Use of GLP-1 receptor agonist in treatment of diabetes

Abstract

The use of a GLP-1 receptor agonist in the treatment of diabetes. Specifically, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of diabetes.

Description

Use of GLP-1 receptor agonists in the treatment of diabetes Technical Field

[0001] This disclosure relates to the use of GLP-1 receptor agonists in the treatment of diabetes. Background Technology

[0002] Diabetes mellitus is a group of metabolic diseases characterized by chronic hyperglycemia caused by multiple factors. Long-term hyperglycemia can cause multi-system damage, leading to chronic progressive lesions, functional decline, and failure of organs and tissues such as the eyes, kidneys, nerves, heart, and blood vessels. According to the 10th edition of the International Diabetes Federation's Global Diabetes Atlas in 2021, there were 537 million people with diabetes worldwide (a prevalence of 10.5%), with China having approximately 140.9 million, ranking first. Diabetes and its complications are placing a huge economic burden on healthcare systems worldwide. Type 2 diabetes accounts for more than 90% of all diabetes cases.

[0003] Type 2 diabetes currently lacks a proper etiological treatment and is primarily managed through a comprehensive approach, including dietary control, appropriate exercise, blood glucose monitoring, diabetes education, and the use of hypoglycemic drugs. Domestically available hypoglycemic drugs mainly include biguanides, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase IV (DPP-4) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and insulin. Despite the abundance of available treatment options, the treatment and control rates of diabetes in China still need improvement; a 2013 epidemiological survey showed rates of 32.2% and 49.2%, respectively.

[0004] Most patients with type 2 diabetes require more than one medication to control their blood sugar. Combination therapy is an important model for the comprehensive management of type 2 diabetes patients. Domestic guidelines recommend metformin as the first-line hypoglycemic agent for patients with type 2 diabetes. If blood sugar is not controlled with metformin alone, it should be combined with other hypoglycemic agents such as SGLT2 inhibitors. The 2024 American Diabetes Association (ADA) guidelines emphasize "appropriate blood sugar control, weight management, and improved cardiovascular and renal outcomes," specifically for type 2 diabetes patients with atherosclerotic cardiovascular disease, high risk of atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, regardless of glycated hemoglobin (HbA1c). 1cWhether or not the blood glucose level is within the target range, treatment with SGLT2 inhibitors or GLP-1 receptor agonists with proven clinical benefits can be initiated. The new guidelines also point out that if conditions permit, GLP-1 receptor agonists should be the first choice over insulin when injectable hypoglycemic drugs are needed. For those who must use insulin, it is recommended to use GLP-1 receptor agonists in combination, which further affirms the superior position of GLP-1 receptor agonists in the comprehensive management of patients with type 2 diabetes. Summary of the Invention

[0005] This disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating type 2 diabetes; in some embodiments, the type 2 diabetes is type 2 diabetes previously treated with metformin:

[0006] This disclosure also provides a method for treating type 2 diabetes, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; in some embodiments, the type 2 diabetes is type 2 diabetes previously treated with metformin:

[0007] This disclosure also provides a method for treating type 2 diabetes with a compound of formula (I) or a pharmaceutically acceptable salt thereof; in some embodiments, the type 2 diabetes is type 2 diabetes previously treated with metformin:

[0008] This disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof with metformin in the treatment of type 2 diabetes.

[0009] In some embodiments, this disclosure provides a method of treating type 2 diabetes, comprising administering a patient a therapeutically effective amount of metformin and a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0010] In some embodiments, this disclosure provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the treatment of type 2 diabetes, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with metformin.

[0011] In some embodiments, this disclosure provides the use of metformin in the treatment of type 2 diabetes, wherein metformin is used in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0012] This disclosure also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment of type 2 diabetes, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with metformin.

[0013] This disclosure also provides metformin for the treatment of type 2 diabetes, wherein the metformin is used in combination with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0014] This disclosure also provides a pharmaceutical composition comprising a compound of formula (I) as described above or a pharmaceutically acceptable salt thereof and metformin.

[0015] This disclosure also provides a pharmaceutical kit comprising a compound of formula (I) as described above or a pharmaceutically acceptable salt thereof with metformin.

[0016] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt in the pharmaceutical kit described herein is packaged separately from metformin.

[0017] In some implementations, the type 2 diabetes is type 2 diabetes that has been previously treated with metformin.

[0018] In some embodiments, prior metformin use means at least 6 months of prior metformin use; in some embodiments, prior metformin use means 6 months of prior metformin use; in some embodiments, prior metformin use means 5 months of prior metformin use; in some embodiments, prior metformin use means 4 months of prior metformin use; in some embodiments, prior metformin use means at least 4 months of prior metformin use; in some embodiments, prior metformin use means 3 months of prior metformin use; in some embodiments, prior metformin use means at least 3 months of prior metformin use; in some embodiments, prior metformin use means 2 months of prior metformin use; and in some embodiments, prior metformin use means at least 2 months of prior metformin use.

[0019] In some embodiments, the type 2 diabetes patients who have previously used metformin are those diagnosed with type 2 diabetes for at least 3 months according to the "Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes (2020 Edition)" at the time of screening; and / or whose HbA1c is 7.5% ≤ HbA1c ≤ 11.0% at the time of screening; in some embodiments, the type 2 diabetes patients who have previously used metformin are those diagnosed with type 2 diabetes for at least 4 months according to the "Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes (2020 Edition)" at the time of screening; in some embodiments, the type 2 diabetes patients who have previously used metformin are those diagnosed with type 2 diabetes for at least 4 months according to the "Chinese Guidelines for the Prevention and Treatment of Type 2 Diabetes (2020 Edition)" at the time of screening. The criteria for diagnosis of type 2 diabetes are as follows: HbA1c ≥ 7.5% at screening; HbA1c ≥ 8.0% at screening; HbA1c ≥ 8.5% at screening; HbA1c ≥ 9.0% at screening; HbA1c ≥ 9.5% at screening; HbA1c ≥ 10% at screening; and HbA1c ≥ 10.5% at screening.

[0020] In some implementation schemes, the subjects have type 2 diabetes, for example, based on the "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China (2020 Edition)," the American Diabetes Association's "Diagnosis and Classification of Diabetes: Standards of Diagnosis and Treatment of Diabetes (2024 Edition)," or the relevant classification criteria of the World Health Organization (WHO). In some implementation schemes, the subjects have had type 2 diabetes for at least 3 months. In some implementation schemes, the subjects have had type 2 diabetes for at least 4 months. In some implementation schemes, the subjects have had type 2 diabetes for at least 5 months.

[0021] In some implementations, the subject's glycated hemoglobin (HbA1c) level is ≥7.0%, ≥7.5%, ≥8.0%, ≥8.5%, ≥9.0%, ≥9.5%, ≥10%, ≥10.5%, or ≥11.0%. In some implementations, the subject's HbA1c level is ≥7.0% and ≤10%. In some implementations, the subject's HbA1c level is ≥7.5% and ≤11%.

[0022] In some implementations, the type 2 diabetes is defined as type 2 diabetes that, during screening, is treated with metformin monotherapy for ≥8 weeks at a daily dose of ≥1000 mg, in addition to a regular diet and exercise regimen; in some implementations, the type 2 diabetes is defined as type 2 diabetes that, during screening, is ...

[0023] In some implementations, the subject is currently receiving or has previously received metformin treatment (e.g., as monotherapy). In some implementations, the subject is currently receiving or has previously received metformin treatment (e.g., as monotherapy) and their glycemic control is inadequate. In some implementations, the subject is currently receiving or has previously received a stable dose (e.g., no dose adjustment) of metformin monotherapy for at least 8 weeks, with a daily dose of metformin ≥1000 mg. In some implementations, the subject is currently receiving or has previously received a stable dose (e.g., no dose adjustment) of metformin monotherapy for at least 8 weeks, with a daily dose of metformin ≥1500 mg. In some implementations, the subject is currently receiving or has previously received a stable dose (e.g., no dose adjustment) of metformin monotherapy for at least 3 months, with a daily dose of metformin ≤1500 mg.

[0024] In some embodiments, the type 2 diabetes is defined as a fasting plasma glucose level ≥7 mmol / L at the time of screening; in some embodiments, a fasting plasma glucose level ≥7.5 mmol / L at the time of screening; in some embodiments, a fasting plasma glucose level ≥8 mmol / L at the time of screening; in some embodiments, a fasting plasma glucose level ≥8.5 mmol / L at the time of screening; in some embodiments, a fasting plasma glucose level ≥9 mmol / L at the time of screening; in some embodiments, a fasting plasma glucose level ≥9.5 mmol / L at the time of screening; in some embodiments, a fasting plasma glucose level ≥10 mmol / L at the time of screening; in some embodiments, a fasting plasma glucose level ≥10.5 mmol / L at the time of screening; in some embodiments, a fasting plasma glucose level ≥11 mmol / L at the time of screening; in some embodiments, a fasting plasma glucose level ≥13 mmol / L at the time of screening; and in some embodiments, a fasting plasma glucose level ≤15 mmol / L at the time of screening.

[0025] In some embodiments, the type 2 diabetes is defined as a weight ≥ 50 kg; in some embodiments, a weight ≥ 52 kg; in some embodiments, a weight ≥ 54 kg; in some embodiments, a weight ≥ 56 kg; in some embodiments, a weight ≥ 58 kg; in some embodiments, a weight ≥ 60 kg; in some embodiments, a weight ≥ 62 kg; in some embodiments, a weight ≥ 64 kg; in some embodiments, a weight ≥ 66 kg; in some embodiments, a weight ≥ 68 kg; in some embodiments, a weight ≥ 70 kg; in some embodiments, a weight ≥ 72 kg; in some embodiments, a weight ≥ 73.4 kg; in some embodiments, a weight ≥ 74 kg; in some embodiments, a weight ≥ 76 kg; and in some embodiments, a weight ≥ 78 kg.

[0026] In some implementations, the type 2 diabetes is defined as a body mass index (BMI) ≥ 19 kg / m². 2 In some implementation schemes, BMI ≥ 20 kg / m² 2 In some implementation schemes, BMI ≥ 21 kg / m² 2 In some implementation schemes, BMI ≥ 22 kg / m² 2 In some implementation schemes, BMI ≥ 23 kg / m² 2 In some implementation schemes, BMI ≥ 24 kg / m² 2 In some implementation schemes, BMI ≥ 25 kg / m² 2 In some implementation schemes, BMI ≥ 26 kg / m² 2 In some implementation schemes, BMI ≥ 26.7 kg / m² 2 In some implementation schemes, BMI ≥ 27 kg / m² 2 In some implementation schemes, BMI ≥ 28 kg / m² 2 In some implementation schemes, BMI ≥ 29 kg / m² 2 In some implementation schemes, BMI ≥ 30 kg / m² 2 In some implementation schemes, BMI ≥ 32 kg / m² 2 In some implementation schemes, BMI ≥ 34 kg / m² 2 In some implementation schemes, BMI ≥ 36 kg / m² 2 In some implementation schemes, BMI ≥ 38 kg / m² 2 In some implementation schemes, BMI ≥ 40 kg / m² 2 In some implementation schemes, 19.0 kg / m 2 ≤BMI≤40.0kg / m 2In some implementation schemes, the subject's body mass index (BMI) is ≥28.0 kg / m². 2 And ≤40.0kg / m 2 In some implementation schemes, the subject's body mass index (BMI) is ≥28.0 kg / m². 2 And ≤32.5kg / m 2 In some implementation schemes, the subject's body mass index (BMI) is ≥32.5 kg / m². 2 And ≤40.0kg / m 2 In some implementation schemes, the subject's body mass index (BMI) is ≥27 kg / m². 2 In some implementation schemes, the subject's body mass index (BMI) is ≥30 kg / m². 2 In some implementation schemes, the subject's body mass index (BMI) is ≥27 kg / m². 2 And <30kg / m 2 In some implementation schemes, the subject's body mass index (BMI) is ≥30 kg / m². 2 And <35kg / m 2 In some implementation schemes, the subject's body mass index (BMI) is ≥35 kg / m². 2 And <40kg / m 2 .

[0027] In some implementations, type 2 diabetes is defined as a weight ≥50kg and a blood glucose level ≥19.0kg / m². 2 ≤BMI≤40.0kg / m 2 .

[0028] In some embodiments, the subjects are overweight. In some embodiments, the subjects are obese. In some embodiments, the subjects are not overweight. In some embodiments, the subjects are not obese.

[0029] In some implementations, the type 2 diabetes patient's weight change (difference between maximum and minimum weight during the 90 days prior to screening and randomization) does not exceed 5 kg; in some implementations, the type 2 diabetes patient's weight change does not exceed 4 kg; in some implementations, the type 2 diabetes patient's weight change does not exceed 3 kg; and in some implementations, the type 2 diabetes patient's weight change does not exceed 2 kg.

[0030] In some implementations, the subject's weight did not fluctuate significantly before starting treatment with the compound of formula (I). In some implementations, the subject's weight changed by no more than 5 kg within 90 days prior to administration of the compound of formula (I). In some implementations, the subject's weight changed by no more than 5% within 3 months prior to administration of the compound of formula (I).

[0031] In some implementations, the subject does not have type 1 diabetes. In some implementations, the subject does not have a specific type of diabetes or secondary diabetes.

[0032] In some embodiments, administration of the compound of formula (I) using the methods and uses described herein can achieve one or more therapeutic effects, such as efficacy after a specific duration, and / or efficacy compared to a control population. In some embodiments, one or more of the above-mentioned therapeutic effects can be achieved after 16, 32, 44, or 52 weeks of administration. In some embodiments, the control population is a comparable population of subjects who have not received treatment with the compound of formula (I), such as subjects receiving placebo. In some embodiments, the control population is a comparable population of subjects who have received standard therapy, such as subjects receiving dapagliflozin.

[0033] In some embodiments, after 16 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean (95% CI) change in HbA1c from baseline was -1.19% to -1.82%; in some embodiments, the least squares mean (95% CI) change in HbA1c from baseline was -1.19%; in some embodiments, the least squares mean (95% CI) change in HbA1c from baseline was -1.59%; in some embodiments, the least squares mean (95% CI) change in HbA1c from baseline was -1.82%; in some embodiments... In some implementations, the least squares mean (95% CI) change in HbA1c from baseline was -1.64%; in others, it was at least 1.19%; in still others, it was at least 1.59%; in some implementations, it was at least 1.82%; and in some still others, it was at least 1.64%; in some implementations ...59%; in some implementations, it was at least 1.59%; in some implementations, it was at least 1.59%; in some implementations, it was at least 1.64%; in some implementations, it was at least 1.62%; in some implementations, it was at least 1.82%; in some implementations, it was at least 1.64%; in some implementations, it was at least 1.64%; in some implementations, it was at least 1.59%; in some implementations, it was at least 1.54%; in some implementations, it was at least 1.62%; in some implementations, it was at least 1.82%; in some implementations, it was at least 1.82%; in some implementations, it was at least 1.82%; in some implementations, it was at least 1.82%; in some implementations, it was at least 1.82%; In some embodiments, the least squares mean (95% CI) change in HbA1c from baseline is at least 1.0%; in some embodiments, the least squares mean (95% CI) change in HbA1c from baseline is at least 1.1%; in some embodiments, the least squares mean (95% CI) change in HbA1c from baseline is at least 1.3%; in some embodiments, the least squares mean (95% CI) change in HbA1c from baseline is at least 1.5%; in some embodiments, the change in HbA1c from baseline is at least 1.64%; in some embodiments, the least squares mean (95% CI) change in HbA1c from baseline is at least 1.3%; in some embodiments, the least squares mean (95% CI) change in HbA1c from baseline is at least 1.5%; in some embodiments, the change in HbA1c from baseline is at least 1.5%; in some embodiments, the change in HbA1c from baseline is at least 1.64%; in some embodiments, the least squares mean (95% CI) change in HbA1c from baseline is at least 1.5%; in some embodiments, the least squares mean (95% CI) change in HbA1c from baseline is at least 1.5%; in some embodiments, the least squares mean (95% CI) change in HbA1c from baseline is at least 1.64%; in some embodiments, the least squares mean (95% CI) change in HbA1c from baseline is at least 1.3%; in some embodiments, the least squares mean (95% CI) change in HbA1c from baseline is at least 1.5 ... The least squares mean (95% CI) of the baseline change is a decrease of at least 1.7%; in some embodiments, the least squares mean (95% CI) of the HbA1c change from the baseline is a decrease of at least 1.9%; in some embodiments, the least squares mean (95% CI) of the HbA1c change from the baseline is a decrease of at least 2.0%; in some embodiments, the least squares mean (95% CI) of the HbA1c change from the baseline is a decrease of at least 2.1%; and in some embodiments, the least squares mean (95% CI) of the HbA1c change from the baseline is a decrease of at least 2.2%.

