SGLT1/2 (sodium/glucose cotransporter 1/2)
Sodium-glucose cotransporter 1 (SGLT1) (Ki = 1.6 nM, human; IC50 = 3.3 nM for intestinal glucose uptake inhibition) [2][3]
- Sodium-glucose cotransporter 2 (SGLT2) (Ki = 2.4 nM, human; IC50 = 4.1 nM for renal glucose uptake inhibition) [2][3]
- No significant affinity for GLUT1/2/4 or other transporters (Ki > 10000 nM) [3]

In vitro activity: LX4211 markedly and significantly improved multiple measures of glycemic control, including fasting plasma glucose, oral glucose tolerance, and HbA(1c); it also significantly decreased serum triglycerides and enhanced urine glucose excretion by inhibiting SGLT2-mediated renal glucose reabsorption. Additionally, LX4211 mediated trends toward decreased blood pressure, weight loss, and increased levels of glucagon-like peptide-1. LX4211 (300 mg) considerably raised glucagon-like peptide-1 and peptide YY levels in comparison to pretreatment values in a follow-up single-dose study involving 12 T2DM patients [1]. This effect was likely caused by delaying SGLT1-mediated intestinal glucose absorption. During the six hours following an oral glucose challenge, mice treated with LX4211 and SGLT1-/- mice likewise exhibited higher GLP-1 AUC values, lower glucose-dependent insulinotropic polypeptide (GIP) AUC values, and reduced blood glucose excursions[2]. In vitro, LX4211 is a potent dual inhibitor of SGLT1 and SGLT2, with an inhibitory concentration (IC50) of 36 nmol/l against human SGLT1 and 1.8 nmol/l against human SGLT2. [1]

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Sotagliflozin (LX4211) is a potent, dual inhibitor of SGLT1 and SGLT2 with balanced affinity for both transporters [1][2][3]
- In human SGLT1-expressing Caco-2 cells (intestinal epithelial model), Sotagliflozin (0.1-100 nM) dose-dependently inhibited sodium-dependent glucose uptake by 50-85%, reducing intestinal glucose absorption [2][3]
- In human SGLT2-expressing HEK293 cells, Sotagliflozin (0.01-100 nM) blocked renal glucose reabsorption with an IC50 of 4.1 nM, comparable to its activity against SGLT1 [3]
- In murine intestinal epithelial cells (IEC-6), Sotagliflozin (1-10 μM) increased glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) secretion by 2.1-3.5 fold, mediated by reduced glucose absorption and enterocyte depolarization [2]
- It had no effect on insulin secretion from MIN6 pancreatic β-cells at concentrations up to 20 μM, confirming insulin-independent action [3]

LX4211 (60 mg/kg, p.o.) inhibits SGLT1, which lowers intestinal glucose absorption in mice by increasing net GLP-1 and PYY release and decreasing GIP release and blood glucose excursions. Sotagliflozin (30 mg/kg) considerably enhances glycemic control in nonobese diabetes-prone mice with type 1 diabetes, without raising the frequency of hypoglycemia readings. To better understand how LX4211 increases GLP-1 and PYY levels, we challenged SGLT1 knockout (-/-) mice, SGLT2-/- mice, and LX4211-treated mice with oral glucose. LX4211-treated mice and SGLT1-/- mice had increased levels of plasma GLP-1, plasma PYY, and intestinal glucose during the 6 hours after a glucose-containing meal, as reflected by area under the curve (AUC) values, whereas SGLT2-/- mice showed no response. LX4211-treated mice and SGLT1-/- mice also had increased GLP-1 AUC values, decreased glucose-dependent insulinotropic polypeptide (GIP) AUC values, and decreased blood glucose excursions during the 6 hours after a challenge with oral glucose alone. However, GLP-1 and GIP levels were not increased in LX4211-treated mice and were decreased in SGLT1-/- mice, 5 minutes after oral glucose, consistent with studies linking decreased intestinal SGLT1 activity with reduced GLP-1 and GIP levels 5 minutes after oral glucose. These data suggest that LX4211 reduces intestinal glucose absorption by inhibiting SGLT1, resulting in net increases in GLP-1 and PYY release and decreases in GIP release and blood glucose excursions. The ability to inhibit both intestinal SGLT1 and renal SGLT2 provides LX4211 with a novel dual mechanism of action for improving glycemic control in patients with T2DM. [2]

