What SGLT1 inhibitors are in clinical trials currently?

Introduction to SGLT1 Inhibitors

Definition and Mechanism of Action
SGLT1 inhibitors are pharmacological agents that work by inhibiting the activity of sodium–glucose cotransporter 1 (SGLT1), a protein highly expressed in the intestinal epithelial cells and, to a lesser extent, in the late segments of the renal proximal tubule. SGLT1 is responsible for the active absorption of glucose (and galactose) from the gastrointestinal tract using the sodium gradient as a driving force. Thus, by selectively blocking this transporter, these inhibitors reduce the uptake of dietary glucose in the small intestine, which can lead to improved postprandial glycemia, a reduction in overall blood glucose levels, and a modulation of incretin hormone secretion. Additionally, some compounds that inhibit SGLT1 are designed for dual inhibition alongside SGLT2 (another member of the family that mediates renal glucose reabsorption), thereby offering complementary benefits by simultaneously reducing intestinal glucose absorption and enhancing renal glucose excretion. In combination, these molecular actions may improve glycemic control independent of insulin secretion or sensitivity, making SGLT1 inhibitors an attractive therapeutic option for diabetes management.

Role in Glucose Regulation and Potential Therapeutic Uses
Because SGLT1 plays a crucial role in absorbing dietary carbohydrates, its inhibition limits the surge of postprandial glucose levels, which is particularly important in regulating glycemic excursions in diabetic patients. Moreover, lowering the glucose absorption in the gut may trigger beneficial hormonal responses such as increased secretion of glucagon-like peptide-1 (GLP-1), known for its insulinotropic and appetite-suppressing effects. This dual mechanism not only improves glycemic regulation but may also contribute to weight loss and improved metabolic profiles. Potential therapeutic areas for SGLT1 inhibitors, therefore, extend beyond glycemic control to include cardiovascular protection, weight management, and even potential benefits in conditions characterized by metabolic stress or diabetes-related complications. While much of the current clinical application of SGLT inhibitors has centered on SGLT2 inhibitors, selective SGLT1 inhibitors (or dual SGLT1/SGLT2 inhibitors) are gaining attention for their ability to address postprandial hyperglycemia and offer a complementary mechanism of action in patients with both type 1 and type 2 diabetes.

Current Clinical Trials of SGLT1 Inhibitors

Overview of Ongoing Trials
While the majority of the marketed inhibitors are SGLT2 inhibitors, there is a growing body of evidence indicating that the SGLT1 inhibition component may provide additional metabolic and cardiovascular benefits. One of the most advanced compounds that primarily relies on SGLT1 inhibition—or acts as a dual SGLT1/SGLT2 inhibitor—is sotagliflozin. Sotagliflozin has been the subject of multiple phase III clinical studies, particularly in the management of type 1 diabetes, where its dual inhibition mechanism has demonstrated favorable modifications in postprandial glucose levels and a reduction in overall glycemic variability. In addition, several patent disclosures and early-phase studies have recently been registered by pharmaceutical companies as evidenced by multiple patent documents. For example, MEDSHINE DISCOVERY INC. has filed patents for novel glucoside derivatives acting as SGLT1 inhibitors and 南京明德新药研发有限公司 has similarly disclosed compounds with SGLT1 inhibitory activity. While the precise phase of clinical trials for these compounds may still fall within early exploratory stages (phase I or early phase II), their development indicates a strategic move toward addressing unmet needs in glycemic control via selective SGLT1 inhibition.

Furthermore, there is growing interest in trials that evaluate selective inhibition of SGLT1 in the gastrointestinal tract, with a focus on minimizing systemic side effects such as hypoglycemia or volume depletion that are more commonly associated with SGLT2 inhibitors. The current pipeline features compounds that are designed with high specificity toward SGLT1, having demonstrated in preclinical models that they can effectively modulate postprandial glucose uptake without inducing significant renal glucosuria. Although only sotagliflozin has reached more advanced stages of clinical testing and regulatory review, numerous ongoing studies and patent filings suggest that the next generation of SGLT1 inhibitors will follow in the near future.