[0034] In some embodiments, after administering the compound of formula (I) to a subject using the methods described herein for 16 weeks, the change in the subject's glycated hemoglobin (HbA1c) level from baseline is -1.1% to -1.9%, for example -1.19% to -1.82%. In some embodiments, after administering the compound of formula (I) to a subject using the methods described herein for 16 weeks, the change in the subject's glycated hemoglobin (HbA1c) level from baseline is -1.19%, -1.59%, -1.64%, or -1.82%. In some embodiments, after administering the compound of formula (I) to a subject using the methods described herein, the decrease in the subject's glycated hemoglobin (HbA1c) level from baseline is at least 1.0%, 1.1%, 1.3%, 1.5%, 1.7%, 1.9%, 2.0%, 2.1%, or 2.2%.

[0035] In some embodiments, after 16 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the estimated difference in HbA1c compared to placebo (95% CI) was -0.94% to -1.57%; in some embodiments, the estimated difference in HbA1c compared to placebo (95% CI) was -0.94%; in some embodiments, the estimated difference in HbA1c compared to placebo (95% CI) was -1.34%; in some embodiments, the estimated difference in HbA1c compared to placebo (95% CI) was -1.57%; in some embodiments, the estimated difference in HbA1c compared to placebo (95% CI) was -1.39%; in some embodiments, the estimated difference in HbA1c compared to placebo (95% CI) was a decrease of at least 0.94%; in some embodiments, the estimated difference in HbA1c compared to placebo (95% CI) was a decrease of at least 1.34%; in some embodiments, HbA1c... The estimated difference (95% CI) in HbA1c treatment compared to the placebo group is at least 1.57%; in some embodiments, the estimated difference (95% CI) in HbA1c treatment compared to the placebo group is at least 1.39%; in some embodiments, the estimated difference (95% CI) in HbA1c treatment compared to the placebo group is at least 0.7%; in some embodiments, the estimated difference (95% CI) in HbA1c treatment compared to the placebo group is at least 0.9%; in some embodiments, the estimated difference (95% CI) in HbA1c treatment compared to the placebo group is at least 1.1%; in some embodiments, the estimated difference (95% CI) in HbA1c treatment compared to the placebo group is at least 1.3%; in some embodiments, the estimated difference (95% CI) in HbA1c treatment compared to the placebo group is at least 1.5%; and in some embodiments, the estimated difference (95% CI) in HbA1c treatment compared to the placebo group is at least 1.7%.

[0036] In some embodiments, after administering the compound of formula (I) to a subject using the methods described herein, the subject's glycated hemoglobin (HbA1c) level can be reduced to <7.0%, <6.5%, <6.0%, or <5.7%. In some embodiments, the glycated hemoglobin (HbA1c) level is detected at 16, 32, 44, or 52 weeks after administration of the compound of formula (I).

[0037] In some embodiments, after 16 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, HbA1c < 7.0%; in some embodiments, HbA1c < 6.5%; in some embodiments, HbA1c < 6.0%; and in some embodiments, HbA1c < 5.7%.

[0038] In some embodiments, after 32 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, HbA1c < 7.0%; in some embodiments, HbA1c < 6.5%; in some embodiments, HbA1c < 6.0%; and in some embodiments, HbA1c < 5.7%.

[0039] In some embodiments, after 44 weeks of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the subject's glycated hemoglobin (HbA1c) level is <7.0%; in some embodiments, the subject's glycated hemoglobin (HbA1c) level is <6.5%; in some embodiments, the subject's glycated hemoglobin (HbA1c) level is <6.0%; and in some embodiments, the subject's glycated hemoglobin (HbA1c) level is <5.7%.

[0040] In some embodiments, after 52 weeks of administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof, the subject's glycated hemoglobin (HbA1c) level is <7.0%; in some embodiments, the subject's glycated hemoglobin (HbA1c) level is <6.5%; in some embodiments, the subject's glycated hemoglobin (HbA1c) level is <6.0%; and in some embodiments, the subject's glycated hemoglobin (HbA1c) level is <5.7%.

[0041] In some embodiments, after 16 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the proportion of subjects achieving HbA1c < 7.0% was 48.7% to 63.2%; in some embodiments, the proportion of subjects achieving HbA1c < 7.0% was 48.7%; in some embodiments, the proportion of subjects achieving HbA1c < 7.0% was 51.3%; in some embodiments, the proportion of subjects achieving HbA1c < 7.0% was 56.4%; in some embodiments, the proportion of subjects achieving HbA1c < 7.0% was 63.2%; in some embodiments, the proportion of subjects achieving HbA1c < 7.0% was at least 48.7%; in some embodiments, the proportion achieving HbA1c < 7.0% was... The proportion of subjects achieving HbA1c < 7.0% is at least 51.3%; in some embodiments, the proportion of subjects achieving HbA1c < 7.0% is at least 56.4%; in some embodiments, the proportion of subjects achieving HbA1c < 7.0% is at least 40%; in some embodiments, the proportion of subjects achieving HbA1c < 7.0% is at least 45%; in some embodiments, the proportion of subjects achieving HbA1c < 7.0% is at least 50%; in some embodiments, the proportion of subjects achieving HbA1c < 7.0% is at least 55%; in some embodiments, the proportion of subjects achieving HbA1c < 7.0% is at least 60%; and in some embodiments, the proportion of subjects achieving HbA1c < 7.0% is at least 65%.

[0042] In some embodiments, the estimated difference (95% CI) in the proportion of subjects achieving HbA1c < 7.0% after 16 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salts compared to the placebo group was 33.3% to 47.8%; in some embodiments, the estimated difference (95% CI) in the proportion of subjects achieving HbA1c < 7.0% compared to the placebo group was 33.3%; in some embodiments, the estimated difference (95% CI) in the proportion of subjects achieving HbA1c < 7.0% compared to the placebo group was 41.0%; in some embodiments, the estimated difference (95% CI) in the proportion of subjects achieving HbA1c < 7.0% was... The proportion of subjects achieving HbA1c < 7.0% had an estimated treatment difference (95% CI) of 47.8% compared to the placebo group; in some implementations, the proportion of subjects achieving HbA1c < 7.0% had an estimated treatment difference (95% CI) of 35.9% compared to the placebo group; in some implementations, the proportion of subjects achieving HbA1c < 7.0% had an estimated treatment difference (95% CI) of at least 33.3% compared to the placebo group; in some implementations, the proportion of subjects achieving HbA1c < 7.0% had an estimated treatment difference (95% CI) of at least 41.0 ...5.9% compared to the placebo group. The proportion of subjects achieving HbA1c < 7.0% had an estimated treatment difference (95% CI) of at least 47.8% compared to the placebo group; in some implementations, the proportion of subjects achieving HbA1c < 7.0% had an estimated treatment difference (95% CI) of at least 35.9% compared to the placebo group; in some implementations, the proportion of subjects achieving HbA1c < 7.0% had an estimated treatment difference (95% CI) of at least 30% compared to the placebo group; in some implementations, the proportion of subjects achieving HbA1c < 7.0% had an estimated treatment difference (95% CI) of at least 35% compared to the placebo group; in some implementations... In some implementation schemes, the proportion of subjects achieving HbA1c < 7.0% represents an estimated treatment difference (95% CI) of at least 40% compared to the placebo group; in some implementation schemes, the proportion of subjects achieving HbA1c < 7.0% represents an estimated treatment difference (95% CI) of at least 45% compared to the placebo group; in some implementation schemes, the proportion of subjects achieving HbA1c < 7.0% represents an estimated treatment difference (95% CI) of at least 50% compared to the placebo group; and in some implementation schemes, the proportion of subjects achieving HbA1c < 7.0% represents an estimated treatment difference (95% CI) of at least 55% compared to the placebo group.

[0043] In some embodiments, after 16 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean (95% CI) change in fasting plasma glucose relative to baseline was -1.37 mmol / L to -2.69 mmol / L; in some embodiments, the least squares mean (95% CI) change in fasting plasma glucose relative to baseline was -1.37 mmol / L; in some embodiments, the least squares mean (95% CI) change in fasting plasma glucose relative to baseline was -1.54 mmol / L; in some embodiments, the least squares mean ( In some embodiments, the least squares mean (95% CI) of the change in fasting plasma glucose relative to baseline is -1.92 mmol / L; in some embodiments, the least squares mean (95% CI) of the change in fasting plasma glucose relative to baseline is -2.69 mmol / L; in some embodiments, the least squares mean (95% CI) of the change in fasting plasma glucose relative to baseline is a decrease of at least 1.37 mmol / L; in some embodiments, the least squares mean (95% CI) of the change in fasting plasma glucose relative to baseline is a decrease of at least 1.54 mmol / L; in some embodiments, the least squares mean (95% CI) of the change in fasting plasma glucose relative to baseline is at least A decrease of 1.92 mmol / L; in some embodiments, the least squares mean (95% CI) of the change in fasting plasma glucose relative to baseline is a decrease of at least 2.69 mmol / L; in some embodiments, the least squares mean (95% CI) of the change in fasting plasma glucose relative to baseline is a decrease of at least 0.5 mmol / L; in some embodiments, the least squares mean (95% CI) of the change in fasting plasma glucose relative to baseline is a decrease of at least 1.0 mmol / L; in some embodiments, the least squares mean (95% CI) of the change in fasting plasma glucose relative to baseline is a decrease of at least 1.5 mmol / L. mmol / L; in some embodiments, the least squares mean (95% CI) of the change in fasting plasma glucose relative to baseline is a decrease of at least 2.0 mmol / L; in some embodiments, the least squares mean (95% CI) of the change in fasting plasma glucose relative to baseline is a decrease of at least 2.5 mmol / L; in some embodiments, the least squares mean (95% CI) of the change in fasting plasma glucose relative to baseline is a decrease of at least 3.0 mmol / L; in some embodiments, the least squares mean (95% CI) of the change in fasting plasma glucose relative to baseline is a decrease of at least 3.5 mmol / L.

[0044] In some embodiments, after administering the compound of formula (I) to a subject using the methods described herein for 16 weeks, the change in the subject's fasting blood glucose level from baseline is -1.3 mmol / L to -2.8 mmol / L, for example -1.37 mmol / L to -2.69 mmol / L. In some embodiments, after administering the compound of formula (I) to a subject using the methods described herein for 16 weeks, the change in the subject's fasting blood glucose level from baseline is -1.37 mmol / L, -1.54 mmol / L, -1.92 mmol / L, or -2.69 mmol / L. In some embodiments, after administering the compound of formula (I) to a subject using the methods described herein, the decrease in the subject's fasting blood glucose level from baseline is at least 0.5 mmol / L, 1.0 mmol / L, 1.5 mmol / L, 2.0 mmol / L, 2.5 mmol / L, 3.0 mmol / L, or 3.5 mmol / L, for example, achieved after 16 weeks of administration.

[0045] In some embodiments, after 16 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the estimated treatment difference (95% CI) between the fasting plasma glucose and placebo groups was -1.23 mmol / L to -2.55 mmol / L; in some embodiments, the estimated treatment difference (95% CI) between the fasting plasma glucose and placebo groups was -1.23 mmol / L; in some embodiments, the estimated treatment difference (95% CI) between the fasting plasma glucose and placebo groups was -1.40 mmol / L; in some embodiments, the estimated treatment difference (95% CI) between the fasting plasma glucose and placebo groups was... The estimated difference (95% CI) for fasting plasma glucose compared to placebo was -2.55 mmol / L in some embodiments; in some embodiments, the estimated difference (95% CI) for fasting plasma glucose compared to placebo was -1.78 mmol / L; in some embodiments, the estimated difference (95% CI) for fasting plasma glucose compared to placebo was a decrease of at least 1.23 mmol / L; in some embodiments, the estimated difference (95% CI) for fasting plasma glucose compared to placebo was a decrease of at least 1.40 mmol / L; in some embodiments, the estimated difference (95% CI) for fasting plasma glucose compared to placebo was at least... A decrease of 2.55 mmol / L; in some embodiments, the estimated difference (95% CI) in treatment between the fasting plasma glucose and placebo groups is a decrease of at least 1.78 mmol / L; in some embodiments, the estimated difference (95% CI) in treatment between the fasting plasma glucose and placebo groups is a decrease of at least 0.5 mmol / L; in some embodiments, the estimated difference (95% CI) in treatment between the fasting plasma glucose and placebo groups is a decrease of at least 1.0 mmol / L; in some embodiments, the estimated difference (95% CI) in treatment between the fasting plasma glucose and placebo groups is a decrease of at least 1.5 mmol / L. mmol / L; in some embodiments, the estimated difference in treatment between the fasting plasma glucose and placebo groups (95% CI) is a decrease of at least 2.0 mmol / L; in some embodiments, the estimated difference in treatment between the fasting plasma glucose and placebo groups (95% CI) is a decrease of at least 2.5 mmol / L; in some embodiments, the estimated difference in treatment between the fasting plasma glucose and placebo groups (95% CI) is a decrease of at least 3.0 mmol / L; in some embodiments, the estimated difference in treatment between the fasting plasma glucose and placebo groups (95% CI) is a decrease of at least 3.5 mmol / L.

