Acylated insulin for lowering blood glucose

Abstract

Involving acylated insulin for glycemic reduction, there is provided a method of treating or preventing metabolic syndrome and type II diabetes in a subject in need thereof by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof. There is also provided a kit comprising instructions for treatment according to the method.

Description

Acylated insulin for glucose lowering

[0001] This application claims priority to Chinese patent application 202311472986.8 with an application date of November 7, 2023, Chinese patent application 202410702372.2 with an application date of June 2, 2024, and Chinese patent application 202411087070.5 with an application date of August 8, 2024. The full text of the above three applications is incorporated into this application by reference. Technical Field

[0002] The invention belongs to the field of biomedicine and relates to acylated insulin for treating type 2 diabetes. Background Art

[0003] Diabetes is a metabolic disorder characterized by hyperglycemia. Optimal glycemic control is the treatment goal for patients with type 2 diabetes. Despite the availability of several oral antidiabetic drugs and insulin, a large proportion of patients with type 2 diabetes do not achieve the recommended glycemic control target levels.

[0004] Insulin is used to treat diabetes and related or resulting diseases and is essential for maintaining normal metabolic regulation. However, natural insulins, such as human insulin, have a short duration of action, necessitating frequent injections and causing significant injection-related discomfort. Consequently, efforts are underway to develop insulin derivatives or analogs with improved efficacy, longer duration of action, and less frequent injections to alleviate the inconvenience and discomfort associated with frequent insulin injections.

[0005] WO1995007931A1 discloses insulin detemir, a long-acting insulin currently on the market. Its molecular structure features the removal of the threonine at position 30 of the human insulin B chain, and the attachment of a 14-carbon fatty acid to the lysine residue at position 29 of the B chain. WO2005012347A2 discloses another long-acting insulin currently on the market, insulin degludec. This insulin degludec is a new, ultra-long-acting insulin with a longer duration of action than insulin detemir. Its molecular structure features the removal of the threonine at position 30 of the human insulin B chain, and the attachment of a 16-carbon fatty acid side chain to the lysine residue at position B29 via a glutamic acid molecule. CN101573133B and WO2009 / 010428 disclose PEGylated insulins, which have a longer duration of action than conventional, unmodified insulins. WO2013086927A1 and WO2018 / 024186 disclose an acylated derivative of a long-acting human insulin analog.

[0006] However, to date, no basal insulin product has been approved for use less frequently than once daily subcutaneous injection.

[0007] Therefore, there is still a need for insulin derivatives or analogs that have better efficacy or effectiveness, longer duration of action, lower administration frequency, and more excellent physicochemical properties than marketed insulin (such as insulin degludec) or known insulin derivatives.

[0008] Summary of the Invention

[0009] The present invention relates to a method for treating or preventing metabolic syndrome, comprising administering a therapeutically effective amount of a compound (I) to a subject in need thereof, the subject having clinical symptoms of hyperglycemia; wherein the method reduces the occurrence of hyperglycemia adverse events (MACE). The dosing regimen described herein provides benefits for treating type II diabetes using a compound of formula (I), maximizing its glucose-lowering efficacy and reducing or eliminating adverse side effects caused by its glucose-lowering properties.

[0010] In a first aspect, the present invention provides a method for treating or preventing metabolic syndrome, comprising administering to a subject in need thereof about 5 to about 400 U, preferably about 5 to about 120 U, of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof; preferably, the method comprises administering to a subject in need thereof about 5 to about 400 U, preferably about 5 to about 120 U, of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, once every 3 days, twice a week, once every 4 days, once every 5 days, once a week or less, wherein each administration dose is independently the same or different,

[0011] Preferably, the metabolic syndrome is diabetes;

[0012] Preferably, the diabetes is type II diabetes (type 2 diabetes);

[0013] Preferably, the subject is an insulin-naive type 2 diabetes patient whose condition is poorly controlled by oral hypoglycemic drugs;

[0014] Preferably, the subject is a type 2 diabetes patient whose diabetes is poorly controlled by oral hypoglycemic drugs combined with basal insulin.

