Beyond SGLT2: Exploring the Therapeutic Potential of Lesser-Known SGLT Isoform Inhibitors

Abstract

This paper presents a review of studies on SGLT protein inhibitors, based on literature published between 2000 and 2025, sourced from the Scopus, ScienceDirect, Google Scholar and PubMed databases. The individual isoforms of SGLT proteins are briefly described, with attention to their distribution in the body and biological functions. Representative inhibitors and their potential biological effects are also discussed. Beyond the well-established glucose-lowering properties, characteristic of the extensively studied SGLT2 inhibitors, this review explores additional effects, including anticancer, anti-inflammatory, antioxidant, and neuroprotective activities. The analysis encompasses synthetic SGLT inhibitors, computer-designed molecules, and a wide range of naturally derived compounds, including medicinal plants and food-based substances. Importantly, the review deliberately excludes SGLT2 inhibitors, such as the well-known gliflozin class due to the abundance of existing reviews focused specifically on them. This review focuses on potential inhibitors of the SGLT1, SGLT3, SGLT4, SGLT5, and SGLT6 isoforms, emphasizing their diverse physiological roles beyond diabetes and cardiovascular disease, including applications in cancer therapy and neuroprotection. Particular attention is given to the SGLT1 isoform, for which numerous synthetic inhibitors with promising therapeutic potential have been identified. Additionally, natural compounds, especially those derived from medicinal plants and dietary sources, are extensively documented for their inhibitory effects. For the remaining isoforms (SGLT3–SGLT6), all available data on selective inhibitors were examined, alongside an evaluation of their possible therapeutic applications in light of current scientific knowledge.

1. Introduction

1.1. Glucose Transporters

Glucose is an essential energy source for most tissue cells, where it is metabolized into adenosine triphosphate. Due to its low lipophilicity and high molecular weight, glucose cannot cross the cell membrane via simple diffusion. Therefore, its transport across lipid bilayers requires specialized mechanisms involving two classes of carrier proteins: glucose transporters (GLUTs) and sodium–glucose co-transporters (SGLTs) [1,2,3]. GLUTs constitute a large family of 14 transporters that differ in their substrate affinity. These proteins are expressed in virtually all cell types, facilitating the transport of glucose, and in some cases, fructose along a concentration gradient (from high to low) via facilitated diffusion. They perform diverse physiological and pathological roles [1,2,3,4]. SGLTs belong to the sodium/glucose co-transporter family SLC5, which is part of the broader sodium/solute symporter superfamily found across all domains of life. The SLC5 family comprises 12 members, including sugar transporters (SGLT1/SLC5A1, SGLT2/SLC5A2, SGLT3/SLC5A4, SGLT4/SLC5A9, and SGLT5/SLC5A10), as well as transporters for other substrates, such as myo-inositol (SLC5A3 and SGLT6/SLC5A11 or SMIT2), iodide (SLC5A5), monocarboxylates (SLC5A8 and SLC5A12), choline (SLC5A7), and vitamins (SLC5A6). Some members, such as SGLT1 and SGLT3, can also function as co-transporters for urea and water [3,5,6]. All these membrane proteins share a common transport mechanism that utilizes the sodium electrochemical gradient to sense or actively import substrates into cells. However, each has distinct substrate specificity, tissue distribution (Figure 1), and regulatory mechanisms [7].

1.2. SGLT Isoforms, Their Localization and Functions in the Body

SGLT1 is a protein composed of 664 amino acids and contains 14 transmembrane α-helical domains, with the amino acid sequence in the transmembrane segment 11 as QSGQLFDYIQSITSYLGPP [8]. It is primarily expressed on the apical membrane of enterocytes in the small intestine, particularly in the duodenum. In the kidneys, it is also expressed in the proximal convoluted tubule of the cortical zone, where it is responsible, under euglycemic conditions, for reabsorbing approximately 5% of the glucose filtered daily. In addition to its main role in glucose transport, SGLT1 appears to participate in sodium transport via a uniport mechanism and may also function as a channel for urea and water. Expression of SGLT1 has also been identified in the brain, especially in glucose-sensitive neurons located in the hypothalamus, midbrain, and brainstem. Moreover, this co-transporter seems to be localized on the luminal side of endothelial cells forming the blood–brain barrier (BBB), where it may play a critical role in supplying energy to neurons during periods of increased glucose demand, such as hypoxia or hypoglycemia. SGLT1 expression has also been detected in other tissues, including the lungs, liver, pancreas, and components of the immune system (Figure 1) [3,5].

SGLT2 is a protein composed of 672 amino acids and shares approximately 60% structural similarity with SGLT1 (the amino acid sequence in the transmembrane segment 11 is QGGQLFDYIQAWSSYLAPP) [8]. It is primarily expressed in the proximal convoluted tubule of the kidney, where it plays a key role in the reabsorption of sodium and glucose. Expression of SGLT2 has also been detected in the pancreas, brain, liver, thyroid, and muscle tissues, as well as in certain cancers, including prostate tumors and glioblastoma. In contrast to SGLT1, SGLT2 is not expressed in intestinal or cardiac tissues (Figure 1) [5]. Currently, SGLT2 is the most well-known member of the sodium–glucose co-transporter family, primarily due to the development of SGLT2 inhibitors, commonly referred to as gliflozins. These compounds inhibit SGLT2 function in the kidney, leading to glucosuria, and are widely used in glucose-lowering therapies. Beyond their hypoglycemic effect, SGLT2 inhibitors have demonstrated substantial clinical benefits, including reduced cardiovascular and all-cause mortality, fewer hospitalizations for heart failure, a decrease in adverse cardiovascular events, and slowed progression of albuminuria when added to standard care in both diabetic and nondiabetic patients with kidney disease. Remarkably, the therapeutic benefits of SGLT2 inhibitors in kidney disease and heart failure have been observed even in the absence of diabetes. Considering these outcomes, it is not surprising that gliflozins have revolutionized the management of some of the most prevalent global diseases, diabetes mellitus, heart failure, and chronic kidney disease [3,5,9].