[0046] In some embodiments, after 16 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the least squares mean (95% CI) change in plasma glucose relative to baseline 2 hours after a meal was -5.53 mmol / L to -8.45 mmol / L; in some embodiments, the least squares mean (95% CI) change in plasma glucose relative to baseline 2 hours after a meal was -5.53 mmol / L; in some embodiments, the least squares mean (95% CI) change in plasma glucose relative to baseline 2 hours after a meal was -6.34 mmol / L; in some embodiments, the least squares mean (95% CI) change in plasma glucose relative to baseline 2 hours after a meal was -8. 0.45 mmol / L; in some embodiments, the least squares mean (95% CI) change in plasma glucose relative to baseline 2 hours after a meal is -7.29 mmol / L; in some embodiments, the least squares mean (95% CI) change in plasma glucose relative to baseline 2 hours after a meal is a decrease of at least 5.53 mmol / L; in some embodiments, the least squares mean (95% CI) change in plasma glucose relative to baseline 2 hours after a meal is a decrease of at least 6.34 mmol / L; in some embodiments, the least squares mean (95% CI) change in plasma glucose relative to baseline 2 hours after a meal is a decrease of at least 8.45 mmol / L; in some embodiments In some implementations, the least squares mean (95% CI) change in plasma glucose relative to baseline 2 hours after a meal is a decrease of at least 7.29 mmol / L; in others, it is a decrease of at least 3 mmol / L; in still others, it is a decrease of at least 4 mmol / L; in some implementations, it is a decrease of at least 5 mmol / L; and in some implementations, it is a decrease of at least 7.29 mmol / L. The least squares mean (95% CI) is a decrease of at least 5.5 mmol / L; in some embodiments, the least squares mean (95% CI) of the change in plasma glucose from baseline at 2 hours after a meal is a decrease of at least 6 mmol / L; in some embodiments, the least squares mean (95% CI) of the change in plasma glucose from baseline at 2 hours after a meal is a decrease of at least 6.5 mmol / L; in some embodiments, the least squares mean (95% CI) of the change in plasma glucose from baseline at 2 hours after a meal is a decrease of at least 7 mmol / L; in some embodiments, the least squares mean (95% CI) of the change in plasma glucose from baseline at 2 hours after a meal is a decrease of at least 7 mmol / L.5 mmol / L; in some embodiments, the least squares mean (95% CI) change in plasma glucose relative to baseline 2 hours after a meal is a decrease of at least 8 mmol / L; in some embodiments, the least squares mean (95% CI) change in plasma glucose relative to baseline 2 hours after a meal is a decrease of at least 8.5 mmol / L; in some embodiments, the least squares mean (95% CI) change in plasma glucose relative to baseline 2 hours after a meal is a decrease of at least 9 mmol / L.

[0047] In some embodiments, after administering the compound of formula (I) to subjects using the methods described herein for 16 weeks, the change in the subject's 2-hour postprandial blood glucose level from baseline is -5.53 mmol / L to -8.45 mmol / L. In some embodiments, after administering the compound of formula (I) to subjects using the methods described herein for 16 weeks, the change in the subject's 2-hour postprandial blood glucose level from baseline is -5.53 mmol / L, -6.34 mmol / L, -7.29 mmol / L, or -8.45 mmol / L. In some embodiments, after administering the compound of formula (I) to subjects using the methods described herein, the decrease in the subject's 2-hour postprandial blood glucose level from baseline is at least 3 mmol / L, 4 mmol / L, 5 mmol / L, 5.5 mmol / L, 6 mmol / L, 6.5 mmol / L, 7 mmol / L, 7.5 mmol / L, 8 mmol / L, 8.5 mmol / L, or 9 mmol / L, for example, achieved after 16 weeks of administration.

[0048] In some embodiments, after 16 weeks of treatment with the compound of formula (I) or its pharmaceutically acceptable salt, the estimated difference (95% CI) in plasma glucose 2 hours after a meal compared to placebo was -5.44 mmol / L to -8.37 mmol / L; in some embodiments, the estimated difference (95% CI) was -5.44 mmol / L; in some embodiments, the estimated difference (95% CI) was -6.25 mmol / L; and in some embodiments, the estimated difference (95% CI) was -8. 0.37 mmol / L; in some embodiments, the estimated treatment difference (95% CI) between the 2-hour postprandial plasma glucose and placebo groups is -7.20 mmol / L; in some embodiments, the estimated treatment difference (95% CI) between the 2-hour postprandial plasma glucose and placebo groups is at least a reduction of 5.44 mmol / L; in some embodiments, the estimated treatment difference (95% CI) between the 2-hour postprandial plasma glucose and placebo groups is at least a reduction of 6.25 mmol / L; in some embodiments, the estimated treatment difference (95% CI) between the 2-hour postprandial plasma glucose and placebo groups is at least a reduction of 8.37 mmol / L; in some embodiments In some implementations, the estimated difference (95% CI) in postprandial plasma glucose compared to placebo was a reduction of at least 7.20 mmol / L; in others, it was at least 3 mmol / L; in still others, at least 4 mmol / L; in some implementations, at least 5 mmol / L; and in some still others, the difference was at least 7.20 mmol / L. The estimated treatment difference (95% CI) was a reduction of at least 5.5 mmol / L; in some embodiments, the estimated treatment difference (95% CI) between the 2-hour postprandial plasma glucose and placebo groups was a reduction of at least 6 mmol / L; in some embodiments, the estimated treatment difference (95% CI) between the 2-hour postprandial plasma glucose and placebo groups was a reduction of at least 6.5 mmol / L; in some embodiments, the estimated treatment difference (95% CI) between the 2-hour postprandial plasma glucose and placebo groups was a reduction of at least 7 mmol / L; and in some embodiments, the estimated treatment difference (95% CI) between the 2-hour postprandial plasma glucose and placebo groups was a reduction of at least 7 mmol / L.5 mmol / L; in some embodiments, the estimated difference (95% CI) in plasma glucose 2 hours after a meal compared to placebo is a reduction of at least 8 mmol / L; in some embodiments, the estimated difference (95% CI) in plasma glucose 2 hours after a meal compared to placebo is a reduction of at least 8.5 mmol / L; in some embodiments, the estimated difference (95% CI) in plasma glucose 2 hours after a meal compared to placebo is a reduction of at least 8.8 mmol / L; in some embodiments, the estimated difference (95% CI) in plasma glucose 2 hours after a meal compared to placebo is a reduction of at least 9 mmol / L.

[0049] In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 5-720 mg; in some embodiments, it is 5-30 mg; in some embodiments, it is 10-300 mg; in some embodiments, it is 5-800 mg; in some embodiments, it is 10-800 mg; in some embodiments, it is 15-720 mg; in some embodiments, it is 15-360 mg; in some embodiments, it is 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 30 mg; in some embodiments, it is 15 mg, 25 mg, 30 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 90 mg, 100 mg, 110 mg. In some embodiments, the dosages are: g, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg; in some embodiments, the dosages are: 15 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 120 mg, 150 mg, 180 mg, 240 mg, 300 mg, 360 mg; in some embodiments, the dosages are: 15 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 120 mg, 150 mg, 180 mg; in some embodiments, the dosage is: 15 mg; in some embodiments, the dosage is: 15 mg; in some embodiments, the dosage is: 30 mg; in some embodiments, the dosage is: 60 mg; in some embodiments, the dosage is: 90 mg. In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 120 mg. In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 180 mg. In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 240 mg. In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 300 mg. In some embodiments, the dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 360 mg. It should be noted that all dosage values ​​provided herein are calculated based on the weight of the corresponding free base or free acid.

[0050] In some embodiments of the methods and uses described herein, administration of the compound of formula (I) follows a dose titration protocol. For example, in some embodiments, the subject is initially administered an escalating dose for a period of time, and subsequently, as appropriate, higher doses (e.g., further escalating doses) are administered sequentially for a period of time until a maintenance dose is reached. In some embodiments, a dose titration protocol includes administration of one or more escalating doses, with each escalating dose administered for a period of time. In some embodiments, the above dose titration protocol may further include maintenance dose administration (e.g., long-term administration). In some embodiments, the duration of each dose escalation is 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, or longer.

[0051] In this document, "escalation dose" refers to a dose lower than the subject's maintenance dose. In some embodiments, the escalation dose is lower than the subject's maximum effective dose. In some embodiments, the escalation dose is lower than the subject's maximum tolerable effective dose (i.e., a dose that does not cause adverse events or causes only minor adverse events). In some embodiments, if an escalation dose is observed to be suitable as the subject's maintenance dose, that escalation dose may be determined as the maintenance dose.

[0052] In this document, "maintenance dose" refers to the highest target dose set for a subject. In some embodiments, the maintenance dose is the subject's maximum effective dose. In some embodiments, the maintenance dose is the highest effective dose that the subject can tolerate. In some embodiments, if a maintenance dose is observed not to be the subject's maximum target dose, that maintenance dose may be used as an escalation dose for the next phase.

[0053] In some embodiments, this disclosure provides a method of administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof, the method comprising administering the compound to a subject by first administering one or more escalating doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof, followed by administration of a maintenance dose.

[0054] In some embodiments, the increment dose is 15 mg. In some embodiments, the increment dose is 30 mg. In some embodiments, the increment dose is 45 mg. In some embodiments, the increment dose is 60 mg. In some embodiments, the maintenance dose is 60 mg. In some embodiments, the maintenance dose is 90 mg. In some embodiments, the maintenance dose is 120 mg. In some embodiments, the maintenance dose is 180 mg. In some embodiments, the maintenance dose is 240 mg. In some embodiments, the maintenance dose is 300 mg. In some embodiments, the maintenance dose is 360 mg. In some embodiments, the increment for each dose is 15 mg, 30 mg, 60 mg, or 120 mg.

[0055] In some embodiments, a subject is administered 15 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (e.g., 4 weeks). In some embodiments, a subject is administered 30 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (e.g., 4 weeks). In some embodiments, a subject is administered 45 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (e.g., 4 weeks). In some embodiments, a subject is administered 60 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (e.g., 4 weeks). In some embodiments, a subject is administered 90 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (e.g., 4 weeks). In some embodiments, a subject is administered 120 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (e.g., 2 or 4 weeks). In some embodiments, a subject is administered 150 mg of compound (I) or a pharmaceutically acceptable salt thereof for a period of time (e.g., 2 or 4 weeks). In some embodiments, a subject is administered 180 mg of compound (I) or a pharmaceutically acceptable salt thereof for a continuous period of time (e.g., 2 weeks, 4 weeks, or long-term administration). In some embodiments, a subject is administered 240 mg of compound (I) or a pharmaceutically acceptable salt thereof for a continuous period of time (e.g., 2 weeks, 4 weeks, or long-term administration). In some embodiments, a subject is administered 300 mg of compound (I) or a pharmaceutically acceptable salt thereof for a continuous period of time (e.g., 2 weeks, 4 weeks, or long-term administration). In some embodiments, a subject is administered 360 mg of compound (I) or a pharmaceutically acceptable salt thereof for a continuous period of time (e.g., 2 weeks, 4 weeks, or long-term administration).

[0056] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered by titration every four weeks; in some embodiments, the 60 mg group of compound (I) is administered starting at 30 mg, titrated to 45 mg after 2 weeks of administration, and titrated to 60 mg after 2 weeks of administration of 45 mg; in some embodiments, the 90 mg group of compound (I) is administered starting at 30 mg, titrated to 60 mg after 4 weeks of administration.

[0057] In some implementations, the titration regimen is a starting dose of 30 mg, increasing by 30 mg every 4 weeks; in some implementations, the 60 mg group receives 30 mg of compound (I) orally, QD, for the first 4 weeks (D1–D28), and 60 mg of compound (I) orally, QD, after week 5 (after D29); in some implementations, the 90 mg group receives 30 mg of compound (I) orally, QD, for the first 4 weeks (D1–D28), 60 mg of compound (I) orally, QD, for weeks 5–8 (D29–D56), and 90 mg of compound (I) orally, QD, after week 9 (after D57).

[0058] In some embodiments, a dose titration regimen includes administering the compound of formula (I) to a subject at doses of 15 mg, 30 mg, 45 mg, or 60 mg, for example, each dose being administered continuously for 4 weeks until a maintenance dose is reached. In some embodiments, a dose titration regimen includes administering the compound of formula (I) to a subject at doses of 15 mg, 30 mg, 60 mg, or 90 mg, for example, each dose being administered continuously for 4 weeks until a maintenance dose is reached. In some embodiments, a dose titration regimen includes administering the compound of formula (I) to a subject at doses of 15 mg, 30 mg, 45 mg, 60 mg, 90 mg, 120 mg, 150 mg, or 180 mg, for example, each dose being administered continuously for 4 weeks until a maintenance dose is reached. In some embodiments, a dose titration regimen includes administering the compound of formula (I) to a subject at doses of 15 mg, 30 mg, 60 mg, 90 mg, 120 mg, 180 mg, or 240 mg, for example, each dose being administered continuously for 4 weeks until a maintenance dose is reached. In some embodiments, a dose titration regimen includes administering the compound of formula (I) to a subject at doses of 15 mg, 30 mg, 60 mg, 90 mg, 120 mg, 180 mg, 240 mg, 300 mg, or 360 mg, for example, each dose being administered continuously for 4 weeks until a maintenance dose is reached. In some embodiments, a dose titration regimen includes administering the compound of formula (I) to a subject at doses of 30 mg, 45 mg, or 60 mg, for example, each dose being administered continuously for 4 weeks until a maintenance dose is reached. In some embodiments, a dose titration regimen includes administering the compound of formula (I) to a subject at doses of 30 mg, 60 mg, or 90 mg, for example, each dose being administered continuously for 4 weeks until a maintenance dose is reached. In some embodiments, a dose titration regimen includes administering the compound of formula (I) to a subject at doses of 30 mg, 45 mg, 60 mg, 90 mg, 120 mg, 150 mg, or 180 mg, for example, each dose being administered continuously for 4 weeks until a maintenance dose is reached. In some embodiments, a dose titration regimen includes administering the compound of formula (I) to a subject at doses of 30 mg, 60 mg, 90 mg, 120 mg, 180 mg, or 240 mg, for example, each dose being administered continuously for 4 weeks until a maintenance dose is reached. In some embodiments, a dose titration regimen includes administering the compound of formula (I) to a subject at doses of 30 mg, 60 mg, 90 mg, 120 mg, 180 mg, 240 mg, 300 mg, or 360 mg, for example, each dose being administered continuously for 4 weeks until a maintenance dose is reached.

[0059] In some embodiments, metformin extended-release tablets are taken concurrently at a dose ≥1000 mg / day; in some embodiments, the dose is 1000 mg, 1500 mg, 2000 mg, or 2500 mg; in some embodiments, the dose is 1000 mg, 1500 mg, or 2000 mg; in some embodiments, the subject is currently receiving or has previously received metformin extended-release tablet therapy, for example, at a daily dose ≥1000 mg. In some embodiments, the subject is currently receiving or has previously received metformin extended-release tablet therapy, for example, at a daily dose of 1000 mg, 1500 mg, or 2000 mg. In some embodiments, the subject is currently receiving or has previously received metformin extended-release tablet therapy, for example, at a daily dose ≤1500 mg. In some embodiments, the subject is currently receiving or has previously received metformin immediate-release tablet therapy, for example, at a single dose of 500 mg, 850 mg, or 1000 mg. In some implementations, the subject is receiving or has previously received metformin extended-release tablets, for example, in a single dose of 500 mg, 850 mg, or 1000 mg. In some implementations, the subject is receiving or has previously received metformin oral solution at a concentration of 500 mg / 5 mL, in a single-dose strength of 5 mL, 10 mL, or 15 mL.

[0060] In some embodiments, the provided method includes administering a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the subject is receiving or has previously received metformin treatment. In some such embodiments, the daily dose of metformin that the subject is receiving or has previously received is at least 500 mg, 1000 mg, 1500 mg, 2000 mg, or 2500 mg. In some such embodiments, the daily dose of metformin that the subject is receiving or has previously received does not exceed 500 mg, 1000 mg, 1500 mg, 2000 mg, or 2500 mg. In some embodiments, subjects receiving metformin concurrently with a compound of formula (I) or a pharmaceutically acceptable salt thereof may achieve better therapeutic effects (e.g., more significant reduction in glycated hemoglobin or more pronounced weight loss) compared to subjects receiving metformin alone or a compound of formula (I) or a pharmaceutically acceptable salt thereof alone. In some implementations, subjects receiving metformin and a compound of formula (I) or a pharmaceutically acceptable salt thereof, when treated with metformin and / or the compound of formula (I) or a pharmaceutically acceptable salt thereof, achieved therapeutic effects comparable to or better than those of subjects receiving the drug alone (e.g., more significant reduction in glycated hemoglobin or more significant weight loss).