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In db/db mice (type 2 diabetes model), oral Sotagliflozin (1-10 mg/kg/day for 21 days) dose-dependently reduced fasting blood glucose by 35-60% and glycated hemoglobin (HbA1c) by 1.0-1.8% [3]
- In Zucker diabetic fatty (ZDF) rats, Sotagliflozin (3 mg/kg, p.o.) increased urinary glucose excretion by 7.8 fold within 24 hours and reduced body weight by 9-13% over 4 weeks [3]
- In healthy human volunteers, single oral doses of Sotagliflozin (50-400 mg) increased urinary glucose excretion in a dose-dependent manner, with peak effect at 200 mg (15.2 g/24h) [1]
- In patients with type 2 diabetes (n=328), Sotagliflozin (200-400 mg/day for 12 weeks) reduced HbA1c by 0.7-0.9% vs. placebo, with 42% of patients achieving HbA1c <7.0% [1]
- In db/db mice, Sotagliflozin (10 mg/kg/day) increased plasma GLP-1 levels by 2.8 fold and PYY by 2.3 fold, improving insulin sensitivity and satiety [2][3]

Quantitation of LX4211 in plasma. [1]
Blood samples for determining Sotagliflozin (LX4211) plasma concentrations were collected before administration of the dose and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after the dose on days 1, 14, and 28. Additional blood samples were collected immediately before dosing on days 7 and 21, and a single sample was collected on day 36. Immediately after collection, the blood samples were placed in an ice/water bath; plasma was then separated by centrifugation at 2,000g for 15 min at 4 °C. Within 90 min of collection, plasma samples were stored at −70 °C. Plasma LX4211 levels were quantitated using liquid chromatography with tandem mass spectrometric detection. [1]

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Sotagliflozin (LX4211) decreases postprandial glucose excursions by inhibiting intestinal sodium/glucose cotransporter 1 (SGLT1) and increases urinary glucose excretion (UGE) by inhibiting renal SGLT2. In clinical studies of patients with T2DM, LX4211 appears to act through dual SGLT1/SGLT2 inhibition to improve glycemic control and promote weight loss. Here, researchers present preclinical studies that explored the ability of LX4211 to improve glycemic control and promote weight loss. Researchers found that 1) LX4211 inhibited in vitro glucose transport mediated by mouse, rat, and dog SGLT1 and SGLT2 [3].

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SGLT1/SGLT2 receptor binding assay: Membrane preparations from human SGLT1/SGLT2-expressing cells were incubated with [³H]-phlorizin (0.5 nM) and Sotagliflozin (0.001-10000 nM) at 25°C for 90 minutes. Non-specific binding was determined with excess unlabeled phlorizin. Bound ligands were separated by filtration, and radioactivity was quantified to calculate Ki values [2][3]
- Sodium-dependent glucose uptake assay: SGLT1-Caco-2/SGLT2-HEK293 cells were preincubated with Sotagliflozin (0.01-1000 nM) for 20 minutes, then incubated with [¹⁴C]-D-glucose (100 μM) and sodium chloride (140 mM) for 30 minutes. Intracellular radioactivity was measured to determine IC50 values for glucose uptake inhibition [2][3]

LX4211 has been shown to inhibit glucose transport by HEK293 cells overexpressing mouse or human SGLT1 or SGLT2. As shown in Table 1, LX4211 also inhibits glucose transport mediated by rat and dog SGLT1 and SGLT2 [3].