SGLT3 is a transmembrane protein composed of 659 amino acids with the amino acid sequence in the transmembrane segment 11 as QNGQLIHYIESISSYLGPP [8]. In contrast to SGLT1 and SGLT2, relatively little is known about its precise localization and physiological role. It is primarily expressed in cholinergic neurons of the enteric nervous system within the gastrointestinal tract (GT), but it is also found at neuromuscular junctions in skeletal muscle, as well as in the brain and testis. Some studies have reported its expression in the kidneys, where it may be involved in sodium transport, although its function in this tissue remains unclear (Figure 1) [4,5]. Despite belonging to the sodium–glucose co-transporter family, SGLT3 does not transport glucose. Instead, it functions as a glucose sensor, depolarizing the cell membrane in the presence of extracellular glucose [10]. Given its predominant localization in the small intestine, particularly in the duodenum, jejunum, and ileum, SGLT3 is believed to play a role in regulating intestinal motility in response to luminal glucose levels [5]. Moreover, SGLT3-mediated glucose sensing has been shown to stimulate electrical activity in neuronal membranes. This can result in either hyperpolarization or excitatory depolarization, particularly in glucose-sensitive neurons of the hypothalamus, where it may contribute to central glucose sensing and energy homeostasis [11].

SGLT4 is a membrane protein with 14 transmembrane α-helices, structurally similar to SGLT1 and SGLT2. It is believed to participate in the transport of glucose, fructose, and mannose in tissues such as the small intestine, kidney, brain, and liver (Figure 1). While SGLT1 and SGLT2 are primarily responsible for renal glucose reabsorption, SGLT4 and likely SGLT5, are involved in apical fructose uptake. Specifically, SGLT4 and SGLT5 are thought to mediate fructose transport across the luminal side of epithelial cell membranes. Recent studies have suggested a potential role for SGLT4 in the pathogenesis of diabetic proliferative retinopathy. Additionally, expression of SGLT4 has been detected in pancreatic and colorectal tumors, indicating possible involvement in tumorigenesis [5].

SGLT5 is another transmembrane protein with 14 α-helices and functions primarily as a mannose transporter. It can also transport glucose, fructose, and 1,5-anhydro-D-glucitol (1,5-AG), albeit with lower affinity. SGLT5 is mainly expressed in the renal cortex, particularly in the proximal straight tubules, and in skeletal muscle (Figure 1). Although its physiological role is not yet fully understood, it is believed to contribute to the tubular reabsorption of filtered fructose (alongside SGLT4), glucose, and mannose. A potential link between renal fructose reabsorption mediated by SGLT5 and hepatic lipid metabolism has also been proposed. In particular, studies using mouse models have hypothesized that SGLT5 inhibition may enhance urinary fructose excretion, thereby mitigating fructose-induced hepatic steatosis [5,6].

SGLT6, also known as sodium/myo-inositol transporter 2 (SMIT2), is believed to share structural features with the LeuT family of transporters. Specifically, it is thought to contain an inverted repeat of five transmembrane segments, a characteristic that supports the alternate access mechanism by which SGLT6 transports myo-inositol and glucose. This transporter is localized to the luminal membrane of epithelial cells in the proximal convoluted tubule of the kidney. More recently, its expression has also been detected in the small intestine and brain (Figure 1) [5]. Glucose transport across BBB is primarily mediated by sodium-independent, facilitated transporters such as GLUT1 and GLUT3. However, other glucose transporters including GLUT4, SGLT1, and SGLT6, have also been reported in both in vitro and in vivo studies [12].

The most well-known isoform, SGLT2, and its inhibitors, now numbering more than a dozen, are increasingly used in the treatment of diabetes, heart failure and chronic kidney disease [3,5,9]. These compounds have been, and continue to be, the focus of extensive research, both in clinical settings and in the development of structural modifications to enhance their therapeutic potential. Numerous studies have explored these aspects in depth [13,14,15,16,17,18,19,20,21,22,23,24]. Building on this well-established body of work, we have turned our attention to potential inhibitors of the other known SGLT isoforms: SGLT1, SGLT3, SGLT4, SGLT5, and SGLT6. Although only a limited number of inhibitors for most of these isoforms have been identified to date, our goal was to examine their potential applications not only in diabetes management but also in a broader range of conditions, including oxidative stress, inflammation, cancer, and hepatic and neurological disorders. Our research has primarily focused on the SGLT1 isoform, for which several synthetic inhibitors with promising therapeutic properties have been discovered. In addition, we extensively discuss natural substances, particularly those derived from medicinal plants and dietary source, which also show considerable potential. For the remaining isoforms, SGLT3 to SGLT6, all available information regarding their selective inhibitors was considered, along with potential therapeutic applications based on the current state of knowledge.

2. Methodology of Data Acquisition

This review analyzed the literature on new selective synthetic and natural inhibitors of SGLT proteins published between January 2001 and October 2025. Several databases were searched, including Google Scholar, Scopus, ScienceDirect, and PubMed, using keywords such as SGLT family, SGLT protein, SGLT isoform, SGLT1, SGLT3, SGLT4, SGLT5, SGLT6, phlorizin analog, synthetic compound, medicinal plant, food, in silico assay, in vitro assay, preclinical trial, and beyond diabetes. Inclusion criteria were English-language publications reporting on studies directly related to new synthetic or natural compounds that selectively target SGLT1, SGLT3, SGLT4, SGLT5, or SGLT6, including their biological activity and potential therapeutic applications. Studies that focused solely on the expression of individual SGLT isoforms in various tissues, without investigating respective inhibitory compounds, were excluded. Using this strategy, we initially identified 110 records. After removing duplicates, 99 unique records remained for screening. Of these, 45 were excluded for not meeting the inclusion criteria. Ultimately, 54 publications were included in this review for qualitative synthesis. These selected studies involve the identification of new synthetic or natural compounds targeting SGLT1, SGLT3, SGLT4, SGLT5, and SGLT6. They include in silico, in vitro, and in vivo investigations, providing evidence of their selective inhibitory activity on specific isoforms. The reported effects relate to various conditions, including diabetes, renal and hepatic disorders, neurological diseases, inflammation, oxidative stress, and cancer. Additionally, 11 supplementary papers concerning selective SGLT2 and dual SGLT1/SGLT2 inhibitors, although not meeting the inclusion criteria, were cited to underscore the clinical relevance of selective SGLT2 inhibition, highlight the extensive research in this area, and better contextualize the rationale for the present study. To identify prospective research avenues and emerging areas of analysis, 4 supplementary references were incorporated. This brings the total number of citations in the review to 69.