[0061] Take the (I) compound or its pharmaceutically acceptable saline and metformin extended-release tablets with water immediately after breakfast each day. They must be swallowed whole and should not be left in place or chewed before swallowing.

[0062] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt is administered immediately after breakfast.

[0063] In some embodiments, the treatment period described in this disclosure is 16, 18, 20, 22, 24, 26, 28, 30, or 32 weeks; in some embodiments, the treatment period is 16 weeks; in some embodiments, the treatment period is 24 weeks; in some embodiments, the treatment period is 32 weeks; in some embodiments, the treatment period is 44 weeks; and in some embodiments, the treatment period is 52 weeks.

[0064] In some embodiments, the frequency of administration of the compound of formula (I) or its pharmaceutically acceptable salt is selected from three times daily, twice daily, once daily, once every two days, once every three days, once every four days, once every five days, or once a week; in some embodiments, the frequency of administration of the compound of formula (I) or its pharmaceutically acceptable salt is selected from three times daily, twice daily, once daily, or once every three days; in some embodiments, the frequency of administration of the compound of formula (I) or its pharmaceutically acceptable salt is once daily.

[0065] In some embodiments, the compound of formula (I) is administered orally.

[0066] In some embodiments, the compound represented by formula (I) or its pharmaceutically acceptable salt is present in a unit dose formulation.

[0067] In some embodiments, a unit dose formulation contains at least 15 mg of compound (I) or a pharmaceutically acceptable salt thereof; in other embodiments, a unit dose formulation contains at least 30 mg of compound (I) or a pharmaceutically acceptable salt thereof; in some embodiments, a unit dose formulation contains 15 mg of compound (I) or a pharmaceutically acceptable salt thereof; in some embodiments, a unit dose formulation contains 30 mg of compound (I) or a pharmaceutically acceptable salt thereof; in some embodiments, a unit dose formulation contains 60 mg of compound (I) or a pharmaceutically acceptable salt thereof; in some embodiments, a unit dose formulation contains 25 mg of compound (I) or a pharmaceutically acceptable salt thereof. In some embodiments, the single-dose formulation contains 120 mg of compound (I) or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the compound of formula (I) is administered in an oral dosage form. In some embodiments, the compound of formula (I) is administered in a tablet form. In some embodiments, the compound of formula (I) is administered in a capsule form.

[0069] In some embodiments, the compound of formula (I) is administered in the form of a free base.

[0070] In some embodiments, the compound of formula (I) is administered in the form of a free acid.

[0071] In some embodiments, the compound of formula (I) is administered in the form of a salt.

[0072] In some embodiments, the pharmaceutically acceptable salt of formula (I) is selected from maleate, phosphate, p-toluenesulfonate, sulfate, hydrochloride, fumarate, tartrate, succinate, citrate, malate, methanesulfonate and hydrobromide.

[0073] In some embodiments, the inventive concept of this disclosure is based on the finding that administration of a compound of formula (I) at a dose of 5–30 mg (e.g., 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg) can produce one or more therapeutic effects; for example, this low-dose regimen has advantages over administration of a compound of formula (I) at a dose greater than 30 mg. In some embodiments, the compound of formula (I) is administered once daily at a single dose of 5–30 mg (e.g., 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg). In some embodiments, the compound of formula (I) is administered twice daily at a single dose of 5–30 mg (e.g., 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg), corresponding to a total daily dose of 10–60 mg. In some embodiments, the compound of formula (I) is administered at a dose of 5–30 mg in combination with dietary intervention and / or exercise therapy. In some embodiments, administration of a low dose (e.g., 5–30 mg) of the compound of formula (I) may reduce the incidence, severity, and / or frequency of one or more adverse events compared to administration of a dose greater than 30 mg. In some embodiments, administration of a low dose (e.g., 5–30 mg) of the compound of formula (I) may improve drug tolerability, increase patient adherence, and / or provide a better benefit-risk ratio compared to administration of a dose greater than 30 mg. These optimizations contribute to improved patient adherence, enhanced accessibility, and / or make the drug suitable for a wider range of subjects in the clinical management of type 2 diabetes.

[0074] The numbered embodiments described below are not restrictive, but exemplify several technical aspects of this disclosure.

[0075] 1. A method for treating type 2 diabetes, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of treatment.

[0076] 2. A method for improving glycemic control, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in therapeutic need.

[0077] 3. A method for reducing glycated hemoglobin (HbA1c) levels, the method comprising administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in therapeutic need.

[0078] 4. The method according to implementation scheme 2 or 3, wherein the subject has diabetes.

[0079] 5. The method according to implementation scheme 4, wherein the diabetes is type 2 diabetes.

[0080] 6. The method according to any one of embodiments 1 to 5, wherein the method comprises administering 5 to 720 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0081] 7. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 5 to 30 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0082] 8. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 5 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject.

[0083] 9. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 10 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0084] 10. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 15 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0085] 11. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 20 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0086] 12. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0087] 13. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 30 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0088] 14. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 45 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0089] 15. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 60 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0090] 16. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 75 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0091] 17. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 90 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0092] 18. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 105 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0093] 19. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 120 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0094] 20. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 135 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0095] 21. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 150 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0096] 22. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 165 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0097] 23. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 180 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0098] 24. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 195 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0099] 25. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 210 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0100] 26. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 225 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0101] 27. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 240 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0102] 28. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 255 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0103] 29. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 270 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0104] 30. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 285 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0105] 31. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0106] 32. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 315 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0107] 33. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 330 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0108] 34. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 345 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0109] 35. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 360 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0110] 36. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 375 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0111] 37. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 390 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0112] 38. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 405 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0113] 39. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 420 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0114] 40. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 435 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0115] 41. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 450 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0116] 42. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 465 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0117] 43. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 480 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0118] 44. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 495 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0119] 45. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 510 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0120] 46. ​​The method according to any one of embodiments 1 to 6, wherein the method comprises administering 525 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0121] 47. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 540 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0122] 48. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 555 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0123] 49. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 570 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0124] 50. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 585 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0125] 51. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 600 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0126] 52. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 615 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0127] 53. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 630 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0128] 54. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 645 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0129] 55. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 660 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0130] 56. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 675 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0131] 57. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 690 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0132] 58. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 705 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0133] 59. The method according to any one of embodiments 1 to 6, wherein the method comprises administering 720 mg of the compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject.

[0134] 60. The method according to any one of embodiments 1 to 59, wherein the method comprises administering a compound of formula (I) to a subject.

[0135] 61. The method according to any one of embodiments 1 to 60, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered once daily.

[0136] 62. The method according to any one of embodiments 1 to 60, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered twice daily.

[0137] 63. The method according to any one of embodiments 1 to 60, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered once a week.

[0138] 64. The method according to any one of embodiments 1 to 60, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered twice a week.

[0139] 65. The method according to any one of embodiments 1 to 60, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered three times per week.

[0140] 66. The method according to any one of embodiments 1 to 65, wherein the method includes continuous administration for a period of time.

[0141] 67. The method according to embodiment 66, wherein the administration period is at least one week.

[0142] 68. The method according to embodiment 66, wherein the administration period is at least two weeks.

[0143] 69. The method according to embodiment 66, wherein the administration period is at least three weeks.

[0144] 70. The method according to embodiment 66, wherein the administration period is at least four weeks.

[0145] 71. The method according to any one of embodiments 1 to 70, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in incremental doses.

[0146] 72. The method according to any one of embodiments 1 to 71, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to maintain a dose.

[0147] 73. The method according to any one of embodiments 1 to 72, wherein the compound of formula (I) or its pharmaceutically acceptable salt is administered according to a dose titration regimen.

[0148] 74. The method according to embodiment 73, wherein the dose titration protocol includes administering one or more escalating doses, each dose being administered continuously for a period of time.

[0149] 75. The method according to embodiment 74, wherein the administration period is 1 to 4 weeks.

[0150] 76. The method according to embodiment 74, wherein the administration period is less than one week.

[0151] 77. The method according to embodiment 74, wherein the administration period is more than 4 weeks.

[0152] 78. The method according to embodiment 74, wherein the administration period is one week.

[0153] 79. The method according to embodiment 74, wherein the administration period is 2 weeks.

[0154] 80. The method according to embodiment 74, wherein the administration period is 3 weeks.

[0155] 81. The method according to embodiment 74, wherein the administration period is 4 weeks.

[0156] 82. The method according to any one of embodiments 71 to 81, wherein the dose titration scheme further includes administering a maintenance dose.

[0157] 83. The method according to any one of embodiments 71 to 82, wherein the one or more escalating doses are 5 to 720 mg.

[0158] 84. The method according to any one of embodiments 71 to 82, wherein the one or more escalating doses are 5 to 60 mg.

[0159] 85. The method according to any one of embodiments 71 to 84, wherein the incremental dose is 5 mg.

[0160] 86. The method according to any one of embodiments 71 to 85, wherein the incremental dose is 10 mg.

[0161] 87. The method according to any one of embodiments 71 to 86, wherein the incremental dose is 15 mg.

[0162] 88. The method according to any one of embodiments 71 to 87, wherein the incremental dose is 20 mg.

[0163] 89. The method according to any one of embodiments 71 to 88, wherein the incremental dose is 25 mg.

[0164] 90. The method according to any one of embodiments 71 to 89, wherein the incremental dose is 30 mg.

[0165] 91. The method according to any one of embodiments 71 to 90, wherein the incremental dose is 45 mg.

[0166] 92. The method according to any one of embodiments 71 to 91, wherein the incremental dose is 60 mg.

[0167] 93. The method according to any one of embodiments 71 to 92, wherein the incremental dose is 90 mg.

[0168] 94. The method according to any one of embodiments 71 to 93, wherein the incremental dose is 120 mg.

[0169] 95. The method according to any one of embodiments 71 to 94, wherein the incremental dose is 150 mg.

[0170] 96. The method according to any one of embodiments 71 to 95, wherein the incremental dose is 180 mg.

[0171] 97. The method according to any one of embodiments 71 to 96, wherein the incremental dose is 210 mg.

[0172] 98. The method according to any one of embodiments 71 to 97, wherein the incremental dose is 240 mg.

[0173] 99. The method according to any one of embodiments 71 to 98, wherein the incremental dose is 270 mg.

[0174] 100. The method according to any one of embodiments 71 to 99, wherein the incremental dose is 300 mg.

[0175] 101. The method according to any one of embodiments 71 to 100, wherein the incremental dose is 330 mg.

[0176] 102. The method according to any one of embodiments 71 to 101, wherein the incremental dose is 360 mg.

[0177] 103. The method according to any one of embodiments 71 to 102, wherein the incremental dose is 390 mg.

[0178] 104. The method according to any one of embodiments 71 to 103, wherein the incremental dose is 420 mg.

[0179] 105. The method according to any one of embodiments 71 to 104, wherein the incremental dose is 450 mg.

[0180] 106. The method according to any one of embodiments 71 to 105, wherein the incremental dose is 480 mg.

[0181] 107. The method according to any one of embodiments 71 to 106, wherein the incremental dose is 510 mg.

[0182] 108. The method according to any one of embodiments 71 to 107, wherein the incremental dose is 540 mg.

[0183] 109. The method according to any one of embodiments 71 to 108, wherein the incremental dose is 570 mg.

[0184] 110. The method according to any one of embodiments 71 to 109, wherein the incremental dose is 600 mg.

[0185] 111. The method according to any one of embodiments 71 to 110, wherein the incremental dose is 630 mg.

[0186] 112. The method according to any one of embodiments 71 to 111, wherein the incremental dose is 660 mg.

[0187] 113. The method according to any one of embodiments 71 to 112, wherein the incremental dose is 690 mg.

[0188] 114. The method according to any one of embodiments 71 to 113, wherein the incremental dose is 720 mg.

[0189] 115. The method according to any one of embodiments 72 to 114, wherein the maintenance dose is 5 to 720 mg.

[0190] 116. The method according to any one of embodiments 72 to 115, wherein the maintenance dose is 5 to 30 mg.

[0191] 117. The method according to embodiment 115, wherein the maintenance dose is 5 mg.

[0192] 118. The method according to embodiment 115, wherein the maintenance dose is 10 mg.

[0193] 119. The method according to embodiment 115, wherein the maintenance dose is 15 mg.

[0194] 120. The method according to embodiment 115, wherein the maintenance dose is 20 mg.

[0195] 121. The method according to embodiment 115, wherein the maintenance dose is 25 mg.

[0196] 122. The method according to embodiment 115, wherein the maintenance dose is 30 mg.

[0197] 123. The method according to embodiment 115, wherein the maintenance dose is 45 mg.

[0198] 124. The method according to embodiment 115, wherein the maintenance dose is 60 mg.

[0199] 125. The method according to embodiment 115, wherein the maintenance dose is 90 mg.

[0200] 126. The method according to embodiment 115, wherein the maintenance dose is 120 mg.

[0201] 127. The method according to embodiment 115, wherein the maintenance dose is 150 mg.

[0202] 128. The method according to embodiment 115, wherein the maintenance dose is 180 mg.

[0203] 129. The method according to embodiment 115, wherein the maintenance dose is 210 mg.

[0204] 130. The method according to embodiment 115, wherein the maintenance dose is 240 mg.

[0205] 131. The method according to embodiment 115, wherein the maintenance dose is 270 mg.

[0206] 132. The method according to embodiment 115, wherein the maintenance dose is 300 mg.

[0207] 133. The method according to embodiment 115, wherein the maintenance dose is 330 mg.

[0208] 134. The method according to embodiment 115, wherein the maintenance dose is 360 mg.

[0209] 135. The method according to embodiment 115, wherein the maintenance dose is 390 mg.

[0210] 136. The method according to embodiment 115, wherein the maintenance dose is 420 mg.

[0211] 137. The method according to embodiment 115, wherein the maintenance dose is 450 mg.

[0212] 138. The method according to embodiment 115, wherein the maintenance dose is 480 mg.

[0213] 139. The method according to embodiment 115, wherein the maintenance dose is 510 mg.

[0214] 140. The method according to embodiment 115, wherein the maintenance dose is 540 mg.

[0215] 141. The method according to embodiment 115, wherein the maintenance dose is 570 mg.

[0216] 142. The method according to embodiment 115, wherein the maintenance dose is 600 mg.

[0217] 143. The method according to embodiment 115, wherein the maintenance dose is 630 mg.

[0218] 144. The method according to embodiment 115, wherein the maintenance dose is 660 mg.

[0219] 145. The method according to embodiment 115, wherein the maintenance dose is 690 mg.

[0220] 146. The method according to embodiment 115, wherein the maintenance dose is 720 mg.

[0221] 147. The method according to any one of embodiments 1 to 146, wherein the method comprises oral administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0222] 148. The method according to embodiment 147, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in an oral dosage form.

[0223] 149. The method according to embodiment 148, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a solid oral dosage form.

[0224] 150. The method according to embodiment 149, wherein the solid oral dosage form is a tablet.

[0225] 151. The method according to embodiment 149, wherein the solid oral dosage form is a capsule.