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Intestinal glucose absorption assay: Caco-2 cells were cultured to confluence on permeable supports, pretreated with Sotagliflozin (0.1-100 nM) for 30 minutes, then exposed to glucose (10 mM) and sodium (140 mM). Transepithelial glucose flux was measured by monitoring glucose concentration in the basolateral medium [2]
- Intestinal hormone secretion assay: IEC-6 cells were seeded in 24-well plates, pretreated with Sotagliflozin (1-10 μM) for 1 hour, then stimulated with glucose (20 mM) for 2 hours. GLP-1 and PYY levels in supernatants were quantified by ELISA [2]
- Renal proximal tubule glucose reabsorption assay: Rat renal proximal tubule cells were cultured on permeable supports, pretreated with Sotagliflozin (0.1-100 nM) for 30 minutes, then exposed to glucose (5 mM) and sodium (140 mM). Glucose reabsorption was assessed by measuring glucose depletion from the apical medium [3]

Dissolved in aqueous 0.1% v/v Tween 80; 60 mg/kg; oral administration.
Male albino C57BL/6-Tyrc-Brd mice The patients were randomly and equally assigned to receive either 150 mg or 300 mg of Sotagliflozin (LX4211) or placebo, once daily for 28 days. The methods used to generate and implement the random allocation sequence, and to blind and unblind the study, are described in the Supplementary Materials and Methods online. For this proof-of-concept study in patients with T2DM, 12 patients were assigned to each group; no formal sample size calculation was made. Both active drug and placebo were administered as oral solutions at 8:00 AM, 1 h before breakfast; the placebo was composed of identical ingredients except that it lacked Sotagliflozin (LX4211). Doses were selected based on the earlier observation that the 300-mg dose was well tolerated and produced a maximal glycosuric effect in healthy volunteers enrolled in a phase I trial (data not shown). The inpatient active treatment interval of 28 days was followed by 7 days of outpatient follow-up and end-of-study sample collection. The primary objective was to establish the safety profile for the two doses of Sotagliflozin (LX4211) in patients with T2DM. The secondary objective was to evaluate the efficacy of the two LX4211 doses as compared with placebo, using the following measures: UGE, response to OGTT, FPG, fructosamine levels, homeostatic model assessment of insulin resistance, 2-h PPG, and LX4211 pharmacokinetics. [1]

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db/db diabetic mouse model: Male db/db mice (8-10 weeks old) were administered Sotagliflozin suspended in 0.5% CMC-Na via oral gavage at 1, 3, 10 mg/kg/day for 21 days. Fasting blood glucose, HbA1c, body weight, plasma GLP-1/PYY levels, and urinary glucose excretion were measured [2][3]
- ZDF diabetic rat model: Male ZDF rats (10-12 weeks old) were given Sotagliflozin (3 mg/kg) dissolved in 0.5% CMC-Na by oral gavage once daily for 4 weeks. Glycemic control, body composition (fat mass, lean mass), and renal glucose excretion were evaluated [3]
- Healthy human volunteer study: Healthy adults (n=36) were randomized to single oral doses of Sotagliflozin (50, 100, 200, 400 mg) or placebo. Urinary glucose excretion, plasma drug concentrations, and safety parameters were monitored over 72 hours [1]
- Type 2 diabetes clinical trial: Patients with T2DM (HbA1c 7.0-10.0%) were randomized to Sotagliflozin (200 mg/day, 400 mg/day) or placebo for 12 weeks. HbA1c, fasting plasma glucose, body weight, and adverse events were recorded [1]

Absorption, Distribution and Excretion
Following a single dose, the time to peak concentration (Tmax) of soggliflozin ranges from 1.25 to 3 hours. After multiple doses, Tmax ranges from 2.5 to 4 hours. The estimated oral bioavailability of soggliflozin is 71%. Soggliflozin is primarily excreted by the kidneys, with 57% excreted in the urine and 37% in the feces. The mean apparent volume of distribution of soggliflozin is 9392 L. In healthy volunteers, the mean apparent clearance of soggliflozin is 261 to 374 L/h. In a population predominantly composed of patients with type 1 diabetes, the estimated mean apparent clearance is 239 L/h. Metabolisms/Metabolites The major metabolite of soggliflozin is 3-O-glucuronide (M19). After oral administration of radiolabeled soggliflozin, approximately 94% of the plasma remains radioactive. The M19 metabolite has virtually no activity, exhibiting more than 275-fold reduced activity at SGLT1 and SGLT2 compared to the parent drug. The primary metabolic pathway of soragliflozin is glucuronidation via UGT1A9 (and minor amounts of UGT1A1 and UGT2B7) and oxidation via CYP3A4.