3. Phlorizin, Selective SGLT2 Inhibitors and Dual SGLT1/SGLT2 Inhibitors

3.1. Phlorizin as a Lead Compound for Selective SGLT2 Inhibitors

Phlorizin (Figure 2), originally isolated from the stem bark of the apple tree, was first identified as an antipyretic compound. It was later shown to induce glucosuria and ultimately confirmed as a competitive inhibitor of SGLT1 in the intestine and SGLT2 in the kidney. Additionally, metabolites of phlorizin have been characterized as potent inhibitors of both SGLT1 and SGLT2, with even higher binding affinity than the parent compound [21]. More recently, phlorizin has been shown to exert multiple health-promoting effects, including cardiovascular protection and antioxidant activity [22]. Furthermore, it has been reported to significantly inhibit the progression of cystic disease in a rat model of polycystic kidney disease (PKD), likely through the induction of glycosuria and osmotic diuresis [23].

After being confirmed as a potent antidiabetic agent, phlorizin, chemically characterized as an O-glycoside, was used as a lead compound for developing further SGLT inhibitors. At the same time, the greater stability of C-glycoside forms, along with their higher lipophilicity, was considered because it allows better absorption after oral administration. These efforts have led to the development and approval of a large group of valuable drugs with selective action on the SGLT2 protein (Figure 3). Selective SGLT2 inhibitors that target the kidneys possess a unique mechanism of action, leading to enhanced glucosuria, osmotic diuresis, and natriuresis. In addition to their antihyperglycemic effects, these agents have demonstrated beneficial impacts on several cardiovascular risk factors, including reductions in body weight, blood pressure, and arterial stiffness, as well as improvements in lipid profiles and endothelial function [21,22,23]. Regarding their presence on the pharmaceutical market, dapagliflozin was approved by the European Medicines Agency (EMA) in 2012 and by the U.S. Food and Drug Administration (FDA) in 2014. Canagliflozin received approval from both the EMA and FDA in 2013, while empagliflozin was approved in 2014. In Japan, luseogliflozin, ipragliflozin, and tofogliflozin were all approved in 2014. Ertugliflozin was approved by the FDA in 2017 and by the EMA in 2018. Remogliflozin received approval in India in 2019, enavogliflozin in South Korea in 2022, and henagliflozin in China in 2022. Most recently, bexagliflozin was approved by the FDA in 2023. Due to their distinct pharmacological profile and broad therapeutic benefits, gliflozins have emerged as one of the most impactful classes of drugs, revolutionizing the treatment of diabetes and other metabolic disorders [13,14,15,16,17].

3.2. Dual SGLT1/SGLT2 Inhibitors

Selective SGLT2 inhibitors, while effective, have shown reduced efficacy in diabetic patients with declining renal function. Consequently, additive SGLT1 inhibition has been proposed and confirmed in several clinical studies as beneficial for this patient population. A confirmation that the inhibition of intestinal, rather than renal, SGLT1 is clinically relevant came from testing sotagliflozin (a dual SGLT1/SGLT2 inhibitor) in patients with low filtered glucose in the kidneys. A double-blind, placebo-controlled study showed a significant reduction in postprandial glucose after 7 days of sotagliflozin treatment, which was maintained in patients with an eGFR < 45 mL/min/1.73 m² [24]. Furthermore, dual SGLT1/SGLT2 inhibition offers a promising therapeutic option for all diabetic patients, as it blocks both intestinal and renal glucose absorption. Accordingly, dual SGLT1/SGLT2 inhibitors have emerged as novel agents for the treatment of type 2 diabetes mellitus (T2DM) [5,25]. Sotagliflozin (Figure 4) is the first dual SGLT1/SGLT2 inhibitor approved by the FDA in 2023 to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adults with heart failure and T2DM, chronic kidney disease, and other cardiovascular risk factors. Its potency in inhibiting SGLT2 is comparable to that of selective SGLT2 inhibitors such as dapagliflozin and canagliflozin, while its inhibition of SGLT1 is more than tenfold stronger than these agents [26].

Given the importance of both selective SGLT2 inhibitors and dual SGLT1/SGLT2 inhibitors in modern therapy, an extensive body of experimental and review literature has been published and continues to grow [13,14,15,16,17,18,19,20,25,26]. Therefore, this review does not cover novel selective SGLT2 inhibitors or dual SGLT1/SGLT2 inhibitors. Instead, it focuses on potential inhibitors of SGLT1, SGLT3, SGLT4, SGLT5, and SGLT6 proteins, considering their diverse physiological roles beyond diabetes and cardiovascular disease.

4. Selective Inhibitors of SGLT1 Transporter

As mentioned above, SGLT1 mediates active absorption of glucose and galactose in the intestine. Consequently, SGLT1 inhibition has been shown to delay postprandial intestinal glucose absorption and increase plasma levels of the incretin hormones gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Additionally, SGLT1 plays a role in renal glucose reabsorption. Therefore, selective SGLT1 inhibitors represent promising therapeutic agents for diabetes management, particularly for patients with renal insufficiency, similarly to dual SGLT1/SGLT2 inhibitors [25].

Beyond glucose transport, SGLT1 also facilitates water and urea transport via a channel-like mechanism, which is important for passive water absorption in the small intestine. Thus, SGLT1 inhibition has potential applications in oral rehydration therapy to treat secretory diarrhea [3,5,6,27].

Recent studies have reported overexpression of SGLT1 in various cancers, including breast, lung, pancreatic, and colon cancers. It has been suggested that the epidermal growth factor receptor (EGFR) contributes to this overexpression by promoting increased glucose uptake in cancer cells and supporting their proliferation, possibly through interference with proteasomal degradation of SGLT1. In this context, selective SGLT1 inhibitors could emerge as novel agents in cancer therapy by reducing glucose uptake and thereby inhibiting tumor growth [5].