[0015] Further, the method comprises administering to a subject in need thereof about 5 to about 400 U, about 5 to about 350 U, about 5 to about 300 U, preferably about 10 to about 250 U, preferably about 10 to about 200 U, preferably about 10 to about 150 U, preferably about 10 to about 120 U, preferably about 10 to about 110 U, preferably about 15 to about 105 U, preferably about 20 to about 100 U, preferably about 30 to about 100 U, preferably about 31 to about 100 U, preferably about 31 to about 105 U. about 7 U, preferably about 35 to about 95 U, preferably about 38 to about 90 U, preferably about 40 to about 90 U, preferably about 40 to about 88 U, preferably about 45 to about 88 U, preferably about 48 to about 85 U, preferably about 49 to about 80 U, preferably about 49 to about 79 U, preferably about 49 to about 70 U, preferably about 40 to about 70 U of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof; preferably, the method comprises administering to a subject in need thereof once every 3 days, once every About 5 to about 400 U, about 5 to about 350 U, about 5 to about 300 U, preferably about 10 to about 250 U, preferably about 10 to about 200 U, preferably about 10 to about 150 U, preferably about 10 to about 120 U, preferably about 10 to about 110 U, preferably about 15 to about 105 U, preferably about 20 to about 100 U, preferably about 30 to about 100 U, preferably about 31 to about 100 U, preferably about 32 to about 100 U, preferably about 30 to about 100 U, preferably about 31 to about 100 U, preferably about 32 to about 100 U About 31 to about 97 U, preferably about 35 to about 95 U, preferably about 38 to about 90 U, preferably about 40 to about 90 U, preferably about 40 to about 88 U, preferably about 45 to about 88 U, preferably about 48 to about 85 U, preferably about 49 to about 80 U, preferably about 49 to about 79 U, preferably about 49 to about 70 U, preferably about 40 to about 70 U of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, wherein the doses administered each are independently the same or different.

[0016] Further, wherein the method comprises administering to a subject in need thereof about 5 to about 300 U, preferably about 10 to about 250 U, preferably about 10 to about 200 U, preferably about 10 to about 150 U, preferably about 10 to about 120 U, preferably about 10 to about 110 U, preferably about 15 to about 105 U, preferably about 20 to about 100 U, preferably about 30 to about 100 U, preferably about 31 to about 100 U, preferably about 31 to about 97 U, preferably about 35 - about 95 U, preferably about 38 to about 90 U, preferably about 40 to about 90 U, preferably about 40 to about 88 U, preferably about 45 to about 88 U, preferably about 48 to about 85 U, preferably about 49 to about 80 U, preferably about 49 to about 79 U, preferably about 49 to about 70 U, preferably about 40 to about 70 U of the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, preferably the weekly administered doses are independently the same or different.

[0017] Further, wherein the method comprises administering to a subject in need thereof a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, at a weekly dose of about 5 U, about 6 U, about 7 U, about 8 U, about 9 U, about 10 U, about 11 U, about 12 U, about 13 U, about 14 U, about 15 U, about 16 U, about 17 U, about 18 U, about 19 U, about 20 U, about 21 U, about 22 U, about 23 U, about 24 U, about 25 U, about 26 U, about 27 U, about 28 U, about 29 U, about 30 U, about 31 U, about 32 U, about 33 U, about 34 U, about 35 U, about 36 U, about 37 U, about 38 U, about 39 U, about 40 U, ​​about 41 U, about 42 U, about 43 U, about 44 U, about 45 U, about 46 U, about 47 U, about 48 U, about 49 U, about 50 U, about 51 U, about 52 U, about 53 U, about 54 U, about 55 U, about 56 U, about 57 U, about 58 U, about 59 U, about 60 U, about 61 U, about 62 U, about 63 U, about 64 U, about 65 U, about 66 U, about 67 U, about 68 U, about 69 U, about 70 U, about 71 U, about 72 U, about 73 U, about 74 U, about 75 U, about 76 U, about 77 U, about 78 U, about 79 U, about 80 U, about 81 U, about about 28U, about 29U, about 30U, about 31U, about 32U, about 33U, about 34U, about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U, about 48U, about 49U, about 50U, about 51U, about 52U, about 53U, about 54U, about 55U, about 56U, about 57U, about 58U, about 59U, about 60U, about 61U, about 62U, about 63U, about 64U, about 65U, about 66U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, about 80U, about 81U, about 82U, about 83U, about 84U, about 85U, about 86U, about 87U, about 88U, about 89U, about 90U, about 91U, about 92U, about 93U, about 94U, about 95U, About 96 U, about 97 U, about 98 U, about 99 U, about 100 U, about 110 U, about 120 U, about 130 U, about 140 U, ​​about 150 U, about 160 U, about 170 U, about 180 U, about 190 U, about 200 U, about 210 U, about 220 U, about 230 U, about 240 U, ​​about 250 U, about 260 U, about 270 U, about 280 U, about 290 U, or about 300 U, preferably the weekly administered doses are independently the same or different.

