Senglitin: A New Generation of Highly Selective DPP-4 Inhibitor in China

Senglitin ( Sengliptin ) It is an oral antidiabetic drug belonging to the dipeptidyl peptidase class. -4 ( DPP-4 ) Inhibitors, primarily used for 2 Glycemic control in patients with type 2 diabetes. It works by inhibiting DPP-4 Enzyme activity, enhancing the body’s intestinal incretin hormones ( GLP-1 and GIP ) level, thereby promoting insulin secretion, inhibiting glucagon release, and ultimately lowering blood glucose. It can be used as monotherapy or in combination with metformin, and is characterized by good glycemic control, neutral effects on body weight, and a low risk of hypoglycemia. Type III Phase I clinical studies have shown that its monotherapy 24 Weekly HbA1c can be used ( HbA1c ) Reduce 1.08% , combined metformin therapy can reduce glycated hemoglobin ( HbA1c ) Reduce 1.23% , while also effectively reducing fasting and postprandial blood glucose levels and improving β-cell function. 

　　Basic Information

Time to Market : 2024 year 12 month 

Dosage form: Tablet 

Registration specifications: 50 mg

Registration Category: Chemical drugs 1 Class-new drug 

Indications: This product is indicated for the improvement of glycemic control in adult patients with type 2 diabetes.

Monotherapy: This product, used as monotherapy, may be administered in conjunction with dietary management and exercise to improve glycemic control in adult patients with type 2 diabetes. 

Combination therapy with metformin hydrochloride: When metformin hydrochloride alone is insufficient to achieve adequate glycemic control, this product may be used in combination with metformin hydrochloride to improve glycemic control in adult patients with type 2 diabetes mellitus, in addition to dietary and exercise interventions. 

Important Usage Restrictions: This product is not indicated for patients with type 1 diabetes or diabetic ketoacidosis.

Usage and Dosage The recommended dose of this product, whether used as monotherapy or in combination with metformin hydrochloride, is 50 mg once daily, preferably taken in the morning, with no dietary restrictions.

　 Research and Development Company : Shengshi Taikang Biopharmaceutical Technology (Suzhou) Co., Ltd. 

I. Compound Introduction 

Basic Information 

Chinese Name: Sitagliptin Phosphate Tablets

Chinese alias: Sheng Jiewei 

English Name: Sentagliptin Phosphate Tablets 

CAS Number: 2243737-33-7 

Molecular formula: C 18 H 18 F 6 N 4 O · H 3 PO 4 · H 2 O 

Structural formula: Molecular weight: 536.36

Physical and Chemical Properties 

Appearance and Physical Characteristics: This product is a yellow film-coated tablet; upon removal of the coating, it appears white or off-white. 

Synthetic route

2. Pharmacological Actions 

Saxagliptin phosphate is a dipeptidyl peptidase-4 (DPP-4) inhibitor. DPP-4 rapidly degrades incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Saxagliptin phosphate inhibits DPP-4 activity, thereby reducing the degradation of incretins and increasing the plasma concentrations of active GLP-1 and GIP. This leads to glucose-dependent stimulation of insulin secretion and suppression of glucagon levels, resulting in reduced blood glucose. 

2. Toxicology Research 

Genotoxicity: The results of the Ames test for saxagliptin phosphate, the in vitro chromosomal aberration assay using Chinese hamster lung fibroblasts, and the in vivo bone marrow micronucleus test in rats were all negative. 

Reproductive toxicity: In fertility and early embryonic developmental toxicity studies, male and female rats were orally administered saxagliptin phosphate at doses of 50, 100, and 300 mg/kg/day. At the highest dose of 300 mg/kg/day, a reduction in pregnant rat body weight was observed, along with decreases in the number of corpora lutea, the number of live fetuses, and the live birth rate. Based on AUC, the 300 mg/kg/day dose is approximately 84.7 times (female) and 54.6 times (male) the recommended human therapeutic dose of 50 mg. In the embryo–fetal developmental toxicity study, pregnant rats were orally administered saxagliptin phosphate at 100, 200, and 400 mg/kg/day during the organogenesis period (gestational days 6–15). At all dose levels, reduced maternal body-weight gain and decreased food intake were noted; at 400 mg/kg/day (which, based on AUC, is approximately 289.8 times the recommended human therapeutic dose of 50 mg), there was a decrease in maternal thymus weight and thymus index, as well as increases in stillbirth rate and pre- and post-implantation loss rates. At ≥200 mg/kg/day (approximately 143.2 times the recommended human therapeutic dose of 50 mg, based on AUC), there were increases in the incidence of visceral malformations in fetuses and skeletal malformations such as short ribs and wavy ribs. In pregnant rabbits, saxagliptin phosphate was administered orally at 6, 20, and 60 mg/kg during the organogenesis period (gestational days 6–19); at 60 mg/kg/day (approximately 42 times the recommended human therapeutic dose of 50 mg, based on AUC), a reduction in maternal body weight was observed, but no obvious effects on embryo–fetal development were noted. In the perinatal toxicity study, pregnant rats were orally administered saxagliptin phosphate at 15, 50, and 150 mg/kg/day from gestational day 6 through lactation day 21. At 150 mg/kg/day (approximately 64.8 times the recommended human therapeutic dose of 50 mg, based on AUC), one F0 female rat died on gestational day 22, exhibiting respiratory distress, lethargy, and dark-red discharge around both eyes. At ≥50 mg/kg/day (approximately 21.6 times the recommended human therapeutic dose of 50 mg, based on AUC), F0-generation rats showed reduced body-weight gain and decreased food intake. At 150 mg/kg/day, the birth survival rate and postnatal survival rate of F1 offspring were reduced; at ≥50 mg/kg/day, F1 offspring exhibited lower body weights before and after weaning. No apparent effects were observed in F2 offspring. Saxagliptin phosphate can cross the placental barrier and is also excreted in milk.