Although selective SGLT1 inhibitors have not yet reached the market for diabetes or other indications, research into SGLT1 and its inhibitors remains active. Both synthetic compounds and numerous natural substances derived from plants and foods are currently under extensive investigation.

4.1. New Synthetic Selective Inhibitors of SGLT1

The first selective SGLT1 inhibitor to be discovered is KGA-2727 (Figure 5), which exhibits approximately 140-fold higher specificity for human SGLT1 compared to SGLT2, based on inhibition constant values. In diabetic rat models, KGA-2727 effectively reduced plasma glucose levels, improving postprandial hyperglycemia and subsequently lowering glycated hemoglobin. Additionally, it preserved glucose-stimulated insulin secretion, enhanced pancreatic islet morphology, and increased GLP-1 levels [3,28].

More recently, elevated SGLT1 gene expression was observed in human hypertrophic and ischemic cardiomyopathy. Consequently, the effects of KGA-2727 on cardiac remodeling and heart failure were investigated in mice. The results demonstrated that KGA-2727 provided protection against left ventricular remodeling induced by myocardial infarction and heart failure. Nevertheless, further studies are required to clarify its mechanisms of action, particularly to determine whether these effects depend on dosage and the extent of SGLT1 inhibition [29].

The next selective SGLT1 inhibitor is mizagliflozin (Figure 5). Like KGA-2727, it features an O-glucoside structure and a pyrazole derivative in the aglycone moiety. Mizagliflozin was initially developed as an antidiabetic agent aimed at modulating postprandial blood glucose excursions. It exhibits greater specificity for SGLT1 than KGA-2727, with approximately 300-fold higher selectivity for SGLT1 over SGLT2. In a Phase I clinical trial evaluating its antidiabetic potential, mizagliflozin increased stool frequency and loosened stool consistency. These effects prompted further investigation into its potential for treating chronic constipation in animal models. Although mizagliflozin advanced to Phase II clinical trials in humans, it was not approved for medical use. Nevertheless, research on alternative therapeutic applications continues [30].

In a study by Lin et al. (2025), mizagliflozin significantly reduced oxidative stress and downregulated proinflammatory cytokine gene expression, thereby alleviating kidney damage in diabetic mice. It also increased levels of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione, while decreasing malondialdehyde levels. Additionally, mizagliflozin notably suppressed expression of extracellular matrix genes, including collagen type 1 alpha 1 mRNA [31].

Mizagliflozin has also been shown to improve cognitive impairment associated with small vessel disease and nerve damage by inhibiting neuronal SGLT1. In the studies by Ishida et al. (2021, 2022), small vessel disease was induced using a mouse model of asymmetric common carotid artery surgery (ACAS). Mizagliflozin, along with phlorizin, reversed the ACAS-induced reduction in latency to fall in the wire hang test. Both compounds also mitigated the prolonged escape latencies observed in the Morris water maze test following ACAS. However, only phlorizin, and not mizagliflozin normalized proinflammatory cytokine gene expression in the mouse brain and restored cerebral blood flow [32,33].

As discussed in Chapter 1.2., SGLT1 inhibitors are hypothesized to inhibit cancer cell proliferation by blocking glucose uptake. Interestingly, in a study by Tsunokake et al. (2023), mizagliflozin was found to attenuate the growth of MCF-7 breast cancer cells under extremely low-glucose conditions. This suggests that mechanisms other than glucose uptake inhibition may be involved. The authors propose that mizagliflozin may inhibit cancer cell proliferation by blocking phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR-2) [34].

The next selective SGLT1 inhibitor, SY-009 (Figure 5), was confirmed in a Phase I clinical study to effectively reduce postprandial blood glucose levels in patients with T2DM. Additionally, SY-009 significantly decreased postprandial C-peptide and insulin secretion, stimulated GLP-1 secretion, and inhibited GIP secretion in healthy subjects. Pharmacokinetic analysis showed that SY-009 is minimally absorbed into the bloodstream and does not accumulate in the body, suggesting that its primary site of action is the digestive tract, with most of the compound being excreted in the stool [35].

Interestingly, SY-009 was reported to induce significant changes in the bile acid profile, offering new insights into its blood glucose-lowering mechanism. Since bile acids play key roles in regulating systemic metabolism and inflammation, they were studied as targeted quantitative metabolites. Following SY-009 administration, all primary bile acids increased significantly in a dose-dependent manner compared to the placebo group. Moreover, the proportions of free, glycine-conjugated, and taurine-conjugated bile acids in the overall bile acid pool also changed substantially. These findings suggest that SY-009 may promote the conversion of cholesterol to primary bile acids [25].

SGL5213 (Figure 5) is a novel and potent intestinal SGLT1 inhibitor. This orally administered compound exhibits low systemic absorption, with its effects largely confined to GT. In studies reported in the literature, SGL5213 suppressed glucose absorption, leading to improved postprandial hyperglycemia and increased glucose delivery to the lower gut. Additionally, it influenced the secretion of GLP-1 and GLP-2 [36]. SGL5213 was also shown to reduce gut-derived uremic toxins, such as phenyl sulfate and trimethylamine N-oxide, in a model of adenine-induced renal fibrosis (RF). Analysis of the gut microbiota revealed that the Firmicutes/Bacteroidetes ratio, a marker of gut dysbiosis, was elevated in RF, and SGL5213 treatment helped restore this balance. Furthermore, the compound affected bacterial phenol-producing enzymes, which are emerging markers and therapeutic targets in diabetic kidney disease. These findings suggest that modulation of the microbial community and reduction in uremic toxins may contribute to the nephroprotective effects of SGL5213. Given its poor absorption, these data highlight gastrointestinal SGLT1 inhibition as a promising therapeutic target for chronic kidney disease [37].

SGL5213 may also contribute to protective effects against non-alcoholic fatty liver disease (NAFLD). In a rodent model of NAFLD, the inhibition of glucose absorption and the resulting increase in residual glucose in GT due to SGL5213 treatment appeared to provide benefits by reducing caloric intake and modulating intestinal hormones. However, further prospective studies are needed to investigate the effects of SGL5213 in human NAFLD, particularly in cases associated with obesity and insulin resistance [38].