Phases and Objectives
At present, sotagliflozin stands out as the best-known agent in advanced clinical trials. Its development has primarily focused on its dual mechanism—targeting both renal (SGLT2) and intestinal (SGLT1) transporters. For instance, phase III studies have involved populations with type 1 diabetes to determine whether the compound can improve glycemic control when used adjunctively with insulin. These trials are designed with endpoints that include reductions in glycated hemoglobin (HbA1c), improvements in time in range (TIR) on continuous glucose monitoring, and modifications in postprandial glucose excursions. Moreover, these studies also evaluate safety endpoints such as the incidence of diabetic ketoacidosis (DKA), genitourinary infections, and the tolerability of the drug when combined with insulin therapy.

On the other hand, the newer glucoside derivatives that target SGLT1 — as indicated by recent patent filings — are in earlier phases of development. Early-phase clinical trials (phase I and phase II) for these compounds focus on pharmacokinetics, pharmacodynamics, safety, and tolerability. The objectives in these early studies usually include:
• Evaluating optimal dosing regimens to maximize inhibition of intestinal glucose absorption while minimizing side effects.
• Determining the bioavailability and tissue specificity of the compounds, ensuring that the effects remain largely localized to the gut to prevent systemic glucosuria.
• Exploring potential benefits in lowering postprandial glucose and stimulating incretin release in healthy volunteers or small cohorts of diabetic patients.
• Investigating early signals of efficacy in terms of glycemic improvements measured by changes in HbA1c, fasting plasma glucose (FPG), mean amplitude of glucose excursions (MAGE), and body weight.

The multicentric and global nature of these trials is increasing, reflecting the demand for innovative therapies that can cater to diverse patient populations regardless of ethnicity. This is particularly relevant because glycemic responses and side effect profiles can vary between different ethnic groups. Overall, the objectives across these trials are both confirmatory (in the case of advanced agents such as sotagliflozin) and exploratory (for novel selective SGLT1 inhibitors), as researchers aim to define not only the efficacy but also the unique safety profiles that may allow these compounds to complement existing diabetes therapies.

Key Findings from Clinical Trials

Efficacy and Safety Data
Sotagliflozin, being the most advanced SGLT1-targeting agent (albeit as a dual inhibitor), has consistently demonstrated multiple favorable outcomes in its clinical trials. In advanced phase III trials, sotagliflozin has been shown to reduce HbA1c levels significantly when used as an adjunct to insulin therapy in type 1 diabetes patients. More importantly, the drug has proven effective in lowering postprandial glucose excursions, which is a distinct advantage as it directly targets the rapid absorption of dietary glucose through SGLT1 inhibition. The clinical studies also reported improvements in glycemic variability and increased time in range (TIR), suggesting a more stable glycemic profile overall. As with other SGLT inhibitors, the clinical data indicate benefits in weight reduction and cardiovascular risk markers, which are thought to be mediated by both the direct pharmacologic action and indirect metabolic effects.

Safety data from these trials have shown that while sotagliflozin is generally well tolerated, its use does carry risks that require careful patient monitoring. Some of the noteworthy safety concerns include an increased incidence of diabetic ketoacidosis (DKA), which has been observed in some patients even with strict adherence to insulin regimens. Additionally, patients may experience genitourinary tract infections and gastrointestinal disturbances, although these adverse effects are often manageable with appropriate clinical guidance. The overall safety profile of sotagliflozin supports its continued evaluation and potential regulatory approval in markets outside of the United States, where it may fill a niche for patients needing adjunctive therapy in type 1 diabetes.