[0018] Further, wherein the method comprises administering a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, to a subject in need thereof once every 3 days, twice a week, once every 4 days, once every 5 days, once a week or less, preferably the dosages administered each time are independently the same or different;

[0019] Preferably, the method comprises administering to a subject in need thereof a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, at a frequency of about 5 U, about 6 U, about 7 U, about 8 U, about 9 U, about 10 U, about 11 U, about 12 U, about 13 U, about 14 U, about 15 U, about 16 U, about 17 U, about 18 U, about 19 U, about 20 U, about 21 U, about 22 U, about 23 U, about 24 U, about 25 U, about 26 U, about 27 U, about 28 U, about 29 U, about 30 U, about 31 U, about 32 U, about 33 U, about 34 U, about 35 U, about 36 U, about 37 U, about 38 U, about 39 U, about 40 U, ​​about 41 U, about 42 U, about 43 U, about 44 U, about 45 U, about 46 U, about 47 U, about 48 U, about 49 U, about 50 U, about 51 U, about 52 U, about 53 U, about 54 U, about 55 U, about 56 U, about 57 U, about 58 U, about 59 U, about 60 U, about 61 U, about 62 U, about 63 U, about 64 U, about 65 U, about 66 U, about 67 U, about 68 U, about 69 U, about 70 U, about 71 U, about 72 U, about 73 U, about 74 U, about 75 U, about 76 U, about 77 U, about 78 U, about 79 U, about 80 U, about 81 U, about 28U, about 29U, about 30U, about 31U, about 32U, about 33U, about 34U, about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U, about 48U, about 49U, about 50U, about 51U, about 52U, about 53U, about 54U, about 55U, about 56U, about 57U, about 58U, about 59U, about 60U, about 61U, about 62U, about 63U, about 64U, about 65U, about 66U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, about 80U, about 81U, about 82U, about 83U, about 84U, about 85U, about 86U, about 87U, about 88U, about 89U, about 90U, about 91U, about 92U, about 93U, about 94U, about 95U, about about 96 U, about 97 U, about 98 U, about 99 U, about 100 U, about 110 U, about 120 U, about 130 U, about 140 U, ​​about 150 U, about 160 U, about 170 U, about 180 U, about 190 U, about 200 U, about 210 U, about 220 U, about 230 U, about 240 U, ​​about 250 U, about 260 U, about 270 U, about 280 U, about 290 U, or about 300 U, wherein the once weekly administration doses are each independently the same or different;

[0020] Preferably, the method comprises administering to a subject in need thereof once a week a fixed dose of:

[0021] About 6 nmol-12 nmol / kg, preferably about 6 nmol / kg, about 7 nmol / kg, about 8 nmol / kg, about 9 nmol / kg, about 10 nmol / kg, about 11 nmol / kg, or about 12 nmol / kg of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof; or

[0022] About 1 U / kg-6 U / kg, preferably 1 U / kg-3 U / kg, preferably about 1 U / kg-2 U / kg, preferably about 1 U / kg, about 1.3 U / kg, about 1.5 U / kg or about 2 U / kg of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof;

[0023] Preferably, for subjects who have previously taken basal insulin once a day or twice a day, when switching to the administration of the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, the dose of each administration of the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is about 2-20 times, preferably about 2-10 times, preferably about 2-7 times, preferably about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, about 4.5 times, about 5 times, about 5 times, or about 6 times the dose of the previous basal insulin. .5 times, about 6 times, about 6.5 times, about 7 times, about 8 times, or about 9 times, preferably, the dose of the compound of formula (I) or its pharmaceutically acceptable salt, amide or ester for the first or each administration is independently about 2-20 times, preferably about 2-10 times, preferably about 2-7 times, preferably about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, about 4.5 times, about 5 times, about 5.5 times, about 6 times, about 6.5 times, about 7 times, about 8 times, or about 9 times the dose of the previous basal insulin.