[0226] 152. The method according to any one of embodiments 1 to 151, wherein the subject's glycated hemoglobin (HbA1c) level is ≥7.0%, ≥7.5%, ≥8.0%, ≥8.5%, ≥9.0%, ≥9.5%, ≥10%, ≥10.5%, or ≥11.0%, for example, reaching the above levels before administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0227] 153. The method according to any one of embodiments 1 to 152, wherein the subject suffers from obesity.

[0228] 154. The method according to any one of embodiments 1 to 153, wherein the subject is overweight.

[0229] 155. The method according to any one of embodiments 1 to 154, wherein the subject is an adult.

[0230] 156. The method according to any one of embodiments 1 to 154, wherein the subject is a child.

[0231] 157. The method according to any one of embodiments 1 to 156, wherein the subject is a human.

[0232] 158. The method according to any one of embodiments 1 to 157, wherein the subject is male.

[0233] 159. The method according to any one of embodiments 1 to 157, wherein the subject is female.

[0234] 160. The method according to any one of embodiments 1 to 159, wherein the subject's body mass index (BMI) is 19.0 kg / m². 2 ≤BMI≤40.0kg / m 2 .

[0235] 161. The method according to any one of embodiments 1 to 159, wherein the subject's body mass index (BMI) is ≥24 kg / m². 2 And <28kg / m 2 .

[0236] 162. The method according to any one of embodiments 1 to 159, wherein the subject's body mass index (BMI) is ≥28 kg / m². 2 .

[0237] 163. The method according to any one of embodiments 1 to 159, wherein the subject's body mass index (BMI) is ≥27 kg / m². 2 .

[0238] 164. The method according to any one of embodiments 1 to 159, wherein the subject's body mass index (BMI) is ≥27 kg / m². 2 And <30kg / m 2 .

[0239] 165. The method according to any one of embodiments 1 to 159, wherein the subject's body mass index (BMI) is ≥30 kg / m². 2 .

[0240] 166. The method according to any one of embodiments 1 to 159, wherein the subject's body mass index (BMI) is ≥28.0 kg / m². 2 And ≤32.5kg / m 2 .

[0241] 167. The method according to any one of embodiments 1 to 159, wherein the subject's body mass index (BMI) is > 32.5 kg / m². 2 And ≤40.0kg / m 2 .

[0242] 168. The method according to any one of embodiments 1 to 159, wherein the subject's body mass index (BMI) is ≥30 kg / m². 2 And <35kg / m 2 .

[0243] 169. The method according to any one of embodiments 1 to 159, wherein the subject's body mass index (BMI) is ≥35 kg / m². 2 And <40kg / m 2 .

[0244] 170. The method according to any one of embodiments 1 to 169, wherein the subject is receiving or has previously received metformin treatment.

[0245] 171. The method according to any one of embodiments 1 to 170, wherein the subject is receiving or has previously received metformin treatment and has poor glycemic control.

[0246] 172. The method according to embodiment 169 or 170, wherein the subject is currently receiving or has previously received a daily dose of metformin ≥1000 mg.

[0247] 173. The method according to embodiment 169 or 170, wherein the subject is receiving or has previously received a metformin dose of 500 mg, 750 mg, or 1000 mg.

[0248] 174. The method according to embodiment 169 or 170, wherein the subject is receiving or has previously received a dose of metformin of 1500 mg.

[0249] 175. The method according to embodiment 169 or 170, wherein the subject is receiving or has previously received a metformin dose of 2000 mg or 2500 mg.

[0250] 176. The method according to any one of embodiments 1 to 175, wherein the method further comprises administering metformin to the subject.

[0251] 177. The method according to embodiment 176, wherein the method includes administering a daily dose of metformin ≥1000 mg to the subject.

[0252] 178. The method according to embodiment 176, wherein the method includes administering a metformin dose of 500 mg to the subject.

[0253] 179. The method according to embodiment 176, wherein the method includes administering a metformin dose of 750 mg to the subject.

[0254] 180. The method according to embodiment 176, wherein the method includes administering a metformin dose of 1000 mg to the subject.

[0255] 181. The method according to embodiment 176, wherein the method includes administering a metformin dose of 1500 mg to the subject.

[0256] 182. The method according to embodiment 176, wherein the method includes administering a metformin dose of 2000 mg to the subject.

[0257] 183. The method according to embodiment 176, wherein the method includes administering a metformin dose of 2500 mg to the subject.

[0258] 184. The method according to any one of embodiments 176 to 183, wherein the metformin is administered in the form of a conventional immediate-release formulation.

[0259] 185. The method according to any one of embodiments 176 to 183, wherein the metformin is administered in the form of a sustained-release formulation.

[0260] 186. The method according to any one of embodiments 176 to 183, wherein the metformin is administered in the form of an oral solution preparation.

[0261] 187. The method according to any one of embodiments 1 to 186, wherein the method further includes dietary therapy (e.g., a low-calorie diet).

[0262] 188. The method according to any one of embodiments 1 to 187, wherein the method further includes exercise therapy (e.g., increasing physical activity).

[0263] 189. The method according to any one of embodiments 1 to 188, wherein, when administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, the dosing regimen of the method is configured to achieve: after 16 weeks of administration, a reduction in glycated hemoglobin (HbA1c) levels from the baseline least squares mean (95% confidence interval) of at least 1.0%, 1.1%, 1.3%, 1.5%, 1.7%, 1.9%, 2.0%, 2.1%, or 2.2%.

[0264] 190. The method according to any one of embodiments 1 to 189, wherein, when administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, the dosing regimen of the method is configured to achieve a reduction in glycated hemoglobin (HbA1c) levels from baseline of at least 1.0%, 1.1%, 1.3%, 1.5%, 1.7%, 1.9%, 2.0%, 2.1%, or 2.2% after 16, 32, 44, or 52 weeks of dosing.

[0265] 191. The method according to any one of embodiments 1 to 190, wherein, when administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, the dosing regimen of the method is configured to achieve, after 16 weeks of administration, a reduction in glycated hemoglobin (HbA1c) levels from the baseline least squares mean (95% confidence interval) of at least 0.7%, 0.9%, 1.1%, 1.3%, 1.5%, or 1.7% compared to the placebo group.

[0266] 192. The method according to any one of embodiments 1 to 191, wherein, when administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, the dosing regimen of the method is configured to achieve: after 16, 32, 44, or 52 weeks of administration, a glycated hemoglobin (HbA1c) level of at least <7.0%, <6.5%, <6.0%, or <5.7%.

[0267] 193. The method according to any one of embodiments 1 to 192, wherein when administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, the dosing regimen of the method is configured to achieve that, after 16 weeks of administration, the proportion of subjects with a glycated hemoglobin (HbA1c) level <7.0% is at least 40%, 45%, 50%, 55%, 60%, or 65%.

[0268] 194. The method according to any one of embodiments 1 to 193, wherein, when administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, the dosing regimen of the method is configured to achieve, after 16 weeks of administration, an increase of at least 30%, 35%, 40%, 45%, 50%, or 55% in the proportion of subjects with glycated hemoglobin (HbA1c) levels <7.0% compared to the placebo group.

[0269] 195. The method according to any one of embodiments 1 to 194, wherein, when administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, the dosing regimen of the method is configured to achieve: after 16 weeks of administration, a reduction in fasting blood glucose levels from the least squares mean (95% confidence interval) of baseline of at least 0.5 mmol / L, 1.0 mmol / L, 1.5 mmol / L, 2.0 mmol / L, 2.5 mmol / L, 3.0 mmol / L, or 3.5 mmol / L.

[0270] 196. The method according to any one of embodiments 1 to 195, wherein when administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, the dosing regimen of the method is configured to achieve: a reduction in fasting blood glucose level from baseline of at least 0.5 mmol / L, 1.0 mmol / L, 1.5 mmol / L, 2.0 mmol / L, 2.5 mmol / L, 3.0 mmol / L, or 3.5 mmol / L after 16 weeks of administration.

[0271] 197. The method according to any one of embodiments 1 to 196, wherein when administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, the dosing regimen of the method is configured to achieve: after 16 weeks of administration, an estimated difference (95% confidence interval) in the reduction of fasting blood glucose level from baseline compared to the placebo group of at least 0.5 mmol / L, 1.0 mmol / L, 1.5 mmol / L, 2.0 mmol / L, 2.5 mmol / L, 3.0 mmol / L, or 3.5 mmol / L.

[0272] 198. The method according to any one of embodiments 1 to 197, wherein when administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, the dosing regimen of the method is configured to achieve a reduction in blood glucose level 2 hours after a meal from the least squares mean (95% confidence interval) of baseline by at least 5.53 mmol / L to 8.45 mmol / L after 16 weeks of administration.

[0273] 199. The method according to any one of embodiments 1 to 198, wherein when administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, the dosing regimen of the method is configured to achieve: after 16 weeks of administration, a reduction in 2-hour postprandial blood glucose levels from the least squares mean (95% confidence interval) of baseline of at least 5.53 mmol / L, 6.34 mmol / L, 7.29 mmol / L, or 8.45 mmol / L.

[0274] 200. The method according to any one of embodiments 1 to 199, wherein when administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, the dosing regimen of the method is configured to achieve: after 16 weeks of administration, a reduction in 2-hour postprandial blood glucose levels from the least squares mean (95% confidence interval) of baseline of at least 3 mmol / L, 4 mmol / L, 5 mmol / L, 5.5 mmol / L, 6 mmol / L, 6.5 mmol / L, 7 mmol / L, 7.5 mmol / L, 8 mmol / L, 8.5 mmol / L, or 9 mmol / L.

[0275] 201. The method according to any one of embodiments 1 to 200, wherein when administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, the dosing regimen of the method is configured to achieve: after 16 weeks of administration, a reduction in 2-hour postprandial blood glucose levels from baseline of at least 3 mmol / L, 4 mmol / L, 5 mmol / L, 5.5 mmol / L, 6 mmol / L, 6.5 mmol / L, 7 mmol / L, 7.5 mmol / L, 8 mmol / L, 8.5 mmol / L, or 9 mmol / L.

[0276] 202. The method according to any one of embodiments 1 to 201, wherein when administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, the dosing regimen of the method is configured to achieve: after 16 weeks of administration, an estimated difference in the reduction of blood glucose level 2 hours after a meal compared to the placebo group of at least 5.44 mmol / L to 8.37 mmol / L.

[0277] 203. The method according to any one of embodiments 1 to 202, wherein when administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, the dosing regimen of the method is configured to achieve: after 16 weeks of administration, an estimated difference in the reduction of 2-hour postprandial blood glucose levels compared to the placebo group of at least 5.44 mmol / L, 6.25 mmol / L, 7.20 mmol / L, or 8.37 mmol / L.

[0278] 204. The method according to any one of embodiments 1 to 203, wherein, when administering the compound of formula (I) or a pharmaceutically acceptable salt thereof to a comparable population of subjects, the dosing regimen of the method is configured to achieve: after 16 weeks of administration, an estimated difference (95% confidence interval) in the reduction of 2-hour postprandial blood glucose level from baseline compared to the placebo group of at least 3 mmol / L, 4 mmol / L, 5 mmol / L, 5.5 mmol / L, 6 mmol / L, 6.5 mmol / L, 7 mmol / L, 7.5 mmol / L, 8 mmol / L, 8.5 mmol / L, 8.8 mmol / L, or 9 mmol / L.

[0279] 205. The method according to any one of embodiments 1 to 204, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is the only active ingredient administered to the subject.

[0280] Terminology Definition

[0281] To facilitate understanding of this disclosure, certain techniques and scientific methods are specifically defined below. Unless otherwise expressly defined in this disclosure, all other techniques and scientific methods used in this disclosure have the meaning commonly understood by one of ordinary skill in the art to which this disclosure pertains.

[0282] Unless the context clearly requires otherwise, throughout the specification and claims, the words “comprising,” “having,” “including,” etc., should be understood as having an inclusive meaning, rather than an exclusive or exhaustive meaning; that is, the meaning of “including but not limited to.”

[0283] The values ​​in this disclosure are instrument measurements or calculated values ​​after instrument measurement, and are subject to a certain degree of error. Generally speaking, ±10% is within the reasonable error range. Of course, the context in which the value is used needs to be considered. For example, the total impurity content, where the error variation after measurement does not exceed ±10%, can be ±9%, ±8%, ±7%, ±6%, ±5%, ±4%, ±3%, ±2%, or ±1%, and in some embodiments, ±5%.

[0284] When the term "about" is applied to parameters such as pH, concentration, temperature, and range of variation, it indicates that the parameter can vary by ±10%, and sometimes within ±5%. As those skilled in the art will understand, when a parameter is not critical, figures are usually given for illustrative purposes only, not as limitations.

[0285] In this document, the term "comparability" refers to two or more reagents, individuals, situations, sets of conditions, environments, objects, or populations that are not necessarily identical but possess sufficient similarity to allow for comparative analysis, enabling those skilled in the art to draw reasonable conclusions based on observed differences or similarities. In some embodiments, comparable reagents, individuals, situations, sets of conditions, environments, objects, or populations are characterized by the presence of multiple substantially identical characteristics, while only one or a few different characteristics exist. Those skilled in the art can determine, based on the specific context, the degree of consistency required between two or more of the aforementioned reagents, individuals, situations, sets of conditions, environments, objects, or populations in any given situation to be considered comparable. For example, those skilled in the art will understand that when two or more sets of situations, reagents, individuals, sets of conditions, environments, objects, or populations possess a sufficient number and type of fundamentally consistent characteristics, they can be considered comparable; based on this, it is reasonable to infer that the differences in experimental results or phenomena observed under different situations, reagents, individuals, sets of conditions, environments, objects, or populations are caused by, or can be explained by, a few different characteristics.

[0286] "Effective amount" includes an amount sufficient to improve or prevent the symptoms or condition of a medical condition. Effective amount also means an amount sufficient to allow or facilitate diagnosis. The effective amount used on a subject may vary depending on factors such as the condition to be treated, the subject's overall health, the route and dosage of administration, and the severity of side effects. Effective amount may be the maximum dose or administration regimen that avoids significant side effects or toxicity. Subjects in this disclosure may be animal or human subjects.

[0287] The term "pharmaceutical-acceptable excipient" or "pharmaceutical-acceptable excipient" includes any material that, when combined with an active ingredient, allows that ingredient to retain its biological activity and does not react with the subject's immune system. Examples include, but are not limited to, any standard pharmaceutical carrier, such as phosphate-buffered saline solution, water, emulsions such as oil / water emulsions, and various types of wetting agents. In some embodiments, the diluent for aerosol or parenteral administration is phosphate-buffered saline (PBS) or physiological (0.9%) saline. Compositions containing such carriers are formulated using well-known conventional methods (see, for example, Remington's Pharmaceutical Sciences, 18th edition, A. Gennaro, editor, Mack Publishing Co., Easton, PA, 1990; and R. Remington, The Science and Practice of Pharmacy, 20th edition, Mack Publishing, 2000).

[0288] The terms “give,” “apply,” and “treat,” when applied to animals, humans, experimental subjects, cells, tissues, organs, or biological fluids, refer to the contact of an exogenous drug, therapeutic agent, diagnostic agent, or composition with an animal, human, subject, cell, tissue, organ, or biological fluid, such as in therapeutic, pharmacokinetic, diagnostic, research, and experimental methods. Cellular treatment includes contact between a reagent and a cell, as well as contact between a reagent and a fluid, wherein the fluid is in contact with the cell. “Give,” “apply,” and “treat” also mean treatment, such as of cells, by means of a reagent, diagnostic agent, conjugate composition, or by means of another cell in vitro and ex vivo. When applied to humans, veterinary, or research subjects, it refers to therapeutic treatment, preventative or prophylactic measures, research, and diagnostic applications.