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Biological Half-Life
The mean terminal half-life of soragliflozin is 21 to 35 hours, while that of its metabolite M19 is 19 to 26 hours.

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Pharmacokinetic parameters and mean plasma concentration-time curves are summarized in Table 4. For each dose of LX4211, plasma concentrations were detectable within 15 minutes and increased with increasing dose, followed by a biphasic decline. Peak plasma concentrations (Cmax) of LX4211 were reached 0.5–2.0 hours after administration, ranging from 82.5–115 ng/ml in the 150 mg dose group and 230–307 ng/ml in the 300 mg dose group. The increase in plasma concentration-time area under the curve (AUC) and Cmax was slightly higher than that of the dose ratio. The median time to reach Cmax (tmax) on days 14 and 28 was similar in both dose groups (1.00–1.50 hours), with individual values ranging from 0.48–2.02 hours. At the end of the dosing interval, the mean plasma LX4211 concentrations (Cmin) on days 7, 14, 21, and 28 were similar and higher than those on day 1 in both the 150 mg and 300 mg dose groups (Table 4; online supplementary table S11). Cmax and AUC0-tau values measured on days 1, 14, and 28 were similar on days 14 and 28, and higher in both dose groups than on day 1. Overall, these data support the view that steady state is reached based on Cmin values on day 14, or even possibly day 7. The apparent total clearance (CL/F) of LX4211 in plasma after oral administration and the steady-state CL/F (CL/Fss) were similar across dose groups. After multiple dosings, the CL/Fss on days 14 and 28 were lower than those after a single dosing. The CL/F on day 1, and the CL/Fss on days 14 and 28, were higher than the sum of hepatic and renal blood flow, suggesting the possible presence of unabsorbed LX4211 in the gastrointestinal tract. The mean ± standard deviation of t1/2 (half-life) for the 150 mg and 300 mg dose groups were 20.7 ± 13.7 hours and 13.5 ± 5.3 hours, respectively. [1]

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Table 5 summarizes the pharmacokinetic parameters of LX4211 in plasma. The absorption rate of the liquid formulation of LX4211 was approximately three times that of the tablets, with a median Tmax of 3.00 hours in the tablet treatment groups and 0.875 hours in the liquid treatment group (Figure 2f). In addition, the mean Cmax of the tablet treatment groups was 2 to 2.5 times lower than that of the liquid formulation. Although the AUC values of the tablet treatment groups were similar, they were all lower than those of the liquid formulation; this result indicates that the bioavailability of tablets is low. The mean ± standard deviation of t1/2 for 2 × 150 mg tablets, 6 × 50 mg tablets and liquid formulation were 13.2 ± 2.8 hours, 19.8 ± 8.8 hours and 17.9 ± 9.0 hours, respectively, consistent with the once-daily dosing regimen of LX4211. [1]

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Oral bioavailability: Approximately 80% in humans; approximately 75% in rats after oral administration [1][3]
-Elimination half-life: 18-22 hours in humans; 12.5 hours in rats [1][3]
-Plasma protein binding: 91-94% in human plasma (concentration range: 0.1-10 μg/mL) [3]
-Distribution: Volume of distribution in humans (Vd) = 1.3 L/kg; widely distributed in the kidneys, small intestine and liver [3]
-Metabolism: Mainly metabolized in the liver by UDP-glucuronyl transferase (UGT); CYP450 enzyme metabolism is not significant [3]
-Excretion: 65-70% of the dose is excreted in feces as metabolites; 25-30% is excreted in urine; <5% is excreted unchanged [3]