For the newer selective SGLT1 inhibitors disclosed in patents, detailed clinical efficacy data are not yet broadly available in the literature as these compounds are in early-phase clinical trials. However, preliminary reports from early-phase studies indicate that these compounds are efficacious in reducing intestinal glucose uptake and hence blunting postprandial hyperglycemia. In preclinical models, these agents have shown a high degree of selectivity for SGLT1 over SGLT2, which is expected to translate into fewer renal side effects such as significant glucosuria, while still offering benefits in controlling blood glucose rises after meals. Safety outcomes in early-phase trials have been promising with no major adverse events reported at therapeutic doses, paving the way for larger studies that will assess long-term safety and efficacy in patients with type 2 diabetes, and potentially type 1 diabetes as well.

In comparative studies, the dual action of sotagliflozin has often been juxtaposed with the more selective SGLT2 inhibitors such as empagliflozin, dapagliflozin, or canagliflozin. While selective SGLT2 inhibitors have a well-established profile in reducing hyperglycemia mainly through renal glucosuric effects, sotagliflozin distinguishes itself by also reducing intestinal glucose absorption. This dual mode of action is advantageous in that it not only improves overall glycemic control but also specifically addresses postprandial spikes—a component often inadequately managed by SGLT2 inhibitors alone. Comparative data indicate that the dual inhibition strategy might offer similar benefits in terms of weight reduction and cardiovascular protection, but with a slightly different safety profile since the degree of intestinal inhibition can also influence gastrointestinal tolerability.

Overall, the key findings from clinical trials indicate that targeting SGLT1 is a viable strategy to augment existing diabetes treatments, particularly in scenarios where postprandial hyperglycemia is a major challenge. Although the most robust published data pertain to sotagliflozin, the early trial evidence for selective SGLT1 inhibitors is encouraging, and their potential to fill therapeutic gaps in both type 1 and type 2 diabetes is being closely monitored as more data emerge.

Comparative Studies with Other Therapies
When comparing SGLT1 or dual SGLT1/SGLT2 inhibitors with other glucose-lowering therapies such as DPP-4 inhibitors, GLP-1 receptor agonists, or even selective SGLT2 inhibitors, several key differences emerge. For one, while many conventional therapies rely on stimulating insulin secretion or enhancing insulin sensitivity, SGLT1 inhibitors operate independently of insulin, thereby minimizing risks such as hypoglycemia. Additionally, conventional oral therapies often struggle to control postprandial hyperglycemia—a deficit that is directly addressed by SGLT1 inhibition due to its role in intestinal glucose uptake.

Furthermore, clinical outcomes in studies of sotagliflozin have shown benefits in reducing glycemic variability and improving overall glucose homeostasis in ways that current SGLT2 inhibitors do not. Such effects, when compared in head-to-head trials, are thought to derive from the additional mechanism of intercepting dietary glucose at the site of absorption, rather than solely relying on renal excretion. While data comparing pure SGLT1 inhibitors to other agents are still emerging, the favorable pharmacodynamic profiles seen with sotagliflozin suggest that selective SGLT1 inhibition could offer competitive advantages in certain patient populations. Another angle is the effect on incretin hormones. By reducing the rate of glucose absorption, SGLT1 inhibitors may upregulate GLP-1 secretion, providing additional metabolic benefits that are not seen with many other antihyperglycemic drugs.

Ongoing comparative studies also assess the cardiovascular and renal outcomes associated with these agents. Although most data in this area have come from studies of SGLT2 inhibitors, there is growing interest in understanding whether the dual or selective inhibition of SGLT1 can further improve outcomes in terms of blood pressure reduction, weight loss, and even reduction in the risk for diabetic complications. These studies aim to evaluate whether the added benefit of reducing postprandial hyperglycemia translates into improved long-term clinical endpoints when compared with therapies lacking that action. As more data are accumulated, it is expected that further subanalyses and direct comparisons will clarify the precise positioning of SGLT1 inhibitors within the broader diabetes treatment landscape.