Carcinogenicity: Tg-rasH2 mice were orally administered saxagliptin phosphate at doses of 50, 150, and 500 mg/kg/day for 26 consecutive weeks. The incidence of malignant neoplasms in the vehicle control group, low-dose group, mid-dose group, and high-dose group was 2/50, 3/50, 1/50, and 4/50, respectively; the major tumor types included non-adenocytic gastric squamous cell papilloma, hemangiosarcoma, bronchioloalveolar adenoma of the lung, Harderian gland adenoma, and cutaneous glandular carcinoma. Based on AUC, the dose of 500 mg/kg/day of saxagliptin phosphate is approximately 220-fold (female) and 149.7-fold (male) the recommended human therapeutic dose of 50 mg. In a 2-year oral administration study in rats, saxagliptin phosphate was given at doses of 20, 60, and 180 mg/kg/day; the incidence of tumor-related mortality was 15/95, 20/92, 20/88, and 41/90, respectively, with the 180 mg/kg/day group showing a significantly higher rate of tumor-related mortality than the negative control group. At the 180 mg/kg/day dose, there was an increase in the number of animals with metastatic tumors, as well as elevated incidences of hepatocellular adenoma/hepatocellular carcinoma and, in female rats, thyroid follicular cell adenoma/carcinoma. Based on AUC, the dose of 180 mg/kg/day of saxagliptin phosphate is approximately 117-fold (female) and 101-fold (male) the recommended human therapeutic dose of 50 mg.

2. Phase III clinical trial data 

Two randomized, double-blind, multicenter, placebo-controlled Phase III trials were conducted to evaluate the efficacy and safety of saxagliptin phosphate tablets as monotherapy and in combination with metformin in Chinese patients with type 2 diabetes mellitus (T2DM). The results were published in the December 2023 issue of Diabetes, Obesity & Metabolism. Research The results are as follows:

• Therapeutic effect 

1. Monotherapy ： In China 60 Conducted by the Clinical Research Center , a total of 504 position T2DM Patient's intention. 50mg Dose therapy 24 Week, HbA _1c Greater than baseline reduction 1.08% ， Compared with Placebo Group reduction 0.72% ， Demonstrates significant statistical and clinical significance. ； HbA _1c <7.0% Compliance rate 45% , is Nearly in the placebo group 3.5 times 。 HbA1c <7.0% <6.5% Compliance rate 19% Yes of the placebo group Near 10 times; Based on the baseline HbA _1c In the stratified subgroup analysis, baseline HbA _1c ≥8.5% Patients who received sengliptin treatment HbA _1c  The reduction was even greater. Subgroup analysis by duration of disease history also showed that saxagliptin monotherapy can Effectively reduce and improve different T2D M Patients with a history of the disease for X years HbA _1c . In addition, Sengliptin monotherapy Also can Significantly reduce T2DM Patient FPG 、 2 h-PPG 。
2. Combination metformin therapy : A total of were included 446 Example 2: Poor glycemic control with metformin T2DM Patient 。 Treatment 24 week Time , glycated hemoglobin (HbA _1c) Reduce 1.23% , compared with the placebo group, decreased 0.79% , with statistical significance and substantial clinical relevance 。 HbA1c < 7.0% Compliance rate 51.1% It is the placebo group. 3.5 times 。 HbA _1c <6.5% Compliance rate 24.2% It is the placebo group. 5.5 times. Based on the baseline HbA _1c For stratified subgroup analysis and Subgroup analysis by duration of disease history middle ， HbA _1c The reduction exhibited a trend similar to that observed in monotherapy studies. Similarly, saxagliptin in combination with metformin significantly reduced inadequate glycemic control with metformin monotherapy. T2DM Patient FPG 、 2 h-PPG . In addition, Senglitin Also can Significantly improve T2D M Patient beta Cell Function 。 In the nth 24 Weekly, saxagliptin combination therapy improves pancreatic β-cell function. beta Beneficial effects on cellular function have also been observed: 100 mg Group and 50 mg The groups each improved compared with baseline. 16.2% and 14.1% 。

• Safety Sex ： Two items III A recent study shows that, The incidence of adverse events was similar in the saxagliptin treatment group and the placebo group. , common adverse reactions such as upper respiratory tract infection, cough, and urinary tract infection all <1% ; and Whether monotherapy or combination therapy, 24 No hypoglycemic events occurred during the weekly treatment period. 。

Overall Conclusion

Saxagliptin monotherapy or in combination with metformin both significantly reduce blood glucose levels and increase the rate of glycemic control in patients with T2DM, with greater efficacy observed at higher baseline glycemic levels; the recommended dose is 50 mg. No hypoglycemic events occurred. The incidence of common adverse reactions is less than 1%, comparable to that in the placebo group, with clear overall efficacy and a favorable safety profile.