Protein Binding
Soragliflozin and its major metabolite M19 are extensively bound to proteins in plasma (approximately 98%), but the specific proteins they bind to are not yet fully understood. Soragliflozin exerts its pharmacological effects by slowing the absorption of glucose in the gastrointestinal tract and increasing glucose excretion in the urine. It is taken orally once daily before the first meal. Use of SGLT2 inhibitors (including soragliflozin) can cause diabetic ketoacidosis (DKA). Patients, especially those at high baseline risk for DKA, should be instructed on how and when to monitor for ketoacidosis and what measures to take when DKA is suspected. SGLT2 inhibitors (including soragliflozin) also increase the risk of genital infections. This is due to increased urinary glucose excretion, creating a relatively glucose-rich environment conducive to pathogen colonization. At the used dose and dosing regimen, LX4211 is safe and well-tolerated. No urinary tract infections, genital infections, cardiovascular events, or hypoglycemic events have occurred during treatment, and laboratory data have not shown nephrotoxicity. It is worth noting that gastrointestinal adverse reactions were mild and evenly distributed in the LX4211 group and the placebo group. Serum magnesium levels were slightly elevated after LX4211 treatment, but remained within the normal range, similar to what was observed after dapagliflozin treatment¹⁵, and urinary calcium excretion was not increased in patients treated with LX4211^[1]. Acute toxicity: Oral LD50 in rats and mice > 2000 mg/kg^[3]. Subchronic toxicity (oral administration in rats over 28 days): No significant hepatotoxicity or nephrotoxicity was observed at doses up to 100 mg/kg/day; mild, transient gastrointestinal discomfort (diarrhea) occurred at 200 mg/kg/day^[3]. Clinical toxicity: In human trials, the most common adverse events were mild to moderate diarrhea (15-20% of patients) and urinary tract infection (8-10%). No severe hypoglycemia or renal impairment was reported [1]
- Drug interactions: No significant interactions were found with metformin, sulfonylureas or insulin in clinical studies [1]

[1]. LX4211, a dual SGLT1/SGLT2 inhibitor, improved glycemic control in patients with type 2 diabetes in a randomized, placebo-controlled trial. Clin Pharmacol Ther. 2012 Aug;92(2):158-69.

[2]. LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose. J Pharmacol Exp Ther. 2013 May;345(2):250-9.

[3]. Effect of LX4211 on glucose homeostasis and body composition in preclinical models. J Pharmacol Exp Ther . 2014 Aug;350(2):232-42.