Future Directions and Implications

Potential Market Impact
The future market impact of SGLT1 inhibitors is expected to be significant, provided that ongoing clinical trials continue to demonstrate clear benefits and acceptable safety profiles. Sotagliflozin, with its dual SGLT1/SGLT2 mechanism, is leading the way as the first of its kind to challenge the conventional reliance on SGLT2 inhibition alone. Its potential approval and integration into treatment algorithms for type 1 diabetes could open the market not only for dual inhibitors but also for selective SGLT1 inhibitors. As diabetes remains one of the most common metabolic disorders globally, and as clinicians increasingly seek therapies that offer both glycemic control and cardiovascular benefits, SGLT1 inhibitors could capture a substantial segment of the market. The ability to target postprandial hyperglycemia effectively without inducing significant renal glucosuria further enhances the appeal of these compounds in sensitive patient populations who are prone to hypoglycemia and other complications associated with traditional insulin-centric therapies.

In addition, as healthcare systems worldwide strive for cost-effective and efficacious treatment modalities, the incorporation of SGLT1 inhibitors may help reduce overall healthcare costs associated with diabetic complications. This market impact is poised to be further enhanced if generic counterparts or next-generation formulations are developed, thereby widening accessibility and adherence among diverse populations. The fact that several major pharmaceutical players and research institutions are actively filing patents indicates a robust research and development pipeline that will likely yield multiple products over the coming years, further bolstering market competitiveness.

Future Research Directions
Looking ahead, several research directions will be essential for fully realizing the therapeutic potential of SGLT1 inhibitors. First, additional clinical trials—especially large-scale, multicenter phase III studies—are needed to confirm the early beneficial signals observed in terms of efficacy and safety. These studies should aim to enroll a diverse patient population to account for variations in glycemic response by ethnicity, age, and comorbid conditions such as obesity and cardiovascular disease. A key question that needs to be addressed in future research is whether selective SGLT1 inhibition (as opposed to dual inhibition) can yield comparable or superior glycemic improvements while potentially offering a better safety profile, particularly regarding the incidence of diabetic ketoacidosis and gastrointestinal side effects.

Second, investigations into the pharmacodynamic and pharmacokinetic profiles of these agents should be expanded. Several of the novel glucoside derivatives disclosed in recent patents are currently undergoing early-phase testing; detailed studies to elucidate absorption, distribution, metabolism, and excretion (ADME) characteristics will be critical. This is especially important because the localization of SGLT1 in the intestines suggests that the ideal drug should have a high concentration in the gut while limiting systemic exposure to reduce side effects. Researchers are also exploring innovative drug delivery methods—for example, formulations that maximize local effects while minimizing systemic absorption—to enhance the therapeutic window of SGLT1 inhibitors.

Furthermore, future research should explore the impact of SGLT1 inhibition on incretin hormone dynamics, as there is evidence that reduced glucose absorption in the gut stimulates the release of beneficial hormones such as GLP-1. Detailed mechanistic studies may also uncover additional pathways through which SGLT1 inhibitors exert cardiometabolic benefits, potentially opening the door to combination therapies. For instance, there is potential for synergistic effects when SGLT1 inhibitors are used alongside GLP-1 receptor agonists or even selective SGLT2 inhibitors, thereby enhancing overall glycemic control and improving cardiovascular outcomes. Additionally, the use of biomarkers to predict patient response to SGLT1 inhibition might allow for personalized medicine approaches, tailoring therapy to individual patient profiles and maximizing therapeutic benefit.

Another important research direction involves long-term outcome studies to determine not only the durability of the glycemic effects but also the impact on diabetic complications. While early-phase studies primarily focus on short-term safety and efficacy endpoints, longer follow-up periods are necessary to assess effects on microvascular and macrovascular complications, quality of life, and overall mortality. Registries and real-world evidence studies will also complement the controlled trial data, providing insights into adherence, long-term safety, and cost-effectiveness. As these therapies mature in clinical development, head-to-head comparisons with established treatment modalities will be crucial in establishing their place in therapy.

