the anticancer effects of SGLT-2i: mechanisms and therapeutic potential
Sun, M., Sun, J., Sun, W., Li, X., Wang, Z., Sun, L., & Wang, Y. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1369352 · Cited by 23
“Moreover, their impeccable safety record in humans has prompted investigations into their viability as prospective treatments for various non-metabolic disorders (Rieg and Vallon, 2018).”
BackgroundTubular effects of sodium–glucose cotransporter 2 inhibitors: intended and unintended consequences
Rieg, J. A. D., Xue, J., & Rieg, T. (2020) · Current Opinion in Nephrology & Hypertension · doi:10.1097/mnh.0000000000000632 · Cited by 32
“The latter are a novel class of antidiabetic drugs [3] that have been approved for the treatment of diabetes mellitus by the US Food and Drug Administration.”
BackgroundSelf-citationMedical and Nonmedical Applications of Synthetic Transmembrane Anion Transporters
Rathnaweera, U. M. C., Chowdhury, S. M., Salam, R., & Busschaert, N. (2025) · Chemical Reviews · doi:10.1021/acs.chemrev.5c00129 · Cited by 38
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“Of note, SGLT2 inhibitors show substantial variance in pharmacological selectivity to SGLT2 over SGLT1 1,11,12 .”
BackgroundMethodGLP-1 Analogs, SGLT-2, and DPP-4 Inhibitors: A Triad of Hope for Alzheimer’s Disease Therapy
Złotek, M., Kurowska, A., Herbet, M., & Piątkowska‐Chmiel, I. (2023) · Biomedicines · doi:10.3390/biomedicines11113035 · Cited by 30
“This group of antidiabetic drugs shows also favorable effects on the cardiovascular system, and it is especially recommended for patients with type 2 diabetes and diagnosed cardiovascular disease [205].”
BackgroundAziri, B., Begić, E., Јаnkovic, S., Mladenović, Z., Stanetić, B., Kovačević-Preradović, T., Iglica, A., & Mujaković, A. (2023) · ESC Heart Failure · doi:10.1002/ehf2.14355 · Cited by 30
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“The risk of hypoglycemia is low due to the compensatory role of SGLT1 in the downstream late proximal tubule and counterregulatory mechanisms, including an increase in plasma glucagon levels and hepatic gluconeogenesis [12-14].”
BackgroundMetabolism and disposition of the SGLT2 inhibitor bexagliflozin in rats, monkeys and humans
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“Affected individuals do not show substantial glucosuria (Rieg & Vallon, 2018).”
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Phloretin alleviates dinitrochlorobenzene-induced dermatitis in BALB/c mice
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“Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a relatively new class of oral antihyper-glycemic agents that suppress glucose reuptake in the renal tubular system [1].”
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PKCδ-mediated SGLT1 upregulation confers the acquired resistance of NSCLC to EGFR TKIs
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Relevance of solute carrier family 5 transporter defects to inherited and acquired human disease
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“SGLT1 is an essential transporter of both sodium and glucose across the apical membrane of epithelial cells, and its primary function is to regulate glucose uptake by the intestine and kidney (15, 42).”
BackgroundJahangiri, S., Malek, M., Kalra, S., & Khamseh, M. E. (2023) · Diabetes Therapy · doi:10.1007/s13300-023-01481-7 · Cited by 16
“In individuals with diabetes, SGLT2 proteins are paradoxically upregulated, resulting in excessive glucose reabsorption despite high blood glucose levels [33].”
BackgroundPotential Therapeutic Strategies in the Treatment of Metabolic-Associated Fatty Liver Disease
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“By inducing glucosuria, they subsequently lower serum glucose levels [18].”
BackgroundPharmacogenetics of new classes of antidiabetic drugs
Imamović, S., Kulo, A., & Dujić, T. (2021) · Biomolecules and Biomedicine · doi:10.17305/bjbms.2021.5646 · Cited by 16
“from the renal proximal tubule, leading to glycosuria [13-16].”
BackgroundNew functions and roles of the Na+-H+-exchanger NHE3
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“Drugs targeting sodium-glucose co-transporters (“gliflozins”) are a new mainstay in the treatment of diabetes mellitus and heart failure [12, 13, 55, 62].”
Self-citation
Metadata
- Authors
- Rieg, T., & Vallon, V.
- Affiliations
- University of South Florida (US)
- University of California San Diego (US)
- Corresponding author
- Rieg, Timo
- Vallon, Volker
- Venue
- Diabetologia
- Published
- 2018-08-22
- Volume
- 61
- Issue
- 10
- Pages
- 2079-2086
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- 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
- 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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