LX2761 (Figure 5) is another potent SGLT1 inhibitor that remains confined to the intestinal lumen after oral administration. In healthy mice and rats, treatment with LX2761 led to lower blood glucose excursions and higher plasma total GLP-1 levels following an oral glucose challenge. In long-term studies involving mice with early- or late-onset experimental diabetes, LX2761 reduced postprandial glucose, fasting glucose, and hemoglobin A1c, while increasing plasma total GLP-1 levels. These findings suggest that clinical trials are warranted to explore whether LX2761 dosing regimens can achieve improved glycemic control with acceptable gastrointestinal tolerability in diabetic patients [24,25,39].

4.2. In Silico Studies

Based on the structure of phlorizin, a non-selective SGLT1/SGLT2 inhibitor, a virtual screening approach identified 400 compounds that aligned well with pharmacophore models. This in silico strategy highlighted promising candidates among phenol glucosides, although challenges remain regarding solubility and pharmacokinetics that require further optimization. The compounds exhibited variable water solubility and moderate lipophilicity, generally complying with drug-likeness rules. However, some limitations were noted, including low absorption in the gastrointestinal tract and an inability to cross the BBB. Molecular docking simulations revealed strong binding affinities to SGLT1, with compound CHEMBL2303983 (Figure 6) demonstrating a particularly high binding energy [40].

Other studies have proposed an intriguing direction for developing SGLT1 inhibitors. While SGLT1 has high affinity for its natural substrates glucose and galactose, it does not transport fructose or structurally similar monosaccharides, although these can bind to the SGLT1 binding pocket. Building on this, modified fructose or sorbose derivatives have the potential to inhibit SGLT1 activity. Designing drugs based on non-glucose sugars could also reduce side effects by replacing the glucose moiety common in most SGLT1 inhibitors [41].

4.3. Medicinal Plant Extracts as Sources of Selective SGLT1 Inhibitors

According to the World Health Organization (WHO), herbal medicine remains the most widely used primary health care modality, especially in developing countries, due to its cultural acceptability, compatibility with the human body, and minimal severe adverse effects. Consequently, the potential of plant bioactive compounds for the prevention and treatment of diabetes is gaining increasing recognition, including their modulatory effects on SGLT proteins [42].

Opuntia dillenii Ker Gawl. (ODSO) is one such medicinal plant traditionally used in Morocco for diabetes management. ODSO is rich in phenolic compounds, among which eleven have been identified, including catechol, cinnamic acid, phenyl propionic acid, psoralen, syringic acid, sinapaldehyde, 3-O-methylcatechin, (+)-gallocatechin, bisdemethoxycurcumin, 4-O-methyl-(–)-epicatechin 3-O-glucuronide, and viscutin 1. These phenolics exhibit strong antioxidant activity and are known for their antidiabetic effects by helping regulate the oxidative imbalance characteristic of diabetic conditions. Using the in situ intestinal single-pass perfusion method and Ussing chamber model, it was demonstrated that ODSO inhibited intestinal D-glucose absorption more effectively than phlorizin. Furthermore, it was confirmed that ODSO blocks glucose transport by inhibiting the SGLT1 protein in the intestine [42].

The potential antidiabetic activity of an ethanolic extract from the leaves of Annona cherimola Miller (A. cherimola), a species of the Annonaceae family, was investigated using isolated minor components from the extract in experimental diabetic mice. Eight polyphenolic compounds were identified: narcissin, hyperin, nicotiflorin, astragalin, isoquercitrin, rutin, myricetin, and chlorogenic acid. Among these, hyperin, myricetin, nicotiflorin, rutin, isoquercitrin, and narcissin demonstrated a significant reduction in hyperglycemic values, while astragalin and chlorogenic acid did not show such effects. Myricetin and rutin were selected as the most potent antihyperglycemic compounds due to their superior ability to lower blood glucose levels. Molecular docking studies targeting the SGLT1 co-transporter revealed that myricetin interacts with seven key amino acid residues (Asn78, His83, Glu102, Thr287, Tyr290, Trp291, Gln457), which are critical for SGLT1 inactivation, as these residues constitute the glucose binding site necessary for transport. In contrast, rutin was found to interact with only three of these residues (Phe101, Tyr290, Gln457). It is hypothesized that steric hindrance prevents rutin from effectively engaging the SGLT1 binding pocket, likely due to its bulky di-glycoside structure, which is incompatible with transport by SGLT1 or GLUT2 [43]. Chemical structures of myricetin and rutin are presented in Figure 7.

In the study by Satsu et al. (2020), the antidiabetic mechanisms of various phytochemicals, namely tangeretin, nobiletin, hesperetin, cardamonin, and sinensetin, were investigated using Caco-2 cells and a CHO cell line expressing human SGLT1. The results showed that tangeretin and nobiletin significantly inhibited SGLT1 activity. Both tangeretin and nobiletin are methoxyflavonoids found in citrus fruits such as Citrus unshiu, Citrus depressa, Citrus tangerina, and Citrus hassaku. Interestingly, while tangeretin and nobiletin showed strong inhibition of SGLT1, sinensetin did not. However, tangeretin, nobiletin, and sinensetin all significantly inhibited fructose uptake via GLUT5 in Caco-2 cells. Structurally, tangeretin and sinensetin each have a flavone backbone with five methoxy groups, whereas nobiletin has six methoxy groups. Despite these structural similarities, only sinensetin failed to inhibit SGLT1, suggesting differences in how these methoxyflavonoids affect SGLT1 and GLUT5. Based on these observations, it was proposed that the methoxy group at position 8 of the A ring, present only in tangeretin and nobiletin, is critical for SGLT1 inhibition but not necessary for GLUT5 inhibition [44]. Chemical structures of tangeretin, nobiletin and sinensetin are presented in Figure 7.

