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Development of SGLT1 and SGLT2 inhibitors
Open accessAbstract
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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Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes
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Marques, F., Valicelli, F. H., Tanaka, D. M., & Simões, M. V. (2024) · ABC Heart Failure & Cardiomyopathy · doi:10.36660/abchf.20240027 · Cited by 1
Dapagliflozin - new solution in chronic kidney disease treatment
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Diabetes Medications and Cardiovascular Disease Prevention
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“Sodium-Glucose Transporter 2 (SGLT2) inhibitors increase the urinary excretion of glucose, allowing a reduction of glycaemia, and are recommended in patients with type 2 diabetes.([6,7]) Currently, some studies have described potential protective effects against progressive renal events and hospitalization rates due t…”
BackgroundA PARADIGM SHIFT FOR THE SGLT2 INHIBITORS – TREATING THE HEART WITH ANTI-HYPERGLYCAEMIC DRUGS
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Historical Background of Diabetic Kidney Disease
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Finally, Some Reason for Hope in Proteinuric Kidney Disease
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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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