[0024] Further, the method comprises administering to a subject in need thereof a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, at a starting dose of about 5 to about 400 U, preferably about 5 to about 350 U, preferably about 5 to about 300 U, preferably about 10 to about 250 U, preferably about 10 to about 200 U, preferably about 10 to about 150 U, preferably about 10 to about 120 U, preferably about 10 to about 110 U, preferably about 10 to about 100 U, preferably about 10 to about 90 U, preferably about 15 to about 85 U, preferably about 20 to about 80 U, preferably about 20 to about 75 U, preferably about 25 to about 75 U, preferably about 30 to about 70 U, preferably about 40 to about 70 U; preferably about 10 to about 40 U; preferably about 20 to about 40 U;

[0025] Preferably, the method comprises administering to a subject in need thereof a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, at a starting dose of about 5 U, about 6 U, about 7 U, about 8 U, about 9 U, about 10 U, about 11 U, about 12 U, about 13 U, about 14 U, about 15 U, about 16 U, about 17 U, about 18 U, about 19 U, about 20 U, about 21 U, about 22 U, about 23 U, about 24 U, about 25 U, about 26 U, about 27U, about 28U, about 29U, about 30U, about 31U, about 32U, about 33U, about 34U, about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U, about 48U, about 49U, about 50U, about 51U, about 52U, about 53U, about 54U, about 55U, about 56U, about 57U, about 58U, about 59U, about 60U, about 61U, about 62U, about 63U, about 64U, about 65U, about 66U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, about 80U, about 81U, about 82U, about 83U, about 84U, about 85U, about 86U, about 87U, about 88U, about 89U, about 90U, about 91U, about 92U U, about 93 U, about 94 U, about 95 U, about 96 U, about 97 U, about 98 U, about 99 U, about 100 U, about 110 U, about 120 U, about 130 U, about 140 U, ​​about 150 U, about 160 U, about 170 U, about 180 U, about 190 U, about 200 U, about 210 U, about 220 U, about 230 U, about 240 U, ​​about 250 U, about 260 U, about 270 U, about 280 U, about 290 U, or about 300 U.

[0026] Furthermore, the method further comprises administering the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, to a subject in need thereof at the starting dose, and then administering the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, once every 3 days, twice a week, once every 4 days, once every 5 days, once a week or less frequently. The dosage administered each time may be the same as or different from the starting dose. Preferably, the dosage administered each time is determined according to the individual condition of the subject.

[0027] Further, the method comprises administering to a subject in need thereof a starting dose of a compound of formula (I) of about 5 to about 400 U, preferably about 5 to about 350 U, preferably about 5 to about 300 U, preferably about 10 to about 250 U, preferably about 10 to about 200 U, preferably about 10 to about 150 U, preferably about 10 to about 120 U, preferably about 10 to about 110 U, preferably about 10 to about 100 U, preferably about 10 to about 90 U, preferably about 15 to about 85 U, preferably about 20 to about 80 U, preferably about 25 to about 75 U, preferably about 30 to about 70 U, preferably about 40 to about 70 U, preferably about 20 to about 40 U, ​​once a week, or a pharmaceutically acceptable salt, amide or ester thereof; preferably, the method comprises administering to a subject in need thereof a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, at a starting dose of about 5 U, about 6 U, about 7 U, about 8 U, about 9 U, about 10 U, about 11 U, about 12 U, about 13 U, about 14 U, about 15 U, about 16 U, about 17 U, about 18 U, about 19 U, about 20 U, about 21 U, about 22 U, about 23 U, about 24 U, about 25 U, about 26 U, about 27 U, about 28 U, about 29 U, about 30 U, about 31 U, about 32 U, about 33 U, about 34 U, about 35 U, about about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U, about 48U, about 49U, about 50U, about 51U, about 52U, about 53U, about 54U, about 55U, about 56U, about 57U, about 58U, about 59U, about 60U, about 61U, about 62U, about 63U, about 64U, about 65U, about 66U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, about 80U U, about 81 U, about 82 U, about 83 U, about 84 U, about 85 U, about 86 U, about 87 U, about 88 U, about 89 U, about 90 U, about 91 U, about 92 U, about 93 U, about 94 U, about 95 U, about 96 U, about 97 U, about 98 U, about 99 U, about 100 U, about 110 U, about 120 U, about 130 U, about 140 U, ​​about 150 U, about 160 U, about 170 U, about 180 U, about 190 U, about 200 U, about 210 U, about 220 U, about 230 U, about 240 U, ​​about 250 U, about 260 U, about 270 U, about 280 U, about 290 U, or about 300 U;Preferably, for subjects who were previously administered once-a-day or twice-a-day basal insulin, when switching to administration of the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, the initial dose of the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is about 2-20 times, preferably about 3-10 times, preferably about 5-7 times, preferably about 5 times, about 5.5 times, about 6 times, about 6.5 times, about 7 times, about 8 times, or about 9 times the dose of the previous basal insulin;