It was also confirmed that cardamonin inhibits SGLT1 activity. Cardamonin is a methoxychalcone (Figure 7) predominantly found in the seeds of Alpinia katsumadai (a ginger plant) and the rhizome of Boesenbergia pandurata (Chinese bamboo shoot). The effects of structural analogs of cardamonin on SGLT1 activity were further investigated, revealing that flavokawain B, sharing the same methoxychalcone scaffold as cardamonin, also exhibited significant SGLT1 inhibitory activity, whereas flavanone derivatives like alpinetin and naringenin showed only limited effects. These findings highlight the importance of the methoxychalcone structure for effective SGLT1 inhibition [44].

3,5,7-trihydroxychromone-3-O-α-L-rhamnopyranoside and 3,5,7,3′,5′-pentahydroxy-flavanonol-3-O-α-L-rhamnopyranoside (Figure 7) derived from Lysiphylum strychnifolium (Craib) A. Schmitz, a traditional Thai medicinal plant, have antioxidant and antidiabetic effects. It was evidenced by α-amylase inhibition activities, α-glucosidase inhibition activities, and decreased glucose absorption in enterocytes of the small intestine by suppressing the gene expression of glucose transporters and inhibiting the binding sites of SGLT1 and GLUT2 in the Caco-2 model. The docking data demonstrated that both compounds could form hydrogen bonds with SGLT1. Disrupting the specific positions where hydrogen bonds occur induces a conformational change in SGLT1, which allows water to penetrate and prevents sugar from binding to the binding site [45].

In the study of Zhouyao et al. (2022), the effect of oat avenanthramides (Figure 7) on human intestinal glucose transporters was examined using Xenopus laevis oocytes expressing GLUT2 or SGLT1, and human Caco-2 cells. As a result, the presence of avenanthramide reduced the glucose uptake in a dose-dependent manner in Caco-2 cells. It was also shown that glucose uptake in oocytes expressing either GLUT2 or SGLT1 was nullified [46].

Glucose uptake via SGLT1 was also significantly inhibited by an aqueous extract of Bistorta officinalis Delarbre rhizome (BODE), when tested in the Caco-2/PD7 model, a Caco-2 clone characterized by high SGLT1 expression. BODE is rich in tannins, predominantly condensed flavan-3-ol derivatives, and demonstrated significant inhibition of intestinal SGLT1. However, when tested in vivo, BODE supplementation failed to confirm antidiabetic effects in the model organism Drosophila melanogaster and did not reduce blood glucose levels in chicken embryos (in ovo). These findings suggest that despite promising in vitro results, BODE is unlikely to be a suitable candidate for developing antidiabetic pharmaceuticals [47].

Additionally, a comprehensive in vitro study reported that several naturally derived pyranocoumarin compounds, such as pteryxin and praeruptorin B (Figure 8), exhibited significant and selective SGLT1 inhibition in cultured CHO and Caco-2 cells. These compounds show potential to modulate transepithelial intestinal glucose absorption, highlighting their promise as therapeutic agents [48].

Given the growing significance of SGLT proteins as targets for novel therapeutic agents, an additional important consideration is the structural resemblance between established inhibitors, such as dapagliflozin, and various naturally occurring compounds, particularly O- and C-linked glycosides of flavones, isoflavones, coumarins, and isocoumarins [49]. Notably, the presence of an isocoumarin moiety in several plant-derived bioactive compounds has prompted further experimental investigation. In the study by Sudarshan and Singh Aidhen (2017), 3-glycosylated isocoumarins (Figure 9) were proposed as novel structural motifs worthy of synthesis and biological evaluation [50].

Ursane and oleanane are pentacyclic triterpenoids that are isomers, differing only in the position of a methyl group attached to either the C-19 or C-20 carbon in the E ring (Figure 10). These compounds naturally occur in many plant species, notably within the Salvia genus. The antihyperglycemic activity of an ethanolic extract from Salvia polystachya and its constituent compounds was evaluated through a combination of in silico, in vivo, and ex vivo approaches. In silico studies aimed to identify the potential binding sites of ursolic acid (UA) and oleanolic acid (OA) on the SGLT1 co-transporter, revealing significant binding affinities for both compounds. Complementary in vivo experiments in diabetic mice, along with ex vivo studies using isolated jejunum and duodenum segments from diabetic rats, suggested that UA and OA may inhibit SGLT1 activity by interacting with an allosteric site rather than the primary glucose binding site [51].

Polysaccharides extracted from the dried fruit of Lycium barbarum L. (LBP) are among the most important active components in traditional Chinese medicine. These polysaccharides consist of monosaccharides such as glucose, xylose, galactose, rhamnose, and mannose. The exact polysaccharide composition varies significantly depending on factors such as the extraction method, temperature, and solvent used, with total polysaccharide content ranging from 50% to 95%. The hypoglycemic effects of LBP in T2DM are likely attributed to multiple mechanisms, including increased insulin sensitivity, amelioration of insulin resistance, regulation of the citrate cycle, modulation of alanine, aspartate, and glutamate metabolism, and adjustment of glyoxylate and dicarboxylate metabolism. Additionally, LBP has been shown to competitively inhibit glucose uptake by reducing the expression of SGLT1 through suppression of its mRNA in Caco-2 cells [52].

4.4. Natural Compounds from Food Potentially Active Towards SGLT1

Grain polyphenols (GBPs) are widely recognized natural bioactive compounds with significant potential for managing chronic metabolic diseases, particularly due to their ability to regulate postprandial hyperglycemia. GBPs primarily consist of two main classes: phenolic acids, such as ferulic acid, and flavonoids, with rutin serving as a representative example. Studies have shown that GBPs can influence the structural conformation and synthesis of intestinal glucose transporters GLUT2 and SGLT1, thereby limiting glucose absorption in the body. Additionally, they activate the GLUT4 pathway, promoting peripheral glucose consumption. GBPs also stimulate the release of short-term satiety signals, which communicate with the hypothalamus via the gastrointestinal–brain axis, helping to suppress food intake and stabilize postprandial glucose levels [53].

Banana flour and peel extract (PGP50), which are rich in phenolic compounds, have shown promise as potential treatments for T2DM. In studies using Caco-2 cells, PGP50 treatment led to a tendency toward decreased SGLT1 protein expression compared to controls, while GLUT2 levels remained unaffected. This suggests that SGLT1 is likely the target transporter for the phenolic compounds present in PGP50. The main phenolics identified in this extract include flavanols and flavones such as 6-C-glucopyranosylepicatechin and (-)-epicatechin 8-C-galactoside [54].