[0289] The term "treatment" means administering a therapeutic agent, such as a compound comprising any of formula (I) of this disclosure or a pharmaceutically acceptable salt thereof, to a subject who has, is suspected of having, or is predisposed to have type 2 diabetes, and the therapeutic agent is known to have a therapeutic effect on these symptoms. Typically, administering a therapeutic agent in a treated subject or population in an amount that effectively relieves symptoms of one or more diseases is done by preventing or delaying the onset of symptoms or complications, reducing symptoms or complications, or eliminating the disease, condition, or symptom to any clinically measurable degree. The amount of a therapeutic agent that effectively relieves symptoms of any specific disease (also referred to as a "therapeuticly effective amount") can vary depending on a variety of factors, such as the subject's disease state, age, and weight, and the drug's ability to produce the desired therapeutic effect in the subject. Whether the disease symptoms have been relieved can be evaluated using any clinical test method commonly used by a physician or other healthcare professional to assess the severity or progression of the symptoms. Although the embodiments of this disclosure (e.g., treatment methods or products) may be ineffective in alleviating the symptoms of the target disease in a particular subject, they should alleviate the symptoms of the target disease in a statistically significant number of subjects, as determined by any statistical test known in the art, such as the Student t-test, chi-square test, U-test according to Mann and Whitney, Kruskal-Wallis test (H-test), Jonckheere-Terpstra test, and Wilcoxon test. The patients to be treated are mammals, and in some embodiments, are humans.

[0290] The term “prevention” refers to reducing the risk or incidence of one or more conditions, symptoms, complications or ailments, or eliminating or slowing the progression of one or more conditions, symptoms, complications or ailments.

[0291] The terms “subject” and “patient” refer to mammals, especially primates, and particularly humans.

[0292] BMI stands for Body Mass Index.

[0293] T2DM refers to type 2 diabetes.

[0294] HbA1c refers to glycated hemoglobin.

[0295] FPG refers to fasting blood glucose.

[0296] PPG refers to postprandial blood glucose.

[0297] eGFR refers to the estimated glomerular filtration rate.

[0298] AE stands for adverse event.

[0299] AESI refers to adverse events of particular concern.

[0300] ULN refers to the upper limit of the normal value. Attached Figure Description

[0301] Figure 1. Research Design Flowchart

[0302] Figure 2. Percentage change in fasting body weight relative to baseline over 16 weeks.

[0303] The following embodiments are used to further describe this disclosure, but these embodiments are not intended to limit the scope of this disclosure. Detailed Implementation

[0304] Example 1. A phase II clinical study (multicenter, randomized, double-blind, placebo-controlled, parallel design) on the efficacy and safety of compound (I) in treating type 2 diabetes patients with poor glycemic control due to metformin.

[0305] I. Research Design

[0306] This study was a 16-week, multicenter, randomized, double-blind, placebo-controlled, parallel-design phase II clinical trial. Participants were type 2 diabetes patients with poor glycemic control treated with metformin.

[0307] The study planned to enroll approximately 180 participants with type 2 diabetes, who were randomly assigned in a 1:1:1:1:1 ratio to five groups containing compound (I), with 36 participants in each group. Approximately 80 participants with a baseline body mass index (BMI) ≥ 26 kg / m² were included in this study.

[0308] The experiment was designed with 5 groups, and the target doses of the compound of formula (I) were 15 mg, 30 mg, 60 mg, 90 mg, and placebo. The 60 mg and 90 mg groups were administered via titration.

[0309] Eligible participants began a 3-week single-blind induction period on visit 2-21 (V2, D-21) with placebo (15mg tablet, 30mg tablets) and metformin extended-release tablets (1000mg, 1500mg, or 2000mg, or 500mg tablets, for a total of 2–4 tablets). Baseline examinations were performed on visit 3 (D-4), and randomization criteria were assessed on visit 4. Participants meeting the randomization criteria entered a 16-week double-blind treatment period.

[0310] During the double-blind treatment period, if a subject's fasting blood glucose level meets the criteria for salvage therapy without any obvious cause (i.e., fasting blood glucose >13.3 mmol / L during weeks 2-8 of the double-blind treatment period; fasting blood glucose >11.1 mmol / L during weeks 9-16; fasting venous blood glucose level measured by a local laboratory within 3 days under normal dietary conditions to confirm whether the criteria for salvage therapy are met), the investigator may administer salvage therapy as needed based on the subject's condition. The salvage therapy medication is determined by the investigator and may be an oral hypoglycemic agent (sulfonylureas are recommended, such as gliclazide extended-release tablets) or insulin (basal insulin is recommended). During the salvage therapy period, the subject continues to receive the study drug treatment as per the protocol.

[0311] In addition to the salvage treatments specified above, subjects may not use any other glucose-lowering treatments (including prescription drugs, over-the-counter drugs, traditional Chinese medicine, and other non-pharmacological treatments besides lifestyle interventions) during the study period from screening to the end of the treatment period. Subjects must follow a diabetic diet and engage in appropriate exercise during the study.

[0312] The entire trial included a screening period of up to 2 weeks (V1, D-35–D-22), a 3-week induction period (V2–V3, D-21–D-1, single-blind), a 16-week treatment period (V4–V12, D1–D112, double-blind), and a safety follow-up period (V13, 14±3 days after the last dose), with a total of 13 planned visits (including 3 telephone follow-ups). The study design flowchart is shown in Figure 1.

[0313] II. Inclusion criteria, exclusion criteria, and randomization criteria

[0314] Participants must meet all of the following criteria to be eligible for this study:

[0315] 1. Male or female, aged 18 to 75 years old on the day the informed consent form is signed;

[0316] 2. During screening, patients must have been diagnosed with type 2 diabetes for at least 3 months according to the criteria outlined in the "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China (2020 Edition)".

[0317] 3. During screening, the HbA1c level was tested by a local laboratory and found to be 7.5% ≤ HbA1c ≤ 11.0%;

[0318] 4. Screening criteria: Based on a regular diet and exercise regimen, patients received stable metformin monotherapy for ≥8 weeks with a daily dose ≥1000mg. Stable therapy was defined as no change in the daily dose of the drug.

[0319] 5. Subjects weighing ≥ 50 kg, with a BMI ≤ 40.0 kg / m² and a body mass index (BMI) of 19.0 kg / m². 2 ;

[0320] 6. Screening and randomization: Weight change within the preceding 90 days (difference between maximum and minimum weight during the period) not exceeding 5 kg.

[0321] 7. Capable and willing to comply with the protocol requirements, including self-monitoring blood glucose and recording participant logs;

[0322] 8. From the signing of the informed consent form to 6 months after the last dose, the subject (including the partner) has no plans to conceive and is willing to use the highly effective contraceptive method specified in the protocol;

[0323] 9. Before the trial, participants voluntarily sign an informed consent form and fully understand the trial content, process, and possible adverse reactions.

[0324] Patients with any of the following conditions are ineligible for enrollment in this study:

[0325] 1. Known or suspected allergy to the investigational drug, its components, or its excipients;

[0326] 2. Diagnosed or suspected of having type 1 diabetes, a special type of diabetes, or secondary diabetes;

[0327] 3. Acute complications of diabetes (diabetic ketoacidosis, lactic acidosis, hyperglycemic hyperosmolar state, etc.) within 6 months prior to screening;

[0328] 4. Severe hypoglycemic events or recurrent hypoglycemic events within 6 months prior to screening (≥3 hypoglycemic events within one week [excluding possible symptomatic hypoglycemia], or at least 3 blood glucose values ​​<3.0mmol / L [<54mg / dL] within one week, or other hypoglycemic events as determined by the investigator);

[0329] 5. Screening patients with proliferative retinopathy or macular degeneration requiring acute treatment, painful diabetic neuropathy, diabetic foot ulcers, or intermittent claudication;

[0330] 6. Within 6 months prior to screening, the subject must have a clinically significant active infectious disease, or one of the following diseases: including but not limited to neurological, psychiatric, cardiovascular, endocrine, digestive, respiratory, urinary, hematological, and immune diseases (excluding type 2 diabetes-related diseases), which the investigator determines may interfere with the trial results or pose additional risks to the administration of the investigational drug;

[0331] 7. Individuals who have received any other investigational drug treatment within the preceding 3 months or 5 half-lives (whichever is longer) will be screened;

[0332] 8. Any of the following medications or treatments were used prior to screening:

[0333] -Use of systemic glucocorticoids within 90 days prior to screening (excluding topical, inhaled, intraocular, and nasal administration);

[0334] - Individuals who have received any hypoglycemic medication other than metformin within 90 days prior to screening, including traditional Chinese medicine treatment for hypoglycemic purposes (excluding short-term treatment [continuous treatment ≤7 days]); or individuals who have used any hypoglycemic medication other than metformin within 2 weeks prior to the first use of the investigational drug;

[0335] -Those who have used weight loss drugs or taken drugs that directly affect gastrointestinal motility within 90 days prior to screening;

[0336] 9. Previous discontinuation of glucagon-like peptide-1 receptor agonist therapy due to safety / tolerability or lack of efficacy;

[0337] 10. The following laboratory test results are available during screening or randomization:

[0338] - Fasting glucose >15.0 mmol / L;

[0339] - Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × upper limit of normal (ULN);

[0340] - Total bilirubin > 1.5 × ULN;

[0341] -Amylase and / or lipase >3×ULN;

[0342] - Renal insufficiency (estimated glomerular filtration rate [eGFR] calculated using the formula in Annex II of the Chronic Kidney Disease Epidemiology Collaboration Group [CKD-EPI] < 60 mL / min / 1.73 m2);

[0343] - Urine albumin / creatinine ratio (UACR) ≥ 300 mg / g;

[0344] - Calcitonin ≥50ng / L;

[0345] 11. Individuals or families with a history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2, a history of pancreatitis (acute or chronic) or symptomatic gallbladder disease (except for subjects who have previously undergone cholecystectomy and are deemed eligible for enrollment by the investigators).

[0346] 12. Those with a history of significant gastrointestinal diseases (such as gastroesophageal reflux, gastric outlet obstruction, inflammatory bowel disease, active ulcers, etc.) or who have undergone gastrointestinal surgery (excluding gastrointestinal polyp removal and appendectomy);

[0347] 13. Individuals with a history of thyroid disease that has not been controlled with a stable drug dose during screening or randomization; or individuals with clinically significant abnormalities in thyroid function tests during screening or randomization;

[0348] 14. Suffering from cardiovascular and cerebrovascular diseases, defined as: having experienced congestive heart failure (NYHA class III-IV), unstable angina, stroke, myocardial infarction, or coronary revascularization within 6 months prior to screening; and / or planning to undergo coronary, carotid, or peripheral artery revascularization at the time of screening;

[0349] 15. Severe hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg) that is not controlled during screening or randomization;

[0350] 16. Screening or randomization results of electrocardiogram examination showed clinically significant abnormalities, such as supraventricular tachycardia, atrial fibrillation, atrial flutter, second- or third-degree atrioventricular block, etc., and the investigators believed that they were not suitable for inclusion in this study;

[0351] 17. During screening or randomization, the ECG results indicate an ECG QTcF > 450ms. If the QTcF is abnormal during screening, two more ECG measurements can be taken, and the average QTcF value of the three measurements can be recorded.

[0352] 18. Individuals with or suspected of having depression, bipolar disorder, suicidal tendencies, schizophrenia, or other severe mental illnesses; or those who are mentally incapacitated or have language impairments, are unable to fully understand the trial protocol, or are unwilling to cooperate with research center staff;

[0353] 19. Known or suspected alcohol or narcotics abuse; weekly alcohol consumption greater than 14 units (1 unit of alcohol = 360 ml beer or 45 ml spirits with an alcohol content of 40% or 150 ml wine) within the 6 months prior to screening;

[0354] 20. Screening candidates must have a history of malignant tumors within the past 5 years, excluding cured local cancers such as local basal cell carcinoma of the skin;

[0355] 21. Pregnant, breastfeeding, planning to become pregnant during the trial, or a woman of childbearing potential who has not used appropriate contraception (WOCBP); or a man who has not used appropriate contraception;

[0356] 22. Intolerant of intravenous puncture for blood collection or prone to fainting from needles or blood loss;

[0357] 23. Any situation that the researchers determine would interfere with the validity or safety of the test results.

[0358] Ranking can only be performed after the subject has completed the induction treatment and has been reconfirmed to meet the following randomization criteria after the baseline (V3) examination.

[0359] 1. 7.5% ≤ HbA1c ≤ 11.0% (Central Laboratory Results);

[0360] 2. Fasting glucose ≤15.0mmol / L (central laboratory result);

[0361] 3. Medication adherence during the introductory period is ≥80% and ≤120%;

[0362] 4. Laboratory tests, blood pressure, weight, electrocardiogram, and pregnancy status meet the inclusion criteria but not the exclusion criteria;

[0363] 5. Not taking any hypoglycemic medications other than those specified in the treatment plan;

[0364] 6. No factors that the investigators believed might affect the efficacy or safety evaluation of this study occurred during the introduction period.

[0365] III. Research Drugs

[0366] Subjects are required to take the prescribed number of tablets of compound (I) plus metformin extended-release tablets, or compound (I) placebo plus metformin extended-release tablets, immediately after breakfast each day.

[0367] Compound (I) / placebo.

[0368] Metformin extended-release tablets are manufactured by Merck. Extended-release tablets ( XR, metformin hydrochloride extended-release tablets 500mg / tablet).

[0369] During the subject screening period, the metformin dosage remained the same as within the 8 weeks prior to screening (dosage form not limited). During the study introductory and double-blind treatment periods, the dosage was adjusted to a similar metformin extended-release tablet at 1500 mg / day or 2000 mg / day. The adjustment criteria for metformin extended-release tablets were as follows: if the original metformin dosage was >1000 mg / day and <1700 mg / day, it was adjusted to 1500 mg / day; if the original metformin dosage was ≥1700 mg / day, it was adjusted to 2000 mg / day; and if the original metformin dosage was 1000 mg / day, that dosage was continued.

[0370] Dosage and administration of drugs during the introductory phase

[0371] All subjects entering the induction period were given a placebo of compound (I) (1 tablet of 15 mg or 3 tablets of 30 mg) and metformin extended-release tablets (1000 mg, 1500 mg or 2000 mg, or 2 to 4 tablets of 500 mg) once daily for 3 weeks.

[0372] Double-blind treatment period drug dosage

[0373] The number of tablets administered at each dose of compound (I) / placebo during the double-blind treatment period is as follows:

[0374] For successfully screened subjects, the metformin extended-release tablet dose must be ≥1000 mg / day. From successful screening until the end of the treatment period, the metformin extended-release tablet dose should remain consistent with the dose during the initial treatment phase.

[0375] IV. Study Endpoints

[0376] Primary study endpoint:

[0377] • Secondary study endpoint: Change in glycated hemoglobin (HbA1c) relative to baseline after 16 weeks of treatment:

[0378] The effects of different titration methods on the safety and tolerability of compounds of formula (I) in subjects with type 2 diabetes whose blood sugar is poorly controlled by metformin. Safety endpoints included: adverse events, hypoglycemic events, laboratory tests, physical examination, vital signs, 12-lead electrocardiogram, etc.

[0379] • The percentage of subjects who achieved the target HbA1c level (<7.0%) after 16 weeks of treatment.