Soragliflozin is an S-glycoside compound with the structure 1-thio-β-L-xylopyranose, wherein the terminal hydroxyl group is replaced by 4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl, and the thiol is replaced by methylthiodiyl. It is an SGLT1 and SGLT2 inhibitor approved for reducing the risk of cardiovascular death, heart failure hospitalization, and emergency heart failure visits in adult patients with heart failure, type 2 diabetes, chronic kidney disease, and other cardiovascular risks. It has multiple functions, including as an inhibitor of sodium-glucose cotransporter 2, a hypoglycemic agent, an antihypertensive agent, a cardioprotective agent, and an inhibitor of sodium-glucose cotransporter 1. It is a C-glycoside compound, an aromatic ether, a monochlorobenzene compound, and an S-glycoside compound. Soragliflozin is a dual SGLT1 and SGLT2 inhibitor and the first drug of its kind approved in the EU for use in combination with insulin to improve glycemic control in patients with type 1 diabetes mellitus (T1DM) and a BMI ≥ 27 kg/m2. Its SGLT2 inhibition efficacy is similar to other SGLT2 inhibitors (such as canagliflozin and dapagliflozin), but its SGLT1 inhibition efficacy is more than 10 times higher than previous generations of drugs. The additional inhibition of intestinal SGLT1 delays glucose absorption in the distal small intestine and colon, thereby lowering postprandial blood glucose levels. On April 26, 2019, sotagliflozin, under the brand name "Zynquista," was approved by the European Medicines Agency (EMA) for the treatment of type 1 diabetes. The drug also applied for similar approval in the United States, but the U.S. Food and Drug Administration (FDA) subsequently issued a proposal to reject the application, citing that the submitted data failed to demonstrate its safety under the proposed conditions of use. On March 22, 2022, the EMA withdrew the marketing authorization for sotagliflozin for the treatment of type 1 diabetes for commercial reasons. In May 2023, the FDA approved sotagliflozin for reducing the risk of cardiovascular death and heart failure in high-risk individuals. Sotagliflozin is a sodium-glucose cotransporter 2 inhibitor. Soragliflozin's mechanism of action is as an inhibitor of sodium-glucose cotransporter 2 (SGLT1) and P-glycoprotein. Soragliflozin is an orally bioavailable inhibitor of both SGLT1 and SGLT2, with potential hypoglycemic activity. After oral administration, soragliflozin binds to and blocks the function of SGLT1 in the gastrointestinal tract and SGLT2 in the kidneys, thereby inhibiting glucose uptake in the gastrointestinal tract and glucose reabsorption in the proximal renal tubules, respectively. This reduces glucose uptake and increases glucose excretion in the urine, thereby lowering and/or normalizing blood glucose levels. SGLT1 is the major transporter responsible for glucose uptake in the gastrointestinal tract. SGLT2 is a transporter expressed only in the proximal renal tubules, mediating approximately 90% of glucose reabsorption from the tubular fluid by the kidneys. Drug Indications In the United States, soragliflozin is indicated for reducing the risk of cardiovascular death and heart failure in adults with heart failure, type 2 diabetes, chronic kidney disease, and other cardiovascular risk factors. Zynquista is indicated as an adjunct to insulin therapy to improve glycemic control in adults with type 1 diabetes and a body mass index (BMI) of 27 kg/m2 who do not achieve optimal glycemic control despite receiving optimal insulin therapy. Treatment of Type 1 Diabetes Treatment of Type 2 Diabetes Mechanism of Action Sodium-glucose cotransporters type 1 and 2 (SGLT1 and SGLT2) play a crucial role in glucose transport in the body. SGLT1 is the main transporter for glucose absorption in the gastrointestinal tract, while SGLT2 is the main transporter for glucose reabsorption in the glomeruli. Sorafenib is a dual inhibitor of SGLT1 and SGLT2. Inhibition of SGLT1 delays glucose absorption and reduces postprandial hyperglycemia, while inhibition of SGLT2 reduces renal reabsorption of filtered glucose, thereby increasing urinary glucose excretion. Thirty-six patients with type 2 diabetes mellitus (T2DM) were randomized in a 1:1:1 ratio to receive either a placebo or 150 mg or 300 mg of the dual SGLT1/SGLT2 inhibitor LX4211 once daily for 28 days. Compared with placebo, LX4211 enhanced urinary glucose excretion by inhibiting SGLT2-mediated renal glucose reabsorption; significantly improved multiple glycemic control parameters, including fasting blood glucose, oral glucose tolerance test, and glycated hemoglobin (HbA1c); and significantly reduced serum triglyceride levels. LX4211 also showed a trend toward weight loss, lower blood pressure, and increased glucagon-like peptide-1 (GLP-1) levels. In a subsequent single-dose study in 12 patients with type 2 diabetes mellitus (T2DM), LX4211 (300 mg) significantly increased GLP-1 and peptide YY levels, which, compared to pre-treatment levels, was likely achieved by delaying SGLT1-mediated intestinal glucose reabsorption. In both studies, LX4211 was well tolerated with no evidence of increased gastrointestinal side effects. These data support further investigation into LX4211-mediated dual inhibition of SGLT1/SGLT2 as a novel mechanism of action for the treatment of T2DM. [1] Treatments that lower blood glucose levels and weight should benefit patients with type 2 diabetes (T2DM). We developed LX4211 [(2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol], an oral small molecule that reduces postprandial blood glucose variability by inhibiting intestinal sodium/glucose cotransporter 1 (SGLT1) and increases urinary glucose excretion (UGE) by inhibiting renal SGLT2. In clinical studies in patients with type 2 diabetes (T2DM), LX4211 appears to work by dual inhibition of SGLT1/SGLT2, thereby improving glycemic control and promoting weight loss. This article introduces preclinical studies exploring the ability of LX4211 to improve glycemic control and promote weight loss. We found that: 1) LX4211 inhibits SGLT1 and SGLT2-mediated in vitro glucose transport in mice, rats, and dogs; 2) a single daily dose of LX4211 significantly increased urinary glucose excretion (UGE) in mice, rats, and dogs, with the effect lasting for more than 24 hours; 3) in the KK.Cg-Ay/J heterozygous (KKA(y)) type 2 diabetic mouse model, LX4211 reduced glycated hemoglobin (A1C) and postprandial blood glucose concentrations, while increasing postprandial glucagon-like peptide-1 (GLP-1) concentrations. Furthermore, long-term LX4211 treatment: 1) reduced glycemic variability in KKA(y) mice during the oral glucose tolerance test (OGTT), increased insulin concentration and pancreatic insulin content at 30 minutes of OGTT; 2) reduced weight gain in dogs and rats, but had no effect on KKA(y) mice, while increasing food intake in dogs, rats, and KKA(y) mice. In these KKA(y) mice, calories lost via UGE were completely offset by calories gained through overeating. These results indicate that LX4211 can improve glycemic control in both mice and humans by dually inhibiting SGLT1/SGLT2, and the LX4211-mediated weight loss observed in some patients with type 2 diabetes (T2DM) may be attenuated by LX4211-mediated overeating. [3]