In the study by Liu et al. (2021), the Caco-2 cell system was employed to investigate the effects of various tea extracts on intestinal glucose transport, specifically examining whether tea extracts preferentially inhibit SGLT1-mediated glucose uptake compared to phlorizin. Four types of tea extracts: green tea (GrT), oolong tea (OoT), black tea (BlT), and dark tea (DaT), were tested. The results demonstrated that these tea extracts effectively inhibited SGLT1-mediated glucose transport in the small intestine, with the inhibitory potency ranking as follows: GrT > OoT > BlT > DaT. A strong correlation was observed between the catechin content of the teas and their ability to inhibit SGLT1-mediated glucose transport, suggesting catechins as the key active compounds responsible for the effect of green tea [55].

Additionally, literature reports indicate that β-glucan can inhibit both the α-glucosidase enzyme and the SGLT1 transporter, thereby potentially slowing starch digestion and subsequent glucose absorption. In HEK293 cells expressing SGLT1, β-glucan was shown to inhibit transporter activity in a dose-dependent manner. It is proposed that the structural characteristics of β-glucan allow it to act as a competitive inhibitor, blocking glucose binding and transport by SGLT1 from the intestinal lumen [56].

Another group of natural compounds that can modulate carbohydrate digestion and absorption, as well as influence sugar interactions with SGLT1, are acidic mushroom polysaccharides from Auricularia auricula-judae (AAP) and Tremella fuciformis (TFP). It is known that glucose forms hydrogen bonds with the Glu503 residue in SGLT1, which is important for glucose transport. These mushroom polysaccharides possess a more complex atomic structure, with a greater number of hydrogen bond donors and acceptors compared to glucose, potentially enhancing their binding affinity for SGLT1. Additionally, factors like molecular weight significantly influence the biological activity of these polysaccharides toward their target receptors. The high glucose adsorption capacity of AAP and TFP likely contributes to their inhibitory effect on glucose transport by delaying glucose’s interaction with SGLT1 [57].

Salmon milt extract (SME), rich in nucleotides, particularly deoxyribonucleoside monophosphates, has shown potential anti-obesity effects. In a study, the uptake of radiolabeled glucose derivatives [14C]-methyl-α-D-glucopyranoside and [3H]-2-deoxy-D-glucose, in Caco-2 cells was significantly reduced following SME treatment. Moreover, a mixture containing the four deoxyribonucleoside monophosphates decreased the expression levels of SGLT1 and GLUT2 transporters [58].

Considering the intestine’s critical role in absorbing dietary sugars, inhibiting this process could be a promising therapeutic strategy to modulate postprandial glycemic control, sugar metabolism, and overall metabolic health. In this context, radiolabeled glucose and fructose tracers were used to study transport dynamics in Caco-2 cells to evaluate the antidiabetic potential of coffee pulp, a by-product of wet coffee processing. The coffee pulp analyzed exhibited high fiber content, mostly insoluble, along with notable levels of minerals and total amino acids, particularly hydroxyproline, aspartic acid, glutamic acid, and leucine. Although it contained low fat, mainly saturated, it also had considerable amounts of polyunsaturated fatty acids with a favorable n6/n3 ratio, as well as vitamin E isoforms (α-, β-, and γ-tocopherols). Importantly, a decrease in glucose uptake, but not fructose uptake, was observed, suggesting a selective inhibition of the SGLT1 transporter and highlighting the potential antidiabetic effect of coffee pulp. These encouraging results may be closely linked to the high content of caffeine and chlorogenic acids in the coffee pulp extract [59].

In the study of Erukainure et al. (2023), the effect of leucine alone was examined in isolated jejunum segments, demonstrating a suppression of intestinal glucose absorption. This finding suggests that leucine can delay the digestion of dietary carbohydrates, thereby reducing the postprandial rise in blood glucose levels. Molecular docking and in silico analyses further confirmed the strong interaction of leucine with both SGLT1 and GLUT2 transporters. The inhibition of intestinal glucose absorption by leucine may also involve alleviation of intestinal oxidative stress and cholinergic dysfunction, along with modulation of intestinal purinergic and glucogenic activities. Therefore, leucine shows promise as a potent nutraceutical for managing postprandial hyperglycemia in diabetic patients [60].

5. SGLT3 Inhibitors

Currently, no drugs selectively targeting SGLT3 are commercially available, and there is a lack of data regarding potential selective inhibitors and their biological activities. However, recent findings have shown that some known SGLT2 inhibitors can influence the brain expression of SGLT3. Specifically, marketed drugs such as dapagliflozin and ertugliflozin, may affect brain tissue by reducing SGLT3-mediated glucose entry and modulating electrical activity on neuronal membranes [11]. In the study of Yan et al. (2017), the effect of L-theanine, a non-proteinogenic amino acid responsible for the umami taste and unique flavor of green tea, on SGLTs and GLUTs was investigated in vivo. The results demonstrated that L-theanine administration in rats led to a dose-dependent decrease in intestinal SGLT3 and ileal GLUT5 transcript levels [61].

6. SGLT4 and SGLT5 Inhibitors

SGLT4 is expressed in the small intestine and functions as a low-affinity transporter for glucose, mannose, fructose, and 1,5-AD [5]. In contrast, SGLT5 is highly expressed in the kidney, where it facilitates the transport of fructose and mannose, serving as a primary fructose entry pathway in the renal tubules. Both SGLT4 and SGLT5 expression, along with fructose reabsorption, were found to be upregulated in rats pretreated with a high-fructose diet, indicating an adaptive response of the fructose uptake system to increased tubular fructose load [62,63]. These mechanisms were investigated in male Sprague Dawley rats fed either a normal diet, a diet containing 60% glucose, or 60% fructose. The findings revealed that the high-fructose diet significantly increased sodium reabsorption, primarily through upregulation of SGLT5, which ultimately contributed to salt-sensitive hypertension. In situ hybridization showed that SGLT5 is predominantly expressed in the renal outer medullary layer. Moreover, SGLT5 mRNA, typically minimally expressed under normal conditions, was markedly upregulated by high fructose intake, suggesting that SGLT5 plays a critical role in enhanced sodium reabsorption and elevated blood pressure in this context [64].