[0028] After one week of administration at the initial dose, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is administered once a week at a dose of M according to the subject's blood glucose condition. The doses M administered each week are the same or different and are each independently about 5-about 400 U, preferably about 5-about 350 U, preferably about 5 U-about 300 U, preferably about 5 U-about 120 U, preferably about 10-about 250 U, preferably about 10-about 200 U, preferably about 10-about 150 U, preferably about 10-about 120 U, preferably about 5-about 400 U. , preferably about 5-about 350U, preferably about 10-about 110U, preferably about 10-about 100U, preferably about 10-about 90U, preferably about 15-about 85U, preferably about 20-about 80U, preferably about 25-about 75U, preferably about 30-about 70U, preferably about 40-about 70U; preferably, the dose M administered each week is each independently about 5U, about 6U, about 7U, about 8U, about 9U, about 10U, about 11U, about 12U, about 13U, about 14U, about 15U, about 16U, about 17U, about 18U, about 19U , about 20U, about 21U, about 22U, about 23U, about 24U, about 25U, about 26U, about 27U, about 28U, about 29U, about 30U, about 31U, about 32U, about 33U, about 34U, about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U, about 48U, about 49U, about 50U, about 51U, about 52U, about 53U, about 54U, about 55U, about 56U, about 57U 7U, about 58U, about 59U, about 60U, about 61U, about 62U, about 63U, about 64U, about 65U, about 66U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, about 80U, about 81U, about 82U, about 83U, about 84U, about 85U, about 86U, about 87U, about 88U, about 89U, about 90U, about 91U, about 92U, about 93U, about 94U, About 95 U, about 96 U, about 97 U, about 98 U, about 99 U, about 100 U, about 110 U, about 120 U, about 130 U, about 140 U, ​​about 150 U, about 160 U, about 170 U, about 180 U, about 190 U, about 200 U, about 210 U, about 220 U, about 230 U, about 240 U, ​​about 250 U, about 260 U, about 270 U, about 280 U, about 290 U, or about 300 U.

[0029] Furthermore, the method described above, wherein the administered dose M is adjusted weekly according to the following rules:

[0030] a) When the subject's fasting blood glucose value is 3.9-4.3 mmol / L before administration, or when the subject's lowest value or average value of fasting peripheral blood glucose before breakfast for three consecutive times starting from 2 days before administration is 3.9-4.3 mmol / L, the administered dose M needs to be adjusted to a decrease of about 1-30 U, preferably about 1-20 U, preferably about 3-18 U, preferably about 5-10 U from the previous dose; or

[0031] b) when the subject's fasting blood glucose value is 4.4-7.2 mmol / L before administration, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 4.4-7.2 mmol / L, the administered dose M is the last administered dose; or

[0032] c) when the subject's fasting blood glucose value is 7.3-8.0 mmol / L before administration, or when the subject's lowest value or average value of fasting peripheral blood glucose before breakfast for three consecutive times starting from 2 days before administration is 7.3-8.0 mmol / L, the administered dose M needs to be adjusted to the last administered dose plus about 1-about 30 U, preferably about 1-about 20 U, preferably about 3-18 U, preferably about 5-about 10 U; or