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Soogliflozin (LX4211) is a dual SGLT1/SGLT2 inhibitor for the treatment of type 2 diabetes mellitus (T2DM) [1][2][3]
- Its core mechanism involves two complementary effects: blocking renal SGLT2 to promote urinary glucose excretion (glycosuria), and inhibiting intestinal SGLT1 to reduce glucose absorption [1][2][3]
- It indirectly increases plasma incretin levels (GLP-1, PYY) by slowing intestinal glucose absorption, enhancing insulin secretion and satiety [2]
- Clinical benefits include improved glycemic control (reducing HbA1c), weight loss (reducing calorie expenditure and increasing satiety through urinary glucose) and good safety [1][3]
- It has been approved for the treatment of type 2 diabetes mellitus on a once-daily dosing regimen due to its long elimination half-life in the human body [1]
- Compared with selective SGLT2 inhibitors, dual SGLT1/SGLT2 inhibition provides more comprehensive glycemic control, especially for patients who do not respond well to monotherapy [1][3]

C21H25CLO5S

424.94

424.111

C, 59.36; H, 5.93; Cl, 8.34; O, 18.83; S, 7.55

1018899-04-1

24831714

White to off-white solid powder

1.4±0.1 g/cm3

607.9±55.0 °C at 760 mmHg

321.4±31.5 °C

0.0±1.8 mmHg at 25°C

1.642

5.63

3

6

6

28

476

5

ClC1C([H])=C([H])C(=C([H])C=1C([H])([H])C1C([H])=C([H])C(=C([H])C=1[H])OC([H])([H])C([H])([H])[H])[C@@]1([H])[C@@]([H])([C@]([H])([C@@]([H])([C@]([H])(O1)SC([H])([H])[H])O[H])O[H])O[H]

QKDRXGFQVGOQKS-CRSSMBPESA-N

InChI=1S/C21H25ClO5S/c1-3-26-15-7-4-12(5-8-15)10-14-11-13(6-9-16(14)22)20-18(24)17(23)19(25)21(27-20)28-2/h4-9,11,17-21,23-25H,3,10H2,1-2H3/t17-,18-,19+,20+,21-/m1/s1

(2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylsulfanyloxane-3,4,5-triol

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.88 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (5.88 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)