Well-known SGLT2 inhibitors, such as empagliflozin, dapagliflozin, and remogliflozin, have also been shown to inhibit human SGLT5. Treatment with these drugs may reduce fructose reabsorption in the pars recta of the proximal tubule via two mechanisms: partial inhibition of SGLT5 itself and competition with glucose in later segments of the nephron. This reduction in fructose reabsorption may contribute to the kidney-protective effects of gliflozins. Considering the role of fructose metabolism in metabolic syndrome and salt-sensitive hypertension, further studies should explore fructose reabsorption and metabolism in the kidney, alongside the effects of inhibiting SGLT2, SGLT4, and SGLT5 during high-fructose diet conditions [65,66,67].

Additionally, while SGLT5 inhibition currently has no direct therapeutic use, its function alongside SGLT4 is important in diagnostic methods for monitoring diabetes therapy. The sugar alcohol 1,5-AG, found in many foods, is a substrate for both SGLT4 and SGLT5 and undergoes renal reabsorption via these transporters. During hyperglycemia, elevated glucose competes with 1,5-AG, impairing its reabsorption and causing increased urinary loss and decreased blood levels. Upon restoration of euglycemia, 1,5-AG blood levels normalize within approximately two weeks. For this reason, the FDA has approved measuring 1,5-AG as a complementary marker for monitoring glycemic control and therapy adherence in diabetic patients, alongside glycosylated hemoglobin testing [64].

Furthermore, certain mutations in SGLT5 have been found to play a protective role in neutropenia caused by glucose-6-phosphatase catalytic subunit 3 (G6PC3) deficiency. In this condition, neutropenia arises from the accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P), an inhibitor of hexokinase derived from 1,5-AG. Rare heterozygous missense mutations in SGLT5 have been linked to milder forms of neutropenia due to increased urinary clearance of 1,5-AG. If these findings are confirmed, selective inhibition of SGLT5 could represent a promising therapeutic strategy for managing neutropenia in children with G6PC3 deficiency [64].

7. SGLT6 Inhibitors

SGLT6 has been previously shown to be expressed in both the small intestine and brain, with particularly strong expression in the hypothalamus and substantia nigra, areas implicated in the regulation of food intake and reward processing. This expression pattern suggests a brain–gut axis role for SGLT6 in nutrient sensing and the integration of reward signals associated with ingestion. In the study by Baader-Pagler et al. (2018), the authors aimed to identify a potent and selective SGLT6 inhibitor capable of central nervous system exposure. A critical goal was to achieve selectivity over SGLT1, since inhibition of SGLT1 is linked to adverse effects such as malaise and gastrointestinal distress. While selectivity versus SGLT2 was preferred, given the established benefits of SGLT2 inhibition in diabetes and cardiovascular mortality, a dual SGLT6/SGLT2 inhibitor would still be considered therapeutically attractive. Through a focused screening campaign followed by structure optimization, a compound termed “Cpd B” was identified, exhibiting both good potency and selectivity for SGLT6. Its apparent permeability in the apical-to-basolateral direction was tested using the Caco-2 cell model and reported as high, indicating favorable intestinal absorption [68].

8. Strengths, Limitations and Future Directions

A key strength of this work is its concise and comprehensive presentation of novel potential inhibitors of SGLT proteins, including isoforms that have not been widely studied to date, namely SGLT1, SGLT3, SGLT4, SGLT5, and SGLT6. The review encompasses both synthetic and natural compounds, including substances derived from medicinal plants and food sources, many of which have not been previously described in the literature concerning SGLT inhibitors. While SGLT inhibitors are primarily recognized for their antidiabetic properties and protective effects in cardiovascular and kidney diseases, this review also highlights their emerging potential in other therapeutic areas such as oxidative stress, inflammation, cancer, neurological disorders, and liver diseases.

However, this study has certain limitations. First, it lacks an in-depth analysis of clinical trial databases. Second, the discussion focuses exclusively on the inhibitory effects of these compounds on individual SGLT isoforms, without exploring alternative mechanisms of action. As demonstrated by the well-studied SGLT2 inhibitors, these compounds exhibit pleiotropic effects through multiple pathophysiological pathways, including the reduction in oxidative stress, preservation of mitochondrial homeostasis, anti-apoptotic activity, inhibition of the sympathetic nervous system, and lowering of blood pressure [4,5,9,13,14,15,16,17]. Given these multifaceted effects, inhibitors targeting other isoforms, such as SGLT1, SGLT3, SGLT4, SGLT5, and SGLT6, should also be investigated across various biological and pathological contexts. Moreover, emerging mechanisms, such as the modulation of non-coding RNAs, particularly through modern computational approaches, warrant further exploration, especially in the context of developing novel cancer therapies [69,70].

9. Conclusions

A review of the current literature highlights that most studies on SGLT1 inhibitors focus on both synthetic compounds and, increasingly, those of natural origin. Several synthetic inhibitors are currently under investigation for their therapeutic potential in the treatment of T2DM, with encouraging prospects for addressing other conditions associated with oxidative stress and inflammation. Among natural compounds, flavonoids, particularly methylated derivatives, have garnered significant attention due to their antidiabetic effects. Additionally, studies examining the binding affinities of various sugars to the SGLT1 structure suggest that modified derivatives of fructose and sorbose may act as effective inhibitors.

Beyond renal glucose reabsorption, novel molecules targeting SGLT 1 through 6 have shown broader effects, particularly on intestinal glucose absorption, thereby expanding their potential therapeutic applications. Emerging research suggests that SGLT inhibitors may have utility in a range of conditions, including cancer, cerebral blood flow enhancement, renal fibrosis, and liver diseases. This growing therapeutic scope, combined with the favorable safety profile of currently approved SGLT2 inhibitors and the increasing identification of novel plant- and food-derived non-SGLT2 inhibitors, as highlighted in this review, supports a promising future for the development of safe and effective therapies targeting various SGLT isoforms.