[0033] d) When the subject's fasting blood glucose value before administration is 8.1-9.9 mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 8.1-9.9 mmol / L, the administered dose M needs to be adjusted to the previous administered dose plus about 5-about 30 U, preferably about 15-about 20 U, and preferably about 15-18 U; or

[0034] e) If the subject's fasting blood glucose value is ≥10.0 mmol / L before administration, or if the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from two days before administration is ≥10.0 mmol / L, the administered dose M needs to be adjusted to the previous administered dose plus about 10-40 U, ​​preferably about 25-30 U, and preferably about 15-18 U; or

[0035] f) If the subject's fasting blood glucose value before administration is ≤3.0 mmol / L, or if the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from two days before administration is ≤3.0 mmol / L, the administered dose should be adjusted to a decrease of about 5 to about 30 U, preferably about 15 to about 20 U from the previous dose; or

[0036] g) When the subject's fasting blood glucose value before administration is 3.1-3.9 mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from two days before administration is 3.1-3.9 mmol / L, the administered dose should be adjusted to the previous administered dose minus about 1-about 20 U, preferably minus about 5-10 U; or

[0037] h) If the subject's fasting blood glucose value before administration is less than 4.4 mmol / L, or if the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from two days before administration is less than 4.4 mmol / L, the dose should be adjusted to the previous dose minus about 5-20 U, preferably minus about 10-18 U;

[0038] i) When the subject's fasting blood glucose value before administration is greater than about 7.2 mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is greater than about 7.2 mmol / L, the administered dose M needs to be adjusted to the last administered dose plus about 1 to about 30 U, preferably about 1 to 20 U, and preferably about 3 to 18 U.

[0039] Furthermore, the administered dose M is adjusted weekly according to the following rules:

[0040] a) When the subject's fasting blood glucose value is 3.9-4.3 mmol / L before administration, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 3.9-4.3 mmol / L, the administered dose M needs to be adjusted to the last administered dose minus approximately 9U-18U; or

[0041] b) when the subject's fasting blood glucose value is 4.4-7.2 mmol / L before administration, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 4.4-7.2 mmol / L, the administered dose M is the last administered dose; or

[0042] c) If the subject's fasting blood glucose value before administration is 7.3-8.0 mmol / L, or if the lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 7.3-8.0 mmol / L, the administered dose M needs to be adjusted to the previous administered dose plus approximately 9-18 U; or

[0043] d) If the subject's fasting blood glucose value before administration is 8.1-9.9 mmol / L, or if the lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 8.1-9.9 mmol / L, the administered dose M needs to be adjusted to the previous dose plus approximately 18-30 U; or

[0044] e) If the subject's fasting blood glucose value before administration is ≥10.0mmol / L, or if the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is ≥10.0mmol / L, the administered dose M needs to be adjusted to the previous administered dose plus approximately 18-27U; or

[0045] f) If the subject's fasting blood glucose value is ≤3.0mmol / L before administration, or if the lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is ≤3.0mmol / L, the administered dose M needs to be adjusted to the last administered dose minus about 18-30U; or

[0046] g) When the subject's fasting blood glucose value is 3.1-3.9 mmol / L before administration, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 3.1-3.9 mmol / L, the administered dose M needs to be adjusted to the last administered dose minus approximately 9-18 U.