2. Pharmacokinetics

Absorption: Saxagliptin phosphate is rapidly absorbed after oral administration in humans; in healthy subjects, following a single fasting dose (12.5–400 mg), peak plasma concentrations are reached within 1.0–3.25 hours. After 5 consecutive days of once-daily fasting administration of saxagliptin phosphate (50, 100, or 200 mg) to healthy subjects, steady-state conditions are achieved, with the time to reach steady-state peak concentration, T _max,SS For 1 to 1.5 hours, compared with the first dose, the in vivo exposure (C _maximum Both AUC and Cmax increased accordingly, with slight accumulation of exposure. Compared with the fasting state, a high-fat diet did not significantly alter the pharmacokinetic profile of a single oral dose of sengliptin phosphate tablets in healthy Chinese adults. In patients with type 2 diabetes, following a single oral dose of sengliptin phosphate tablets (50 mg or 100 mg), absorption is rapid, with peak plasma concentrations reached at 1 hour and 2 hours, respectively. After once-daily administration for 10 days, steady-state plasma concentrations are achieved, with a time to peak of 1 hour at steady state. 

Distribution: Saxagliptin phosphate exhibits a plasma protein binding rate of 52.87% to 54.32%. 

Metabolism and Excretion: The primary metabolic pathways of saxagliptin phosphate in vivo include oxidative defluorination, monooxygenation, and sulfation or glucuronidation; the total radioactivity in plasma, urine, and feces is predominantly in the form of the parent drug. Following oral administration of ¹⁴C-radioactively labeled saxagliptin phosphate, a total of 91.68% of the administered dose is recovered in urine and feces, with the majority—72.88% of the dose—excreted in the urine and a portion—approximately 18.81% of the dose—excreted in the feces. The estimated elimination half-life (t _One-half ) is 23.4 hours, with a clearance rate of 33.5 L/h. 

2. Adverse reactions

Clinical Trials: The pooled analysis of safety data was derived from two 52-week Phase III clinical trials—one evaluating this product as monotherapy and the other evaluating it in combination with metformin—both of which included a 24-week core treatment period (placebo-controlled) followed by a 28-week extension period during which all participants received 100 mg of this product. Overall safety results demonstrated that this product exhibits a favorable safety and tolerability profile, regardless of whether it is used as monotherapy or in combination with metformin. 

Summary of Adverse Reactions: Adverse reactions reported by subjects receiving this product for 24 weeks with an incidence of ≥1% and higher than that observed with placebo include: hyperuricemia (2.7%), elevated alanine aminotransferase (1.1%), elevated lipase (1.6%), and hypertriglyceridemia (1.3%). 

Hypoglycemia Risk ： At the recommended dose of 50 mg, whether used as monotherapy or in combination with metformin, the incidence of hypoglycemia over the 24-week treatment period was 0%, and no severe hypoglycemic events occurred.

Abnormal liver function: The incidence was low, and no severe hepatic dysfunction occurred. 

Hypersensitivity: No allergic reactions related to this product have been observed. 

Pancreatitis: No cases of pancreatitis were reported in the pooled analysis of two Phase III clinical trials. 

Laboratory tests: Serum amylase and lipase showed a slight upward trend compared with baseline, while no significant changes were observed in other parameters. 

2. Taboo 

Contraindicated in individuals with hypersensitivity to any of the ingredients of this product. 

Eight, Special Groups

Patients with renal insufficiency 

It is recommended to assess renal function prior to initiating this product and to perform periodic assessments thereafter. No dose adjustment is required for patients with mild renal impairment (eGFR ≥60 and <90 mL/min/1.73 m²). Currently, there are no clinical study data on the use of this product in patients with moderate or severe renal impairment; therefore, its use is not currently recommended in such patients. 

Patients with hepatic insufficiency 

To date, no studies have been conducted in patients with hepatic impairment, and there are currently no pharmacokinetic or safety data available for this product in such patients. 

Nine, Drug Interactions 

No clinically significant pharmacokinetic drug interactions were observed when saxagliptin phosphate tablets were co-administered with metformin hydrochloride. To date, no drug interaction studies have been conducted with this product in combination with drugs other than metformin. 

X. References

Instruction Manual for Sitagliptin Phosphate Tablets (National Drug Approval No. H20240043) Shengshi Taikang Biopharmaceutical Technology (Suzhou) Co., Ltd.