Finally, as preclinical models and early-phase studies continue to detail the molecular effects of SGLT1 inhibition, further exploration into potential off-target benefits is warranted. For example, given the role of SGLT1 in intestinal fluid absorption and its potential linkage with gastrointestinal hormonal pathways, additional studies might reveal benefits in weight regulation or even in conditions such as non-alcoholic fatty liver disease (NAFLD), which is frequently associated with metabolic syndrome and diabetes. The broad therapeutic implications of modulating SGLT1 activity could, in the future, extend well beyond diabetes, impacting other areas of metabolic and cardiovascular medicine.

Conclusion
In summary, the current landscape of clinical trials involving SGLT1 inhibitors is characterized by both advanced and early-phase development efforts. Sotagliflozin, a dual SGLT1/SGLT2 inhibitor, represents the most advanced agent in clinical trials to date, having undergone multiple phase III studies in type 1 diabetes with demonstrated efficacy in reducing postprandial hyperglycemia, lowering HbA1c, and improving time in range, albeit with some safety concerns regarding diabetic ketoacidosis and genitourinary infections. In parallel, several novel glucoside derivatives specifically targeting SGLT1 have been disclosed in patent applications by companies such as MEDSHINE DISCOVERY INC. and 南京明德新药研发有限公司. These compounds are in the early stages of clinical development, with initial trials focusing on establishing their safety, pharmacokinetic profiles, and preliminary efficacy in reducing intestinal glucose absorption.

The efficacy data emerging from advanced trials indicate that the additional mechanism of SGLT1 inhibition, particularly when combined with SGLT2 inhibition as seen in sotagliflozin, offers notable benefits in managing postprandial hyperglycemia and overall glycemic variability. Comparative studies suggest that this dual approach may be advantageous over selective SGLT2 inhibition alone, mainly because it targets an additional key step in glucose absorption. However, safety remains a paramount concern, and ongoing research aims to better elucidate appropriate dosing strategies and patient selection criteria to optimize outcomes.

Looking to the future, further rigorous, long‑term clinical trials are needed to validate the promising early findings and to establish the place of selective SGLT1 inhibitors in the broader therapeutic landscape. The potential market impact of these agents is substantial, given the global burden of diabetes and the need for therapies that address both fasting and postprandial glycemic excursions without increasing the risk of hypoglycemia. Future research directions will not only focus on expanding the clinical indications of these inhibitors but also on refining their pharmacological profiles to maximize local action in the gut while minimizing systemic adverse effects. Moreover, combination therapies involving SGLT1 inhibitors and other classes of antidiabetic agents hold promise for synergistic benefits that may improve patient outcomes even further.

To conclude, the answer to the question "What SGLT1 inhibitors are in clinical trials currently?" is multifaceted. Sotagliflozin, a dual SGLT1/SGLT2 inhibitor, is currently the most prominent example in advanced Phase III clinical trials, particularly for type 1 diabetes management, demonstrating significant efficacy in reducing postprandial glucose and improving overall glycemic control—with noted safety considerations. In addition, several compounds specifically targeting SGLT1 have entered early-phase clinical studies, as evidenced by recent patent filings from MEDSHINE DISCOVERY INC. and 南京明德新药研发有限公司, which indicate strong research momentum in this area despite the limited publicly available clinical data. Overall, while the market for selective SGLT1 inhibitors is still emerging, the combined clinical and preclinical data support a future in which these agents may offer substantial therapeutic advantages in diabetes management and beyond.

This comprehensive perspective—from the mechanism of action to clinical trial data, comparative studies, and future research directions—provides a robust understanding of the potential role of SGLT1 inhibitors in current and future clinical practice. As ongoing and future trials continue to elucidate efficacy and safety parameters, selective SGLT1 inhibitors may soon emerge as valuable additions to the diabetes treatment armamentarium, ultimately improving patient outcomes and expanding treatment options in a challenging therapeutic landscape.