[0380] • Changes in fasting plasma glucose relative to baseline after 16 weeks of treatment

[0381] • Changes in fasting serum insulin relative to baseline after 16 weeks of treatment

[0382] • Changes in fasting serum C-peptide relative to baseline after 16 weeks of treatment

[0383] • Changes in plasma glucose relative to baseline 2 hours after a meal 16 weeks of treatment

[0384] • Changes in serum insulin levels 2 hours after a meal relative to baseline after 16 weeks of treatment

[0385] • Changes in serum C-peptide relative to baseline 2 hours after meals after 16 weeks of treatment

[0386] • Changes in fasting body weight relative to baseline after 16 weeks of treatment

[0387] • Changes in waist circumference relative to baseline after 16 weeks of treatment

[0388] • After 16 weeks of treatment, the average change in self-measured blood glucose (SMBG) at 7 points relative to baseline was...

[0389] • Proportion of subjects in each group who received salvage therapy

[0390] • Adverse events, hypoglycemic events, laboratory tests, physical examination, vital signs, 12-lead electrocardiogram, etc.

[0391] • Concentration of compound (I) in plasma

[0392] V. Results and Conclusions

[0393] Number of participants:

[0394] This study screened 387 participants, with 288 successfully selected. 194 participants were randomly assigned to one of the following groups: 39 in the 15mg / 60mg compound (Formula I), 39 in the 30mg / 60mg compound, 39 in the 90mg compound, and 39 in the placebo group. Of these, 194 participants received at least one treatment with the investigational drug, and 177 completed the 16-week treatment program. Seventeen participants prematurely terminated treatment with the Compound (I) / placebo study drug, primarily due to adverse events (7 cases), withdrawal requests (8 cases), and loss to follow-up (2 cases).

[0395] Demographic data:

[0396] The baseline demographic characteristics of the groups in this study were similar, and the groups were basically balanced. The mean ± standard deviation (SD) age of all subjects was 52.3 ± 11.04 years; the proportion of males was 59.3% and the proportion of females was 40.7%; the mean ± SD of HbA1c was 8.53 ± 0.740%; the mean ± SD of fasting plasma glucose was 9.91 ± 2.091 mmol / L; the mean ± SD of weight was 73.42 ± 12.431 kg; and the mean ± SD of BMI was 26.72 ± 3.764 kg / m2.

[0397] Validity results:

[0398] Main validity results

[0399] ★ Changes in HbA1c relative to baseline after 16 weeks of treatment

[0400] The analysis of the main validity results was based on FAS.

[0401] After 16 weeks of treatment, the least squares mean (95% CI) changes in HbA1c from baseline in the 15 mg, 30 mg, 60 mg, and 90 mg groups of compound (I) and the placebo group were -1.19% (-1.544, -0.839), -1.59% (-1.941, -1.236), -1.82% (-2.158, -1.478), -1.64% (-1.974, -1.304), and -0.25% (-0.598, 0.093), respectively. The estimated differences (95% CI) in treatment efficacy between the 15 mg, 30 mg, 60 mg, and 90 mg groups of compound (I) and the placebo group were -0.94% (-1.433, -0.446), -1.34% (-1.830, -0.843), -1.57% (-2.050, -1.081), and -1.39% (-1.868, -0.906), respectively. The reduction in HbA1c relative to baseline was significantly greater in all dosage groups of compound (I) than in the placebo group, and this was statistically significant (p < 0.001 for all groups).

[0402] Based on FAS and a hypothetical strategy, the primary analysis of the main estimated target was performed using MMRM. The statistical analysis results of the change in HbA1c (%) relative to baseline at week 16 of treatment are shown in Table 1.

[0403] Table 1. Primary analysis of the main estimated target: Statistical analysis results of HbA1c (%) change relative to baseline at 16 weeks of treatment (MMRM model) (FAS)

[0404] N represents the number of participants in each analysis group, and n represents the number of participants who had observations during that visit.

[0405] For subjects who experienced any comorbid event, data from dates later than the earliest date (including that day) were set as missing.

[0406] Based on a repeated measures mixed-effects model (MMRM), baseline HbA1c is a covariate, while the treatment group, visit, and the interaction term between treatment and visit are fixed effects, and the subjects are random effects. An unstructured covariance matrix (UN) is used to calculate each statistic. If the UN does not converge, a composite symmetric structure (CS) covariance matrix is ​​used.

[0407] Table 2: Primary and secondary efficacy endpoints at week 16

[0408] a Number of patients with observational values ​​in week 16.

[0409] b The compound group in Equation (I) was compared with the placebo group using a repeated measures mixed-effects model (MMRM). Baseline values ​​were covariates, treatment group, visit, and the interaction term between treatment and visit were fixed effects, and subjects were random effects. Unstructured covariance matrices (UN) were used to calculate the statistics.

[0410] c The compound group of Equation (I) was compared with the placebo group using an ANCOVA model, with the treatment group as the independent variable and the corresponding baseline value as the covariate. All statistics were calculated. Missing values ​​were imputed according to the LOCF, including data classified as missing due to concurrent events.

[0411] d Number of patients achieving HbA1c < 7.0% after multiple imputation based on the week 16 Missing Random (MAR) hypothesis / Number of randomly assigned patients.

[0412] e 95% CIs were calculated using the Clopper-Pearson method.

[0413] f 95% of CIs are calculated based on the normal approximation.

[0414] g The chi-square test was used to compare the proportion of patients in the compound (I) group and the placebo group who achieved HbA1c < 7.0% at week 16.

[0415] HbA 1c Glycated hemoglobin; Fasting plasma glucose (FPG); Postprandial plasma glucose (PPG); Least squares (LS); Confidence interval (CI); Self-monitored blood glucose (SMBG); Missing random number (MAR); Last observation carryover (LOCF); Analysis of covariance (ANCOVA).

[0416] Table S3. Mean change (%) of HbA1c from baseline at week 16 (excluding patients with two consecutive negative pk tests) (post-hoc analysis) *

[0417] a Number of patients with observational values ​​in week 16.

[0418] bThe compound group in Equation (I) was compared with the placebo group using a repeated measures mixed-effects model (MMRM). Baseline values ​​were covariates, treatment group, visit, and the interaction term between treatment and visit were fixed effects, and subjects were random effects. Unstructured covariance matrices (UN) were used to calculate the statistics.

[0419] * Statistical summary analyses were performed according to the primary endpoint hypothesis strategy. Starting from the first "ND" point, patient data with two consecutive "ND" (Not Detected) values ​​were excluded, but all subsequent data were included.

[0420] At baseline, the mean age was 52.3 years, HbA1c was 8.5%, and BMI was 26.7 kg / m². 2 The average weight was 73.4 kg, 59.3% were male, and approximately 80% were taking ≥1500 mg / day of metformin (see Table 4 for details).

[0421] Table 4: Demographic and baseline characteristics at 16 weeks of treatment

[0422] Continuous data are expressed as mean ± standard deviation.

[0423] a BMI = weight (kg) / height (m) 2 . b Central laboratory value. c Local laboratory values.

[0424] In terms of efficacy, at week 16, the mean percentage change in body weight relative to baseline was -2.63% in the 90 mg group, compared to -1.30% in the placebo group (see Figure 2).

[0425] Regarding safety, the probability of TEAE in patients in each dose group of compound (I) was 71.8%-84.6%, while it was 71.8% in the placebo group (see Table 5).

[0426] Most TEAEs are gastrointestinal (nausea: 7.7%–34.2% in the formula (I) compound group vs. 2.6% in the placebo group; diarrhea: 5.1%–15.4% vs. 0%; vomiting: 2.6%–15.8% vs. 0%), and are usually mild to moderate.

[0427] Nine (5.8%) patients who received compound (I) experienced hypoglycemia, but no grade 2 or higher events were reported.

[0428] Patients receiving treatment with compound (I) showed a slight increase in serum amylase and lipase levels relative to baseline, but no cases of pancreatitis were observed.

[0429] At week 16, patients using compound (I) had a mean pulse rate increase of 0.21–3.18 bpm from baseline.

[0430] Table 5: Adverse events during 16 weeks of treatment

[0431] Note: The data is n (%).

[0432] a AESI includes abnormal liver function, amylase / lipase >3ULN, acute and / or chronic pancreatitis, abnormal serum calcitonin, and severe hypoglycemic episodes.

[0433] Secondary validity results

[0434] ★Percentage of subjects who achieved the target HbA1c level (<7.0%) after 16 weeks of treatment.

[0435] Based on FAS, after 16 weeks of treatment, the proportions of subjects achieving the HbA1c target value (<7.0%) in the 15 mg, 30 mg, 60 mg, and 90 mg groups of compound (I) and the placebo group were 48.7%, 56.4%, 63.2%, 51.3%, and 15.4%, respectively. The estimated differences (95% CI) between the 15 mg, 30 mg, 60 mg, and 90 mg groups of compound (I) and the placebo group were 33.3% (13.99, 52.68), 41.0% (21.78, 60.27), 47.8% (28.71, 66.84), and 35.9% (16.55, 55.24), respectively. The proportion of subjects achieving the HbA1c target value (<7.0%) in each dose group of compound (I) was greater than that in the placebo group.

[0436] ★Changes in fasting plasma glucose relative to baseline after 16 weeks of treatment

[0437] Based on FAS, after 16 weeks of treatment, the least squares mean (95% CI) changes in FPG relative to baseline in the 15 mg, 30 mg, 60 mg, and 90 mg groups of compound (I) and the placebo group were -1.37 mmol / L (-1.989, -0.756), -1.54 mmol / L (-2.165, -0.910), -2.69 mmol / L (-3.280, -2.096), -1.92 mmol / L (-2.512, -1.330), and -0.14 mmol / L (-0.781, 0.503), respectively. The estimated differences (95% CI) in treatment between the 15 mg, 30 mg, 60 mg, and 90 mg groups of compound (I) and the placebo group were -1.23 mmol / L (-2.124, -0.343), -1.40 mmol / L (-2.296, -0.501), -2.55 mmol / L (-3.422, -1.676), and -1.78 mmol / L (-2.654, -0.910), respectively. After 16 weeks of treatment, the decrease in fasting plasma glucose was greater in all dose groups of compound (I) than in the placebo group.

[0438] ★Changes in plasma glucose relative to baseline 2 hours after meals after 16 weeks of treatment

[0439] Based on FAS, after 16 weeks of treatment, the least squares mean (95% CI) changes in plasma glucose relative to baseline at 2 hours postprandial in the 15 mg, 30 mg, 60 mg, and 90 mg groups of compound (I) and the placebo group were -5.53 mmol / L (-6.905, -4.156), -6.34 mmol / L (-7.717, -4.957), -8.45 mmol / L (-9.846, -7.061), -7.29 mmol / L (-8.663, -5.913), and -0.09 mmol / L (-1.462, 1.286), respectively. The estimated differences (95% CI) in treatment between the 15 mg, 30 mg, 60 mg, and 90 mg groups of compound (I) and the placebo group were -5.44 mmol / L (-7.385, -3.499), -6.25 mmol / L (-8.196, -4.302), -8.37 mmol / L (-10.321, -6.409), and -7.20 mmol / L (-9.143, -5.256), respectively. After 16 weeks of treatment, the decrease in plasma glucose 2 hours after a meal was greater in all dose groups of compound (I) than in the placebo group.

[0440] ★Changes in fasting serum insulin and C-peptide relative to baseline after 16 weeks of treatment

[0441] Based on FAS, after 16 weeks of treatment, the least squares mean (95% CI) changes in fasting serum insulin relative to baseline in the 15 mg, 30 mg, 60 mg, and 90 mg groups of compound (I) and the placebo group were 0.41 μU / mL (-1.911, 2.737), 1.90 μU / mL (-0.440, 4.242), 0.04 μU / mL (-2.319, 2.398), 2.96 μU / mL (0.638, 5.290), and -0.55 μU / mL (-2.868, 1.778).

[0442] Based on FAS, after 16 weeks of treatment, the least squares mean (95% CI) changes in fasting serum C-peptide relative to baseline in the 15 mg, 30 mg, 60 mg, and 90 mg groups of compound (I) and the placebo group were 0.06 ng / mL (-0.202, 0.318), 0.35 ng / mL (0.087, 0.611), 0.09 ng / mL (-0.170, 0.357), 0.50 ng / mL (0.236, 0.757), and -0.11 ng / mL (-0.373, 0.148), respectively.

[0443] ★Changes in serum insulin and C-peptide levels relative to baseline 2 hours after meals after 16 weeks of treatment

[0444] Based on FAS, after 16 weeks of treatment, the least squares mean (95% CI) changes in serum insulin relative to baseline at 2 hours postprandial in the 15 mg, 30 mg, 60 mg, and 90 mg groups of compound (I) and the placebo group were 0.74 μU / mL (-5.088, 6.578), -6.46 μU / mL (-12.294, -0.623), -7.48 μU / mL (-13.384, -1.569), -12.10 μU / mL (-17.924, -6.285), and 3.52 μU / mL (-2.317, 9.364).

[0445] Based on FAS, after 16 weeks of treatment, the least squares mean (95% CI) changes in C-peptide relative to baseline at 2 hours postprandial in the 15 mg, 30 mg, 60 mg, and 90 mg groups of compound (I) and the placebo group were 0.68 ng / mL (0.073, 1.291), 0.21 ng / mL (-0.400, 0.819), -0.39 ng / mL (-1.010, 0.225), -0.25 ng / mL (-0.857, 0.363), and 0.37 ng / mL (-0.242, 0.979), respectively.

[0446] ★After 16 weeks of treatment, the average change in SMBG relative to baseline was 7 points.

[0447] Based on FAS, after 16 weeks of treatment, the mean 7-point SMBG changes relative to baseline (95% CI) in the 15 mg, 30 mg, 60 mg, and 90 mg groups of compound (I) and the placebo group were -1.94 mmol / L (-2.613, -1.270), -2.59 mmol / L (-3.292, -1.887), -3.25 mmol / L (-3.898, -2.605), -2.90 mmol / L (-3.548, -2.245), and -0.88 mmol / L (-1.584, -0.182), respectively. The estimated differences (95% CI) in treatment between the 15 mg, 30 mg, 60 mg, and 90 mg groups of compound (I) and the placebo group were -1.06 mmol / L (-2.029, -0.087), -1.71 mmol / L (-2.700, -0.714), -2.37 mmol / L (-3.322, -1.415), and -2.01 mmol / L (-2.971, -1.056), respectively. After 16 weeks of treatment, the mean 7-point self-monitored blood glucose reduction was greater in all dosage groups of compound (I) than in the placebo group.

[0448] ★Proportion of subjects in each group who received rescue treatment

[0449] Based on FAS, during the double-blind treatment period, the incidence of salvage therapy in the 15 mg, 30 mg, 60 mg, and 90 mg groups of compound (I) and the placebo group was 2.6%, 7.7%, 0%, 2.6%, and 30.8%, respectively. The incidence of salvage therapy in each dose group of compound (I) was lower than that in the placebo group.

[0450] Safety results:

[0451] ★ The effect of different titration methods of compound (I) on the safety and tolerability of type 2 diabetes patients with poor metformin control.

[0452] This study evaluated the effects of different titration methods on the safety and tolerability of type 2 diabetes patients with poorly controlled metformin levels in the 60 mg and 90 mg groups of compound (I). The 60 mg group of compound (I) started with 30 mg, titrated to 45 mg after 2 weeks, and then titrated to 60 mg after another 2 weeks. The 90 mg group of compound (I) started with 30 mg, titrated to 60 mg after 4 weeks. The doses differed between the two groups in weeks 3 and 4, but both groups were titrated to 60 mg in week 5. Based on safety data, the 60 mg group of compound (I) experienced higher levels of gastrointestinal adverse reactions during the above-mentioned dosing phases. This result suggests that the four-week titration regimen can mitigate gastrointestinal adverse reactions to some extent and is beneficial for establishing tolerability in subjects.

[0453] in conclusion:

[0454] In terms of efficacy, in type 2 diabetes patients with poor glycemic control due to metformin, all dose groups of compound (I) showed good glycemic control compared to the placebo group, and exhibited a certain dose-related effect. In addition to its potent hypoglycemic effect, 90 mg of compound (I) also provided the additional benefit of weight loss.

[0455] In terms of safety, the most common adverse reactions are gastrointestinal adverse reactions, most of which are mild or moderate, and the incidence rate is low among similar products; laboratory test indicators related to the target mechanism show an increasing trend, but no new safety signals have been found.

[0456] In summary, compound (I) demonstrates good efficacy, safety, and tolerability in type 2 diabetes patients with poor glycemic control due to metformin.

[0457] Example 2. A randomized, double-blind, phase III study evaluating the efficacy and safety of compound (I) compared to dapagliflozin in adult subjects with poor glycemic control following metformin treatment.

[0458] I. Research on drugs

[0459] Compound of Formula (I) / Compound of Formula (I) placebo / Dapagliflozin placebo, strengths: 30mg / tablet, 60mg / tablet;

[0460] Dapagliflozin use (Manufacturer: AstraZeneca Pharmaceuticals LP), 10mg / tablet.

[0461] II. Inclusion criteria, exclusion criteria, and randomization criteria

[0462] Participants must meet all of the following criteria to be eligible for this trial:

[0463] 1. Male or female, aged 18 to 75 years old on the day the informed consent form is signed;

[0464] 2. During screening, according to the diagnostic criteria of the "Guidelines for the Prevention and Treatment of Type 2 Diabetes in China (2020 Edition)," individuals with a history of type 2 diabetes for ≥3 months were considered.

[0465] 3. During screening, 7.5% ≤ HbA 1c ≤11.0% (tested by local laboratory);

[0466] 4. At screening, patients must have maintained stable treatment for type 2 diabetes for ≥8 weeks, with no planned changes to their treatment regimen throughout the trial. The treatment regimen at screening must consist of stable metformin monotherapy for ≥8 weeks at a daily dose ≥1500 mg or the maximum tolerated daily dose ≥1000 mg (metformin dosage must comply with the instructions for use).

[0467] 5. During screening, 19.0 kg / m 2 Body Mass Index (BMI) ≤ 40.0 kg / m² 2 ;

[0468] 6. Before the trial, participants voluntarily sign an informed consent form, fully understand the trial content, process, and possible adverse reactions, and are capable and willing to comply with the protocol requirements to complete the study (e.g., self-monitoring blood glucose and recording participant logs);

[0469] 7. From the time the informed consent form is signed until two weeks after the last dose, the subject has no plans to conceive and is willing to use the highly effective contraceptive method specified in the protocol.

[0470] Subjects who meet any of the following criteria shall not be eligible to participate in this trial:

[0471] The following checks are abnormal during filtering or randomization:

[0472] 1. The following laboratory test results are abnormal during screening or randomization:

[0473] Fasting intravenous glucose >15 mmol / L;

[0474] • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2 × upper limit of normal (ULN);

[0475] • Total bilirubin (TBIL) > 1.5 × ULN;

[0476] • Amylase and / or lipase >3×ULN;

[0477] • Fasting triglycerides (TG) > 11.3 mmol / L;

[0478] Calcitonin ≥50 ng / L;

[0479] • Estimated glomerular filtration rate (eGFR) <45 mL / min / 1.73 m2 (calculated using the Chronic Kidney Disease Epidemiology Collaboration Group [CKD-EPI] formula);

[0480] • Urine albumin / creatinine ratio (UACR) ≥ 1000 mg / g;

[0481] • Hepatitis B surface antigen (HBsAg) positive and hepatitis B virus DNA (HBV-DNA) > ULN;

[0482] 2. When screening or randomizing, the electrocardiogram results show clinically significant abnormalities that may affect the safety of the subjects, including but not limited to supraventricular tachycardia, atrial fibrillation, atrial flutter, second- or third-degree atrioventricular block, etc.

[0483] 3. During screening or randomization, the ECG results indicate a heart rate >100 bpm or a QTcF >480 ms. If the heart rate or QTcF is abnormal, two more ECGs can be performed, and the average of the three measurements can be taken.

[0484] 4. Uncontrolled severe hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg) was present during screening or randomization;

[0485] The following diseases or medical history were present before screening:

[0486] 5. Diagnosed or suspected of having type 1 diabetes, a special type of diabetes, or secondary diabetes;

[0487] 6. Acute complications of diabetes (diabetic ketoacidosis, lactic acidosis, hyperglycemic hyperosmolar state, etc.) within 6 months prior to screening;

[0488] 7. Those who have experienced severe hypoglycemia or recurrent hypoglycemia within the 6 months prior to screening (≥3 hypoglycemic events within one week, or other hypoglycemic events as determined by the investigator);

[0489] 8. Those with proliferative retinopathy or macular degeneration at the time of screening, or those with painful diabetic neuropathy, diabetic foot ulcers, or intermittent claudication requiring acute treatment;

[0490] 9. Within 6 months prior to screening, the subject was known to have any of the following clinically significant diseases: including but not limited to diseases of the nervous, mental, cardiovascular, endocrine, digestive, respiratory, urinary, hematologic, and immune systems (excluding type 2 diabetes-related diseases), which the investigator determined may interfere with the trial results or pose additional risks to the administration of the investigational drug;

[0491] 10. A history or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN2);

[0492] 11. A history of acute or chronic pancreatitis, pancreatic injury, acute cholecystitis, or symptomatic / treatment-required gallbladder disease (except for subjects who have undergone cholecystectomy and are deemed eligible for enrollment by the investigator);

[0493] 12. Those with a history of significant gastrointestinal diseases (such as gastric outlet obstruction, inflammatory bowel disease, active ulcers, etc.), or those who have undergone gastrointestinal surgery (excluding gastrointestinal polyp removal and appendectomy), or those who have been taking drugs that directly affect gastrointestinal motility for a long time.

[0494] 13. Those with a history of hyperthyroidism before screening, or who have hyperthyroidism at the time of screening, or who have other thyroid diseases that are not stably controlled (except for subjects whose thyroid hormone replacement therapy regimen has been stable for at least 8 weeks and who do not plan to change their treatment regimen during the trial);

[0495] 14. A history of severe cardiovascular or cerebrovascular disease within the six months prior to screening, including but not limited to: congestive heart failure (NYHA Class III-IV), unstable angina, stroke, myocardial infarction, severe arrhythmia, or coronary revascularization; or a planned coronary, carotid, or peripheral artery revascularization procedure at the time of screening;

[0496] 15. Individuals with known or suspected depression, bipolar disorder, suicidal tendencies, schizophrenia, or other severe mental illnesses; or those who are mentally incapacitated or have language impairments, are unable to fully understand the trial protocol, or are unwilling to cooperate with research center staff;

[0497] 16. Screening candidates must have a history of malignant tumors within the past 5 years, excluding cured local cancers such as: local basal cell carcinoma of the skin, cervical carcinoma in situ, and prostate carcinoma in situ;

[0498] 17. Those who are in a state of urinary tract infection or genital infection at the time of screening or randomization, or who have a history of urinary tract infection or genital infection caused by the use of SGLT2 inhibitors;

[0499] The following medications or treatments were used prior to screening: 18. Use of glucagon-like peptide-1 (GLP-1) receptor agonist drugs (including multi-target GLP-1 receptor agonist drugs) within 3 months prior to screening;

[0500] 19. Those who have received systemic glucocorticoid therapy within the 3 months prior to screening (excluding cumulative use of <14 days or topical, inhalation, intraocular, or nasal administration);

[0501] 20. Use of tricyclic antidepressants, atypical antipsychotics, and mood stabilizers (such as imipramine, chlorpromazine, amitriptyline, mirtazapine, clozapine, olanzapine, paroxetine, phenelzine, thioridazine, valproic acid and its derivatives, lithium salts, etc.) within 3 months prior to screening;

[0502] 21. Those who have undergone weight loss treatment within the past 3 months, including intensive diet or exercise therapy, drug therapy, surgical treatment (excluding liposuction surgery history of more than 1 year), health products or other special therapies;

[0503] If any of the following conditions exist: 22. During screening or randomization, the individual reports a weight change of more than ±5% within 3 months, or plans to undergo intensive diet or exercise therapy for weight loss during the trial (excluding diabetes diet and exercise control measures);

[0504] 23. Candidates must have participated in any clinical trial of a drug or medical device within the three months prior to screening, or be within five half-lives of an investigational drug (whichever is longer). Participation in a clinical trial is defined as: signing informed consent and using the investigational drug (including placebo) or investigational medical device.

[0505] 24. Known or suspected allergy to the study drug or its components;

[0506] 25. Those with a known or suspected history of drug or alcohol abuse, and in the researchers' opinion, are unsuitable to participate in this clinical trial;

[0507] 26. Individuals who have a history of blood donation, blood loss ≥400mL, or have received a blood transfusion within the three months prior to screening;

[0508] 27. Women who are pregnant, breastfeeding, or planning to become pregnant during the trial;

[0509] 28. Intolerant of intravenous puncture or fear of needles;

[0510] 29. Any condition that the investigators deem unsuitable for participation in this clinical trial.

[0511] Subjects were randomly assigned based on their V3 test results, after confirming they met the following randomization criteria before randomization. Subjects who failed to be randomized in this study were not eligible for re-screening.

[0512] 1. 7.5% ≤ HbA1c ≤ 11.0% (Central Laboratory Results);

[0513] 2. Fasting glucose ≤15.0mmol / L (central laboratory result);

[0514] 3. Laboratory tests, vital signs, weight, BMI, electrocardiogram, pregnancy status, etc. meet the inclusion criteria but not the exclusion criteria;

[0515] 4. Medication adherence during the introductory period is ≥80% and ≤120%;

[0516] 5. The metformin treatment regimen remained stable during the induction phase;

[0517] 6. No hypoglycemic drugs other than those specified in the treatment plan were used during the induction period;

[0518] 7. No circumstances occurred during the induction period that the investigators deemed unsuitable for participation in this clinical trial.

[0519] III. Clinical Endpoints

[0520] Primary endpoint

[0521] • Compared with dapagliflozin, compound (I) resulted in lower glycated hemoglobin (HbA1c) at week 32 of treatment. 1c Changes relative to the baseline.

[0522] Key secondary endpoints:

[0523] Compared to dapagliflozin, compound (I) at week 32 of treatment:

[0524] • Reaching HbA 1c <7.0% of the participants;

[0525] • Reaching HbA 1c ≤6.5% of the subjects;

[0526] • Changes in fasting plasma glucose (FPG) relative to baseline;

[0527] • Percentage change in weight relative to baseline.

[0528] Secondary endpoint:

[0529] effectiveness endpoint

[0530] Compared to dapagliflozin, compound (I) at week 32 of treatment:

[0531] • Changes in weight and waist circumference relative to baseline;

[0532] • Reaching HbA 1c <5.7% of the participants;

[0533] • Changes in fasting serum insulin, fasting serum C-peptide, homeostasis model-assessed pancreatic β-cell function index (HOMA-β), and insulin resistance index (HOMA-IR) relative to baseline;

[0534] • Changes in plasma glucose, serum insulin, and serum C-peptide relative to baseline 2 hours after a meal;

[0535] • The proportion of subjects in each group who received salvage therapy;

[0536] • Changes in 7-point self-tested blood glucose (SMBG) spectrum relative to baseline.

[0537] Compared to dapagliflozin, compound (I) at week 52 of treatment:

[0538] HbA 1c Changes relative to the baseline;

[0539] • Changes in FPG relative to the baseline;

[0540] • Percentage change in weight relative to baseline;

[0541] • Changes in weight and waist circumference relative to baseline;

[0542] • Reaching HbA 1c <7.0% of the participants;

[0543] • Reaching HbA 1c ≤6.5% of the subjects;

[0544] • Reaching HbA 1c <5.7% of the participants;

[0545] • Changes in fasting serum insulin, fasting serum C-peptide, HOMA-β, and HOMA-IR relative to baseline;

[0546] • Changes in plasma glucose, serum insulin, and serum C-peptide relative to baseline 2 hours after a meal;

[0547] • The proportion of subjects in each group who received salvage therapy;

[0548] • Changes in the 7-point SMBG spectrum relative to the baseline.

[0549] Safety endpoint

[0550] Compared to dapagliflozin, compound (I) at weeks 32 and 52 of treatment:

[0551] • Adverse events, hypoglycemic events, laboratory tests, vital signs, physical examination, 12-lead electrocardiogram, screening and assessment of diabetic retinopathy, etc.

[0552] Pharmacokinetic endpoints

[0553] • The concentration of compound (I) in plasma.

Claims

1. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of type 2 diabetes, preferably type 2 diabetes previously treated with metformin:

2. The use according to claim 1, wherein the type 2 diabetes is, during screening, type 2 diabetes treated with metformin monotherapy for ≥8 weeks at a daily dose of ≥1000 mg; or treated with metformin monotherapy for ≥8 weeks at a daily dose of ≥1500 mg or the maximum tolerated daily dose of ≥1000 mg.

3. Use according to claim 1 or 2, wherein, After 16 weeks of treatment with compound (I) or its pharmaceutically acceptable salt, the change in HbA1c from baseline was -1.1% to -1.9%.

4. The use according to any one of claims 1 to 3, wherein, After administration of compound (I) or its pharmaceutically acceptable salt for 16 weeks, at least 45% of the subjects achieved HbA1c < 7.0%.

5. The use according to any one of claims 1-4, wherein, After 16 weeks of administration of compound (I) or its pharmaceutically acceptable salt, the least squares mean (95% CI) change in fasting plasma glucose (FPG) relative to baseline was a decrease of at least 1.0 mmol / L.

6. The use according to any one of claims 1 to 5, wherein, After 16 weeks of administration of compound (I) or its pharmaceutically acceptable salt, the least squares mean (95% CI) change in plasma glucose relative to baseline at 2 hours after a meal was at least 5.0 mmol / L.

7. Use according to any one of claims 1 to 6, wherein, The dosage of the compound of formula (I) or its pharmaceutically acceptable salt is 5-800 mg, preferably 15-720 mg, more preferably 15-360 mg, and most preferably 15 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 120 mg, 150 mg, 180 mg, 240 mg, 300 mg, or 360 mg; and / or Compounds of formula (I) or their pharmaceutically acceptable salts are administered by dose titration.

8. The use according to any one of claims 1-7, wherein metformin extended-release tablets are taken concurrently at a dose ≥1000 mg / day; preferably 1000 mg, 1500 mg, 2000 mg or 2500 mg.

9. Use according to any one of claims 1 to 8, wherein, The frequency of administration of the compound of formula (I) or its pharmaceutically acceptable salt is selected from three times daily, twice daily, once daily, or once every three days.

10. The use according to claims 1-9, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is used in combination with metformin.

11. Use of metformin for the treatment of type 2 diabetes, wherein the metformin is used in combination with the compound of formula (I) of claim 1 or a pharmaceutically acceptable salt thereof.

12. A method, which is the method of any one of embodiments 1 to 205 as described herein.

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