[0047] Furthermore,

[0048] The method comprises administering about 10 to about 400 U, 10 to about 300 U, about 10 to about 100 U, about 10 to about 70 U, about 20 to about 60 U, preferably about 25 to about 55 U, preferably about 28 to about 55 U, preferably about 30 to about 50 U, preferably about 30 U, about 31 U, about 32 U, about 33 U, about 34 U, about 35 U once a week to an adult insulin-naive type 2 diabetic subject who is poorly controlled with oral hypoglycemic drugs. , about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U, about 48U, about 49U, about 50U, about 51U, about 52U, about 53U, about 54U, about 55U, about 56U, about 57U, about 58U, about 59U, about 60U, about 61U, about 62U, about 63U, about 64U, about 65U, about 66U, about 67U U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, about 80U, about 81U, about 82U, about 83U, about 84U, about 85U, about 86U, about 87U, about 88U, about 89U, about 90U, about 91U, about 92U, about 93U, about 94U, about 95U, about 96U, about 97U, about 98U, about 99U about 100 U, about 110 U, about 120 U, about 130 U, about 140 U, ​​about 150 U, about 160 U, about 170 U, about 180 U, about 190 U, about 200 U, about 210 U, about 220 U, about 230 U, about 240 U, ​​about 250 U, about 260 U, about 270 U, about 280 U, about 290 U, or about 300 U of a compound of Formula (I), or a pharmaceutically acceptable salt, amide or ester thereof;

[0049] After one week of administration at the initial dose, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is administered at a dose of M according to the subject's blood glucose status once a week, and the M administered each week is the same or different and is independently about 5U-about 300U, preferably about 10-about 250U, preferably about 10-about 200U, preferably about 10-about 150U, preferably about 5-about 120U, preferably about 10-about 120U, preferably about 10-about 110U, preferably about 10-about 100U, preferably about 30-about 70U, preferably about 31-about 67U, preferably about 31U, about 32U, about 33U, about 34U, about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U , about 44U, about 45U, about 46U, about 47U, about 48U, about 49U, about 50U, about 51U, about 52U, about 53U, about 54U, about 55U, about 56U, about 57U, about 58U, about 59U, about 60U, about 61U, about 62U, about 63U, about 64U, about 65U, about 66U, about 67U, about 70U, about 80U, About 90U, about 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, about 200U, about 210U, about 220U, about 230U, about 240U, about 250U, about 260U, about 270U, ​​about 280U, about 290U, or about 300U.

[0050] Further, wherein the method comprises administering about 50 to about 90 U, preferably about 50 to about 90 U, preferably 55 to about 85 U, preferably about 60 to about 80 U, preferably about 60 U, about 61 U, about 62 U, about 63 U, about 64 U, about 65 U, about 66 U, about 67 U, about 68 U, about 69 U, about 70 U, about 71 U, about 72 U, about 73 U, about 74 U, about 75 U, about 76 U, about 77 U, about 78 U, about 79 U, about 80 U, about 90 U, about 100 U, about 110 U, about 120 U, about 130 U, about 140 U, ​​about 150 U, about 160 U about 150 U, about 160 U, about 170 U, about 180 U, about 190 U, about 200 U, about 210 U, about 220 U, about 230 U, about 240 U, ​​about 250 U, about 260 U, about 270 U, about 280 U, about 290 U, or about 300 U of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof; or the starting dose of the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is about 2-20 times, preferably about 3-10 times, preferably about 5-7 times, preferably about 2.5 times, about 3 times, about 5 times, about 5.5 times, about 6 times, about 6.5 times, about 7 times, about 8 times, or about 9 times the previous basal insulin dose;

[0051] After one week of administration at the initial dose, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is administered at a dose of M according to the subject's blood glucose status once a week, wherein the M administered each week is the same or different and is independently about 5 U to about 300 U, preferably about 10 to about 250 U, preferably about 20 to about 200 U, preferably about 30 to about 150 U, preferably about 40 to about 120 U, preferably about 50 to about 110 U, preferably about 50 to about 100 U, preferably about 60 to about 100 U, preferably about 61 to about 97 U, preferably about 60 U, about 61 U, about 62 U, about 63 U, about 64 U, about 65 U, about 66 U, about 67 U, about 68 U, about 69 U, about 70 U, about 71 U, about 72 U, about 73 U U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, about 80U, about 81U, about 82U, about 83U, about 84U, about 85U, about 86U, about 87U, about 88U, about 89U, about 90U, about 91U, about 92U, about 93U, about 94U, about 95U, about 96U, about 97U, about 98U, about 99U 9U, about 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, about 200U, about 210U, about 220U, about 230U, about 240U, about 250U, about 260U, about 270U, ​​about 280U, about 290U, or about 300U.

[0052] A second aspect of the present invention provides a method for treating or preventing type 2 diabetes, comprising administering a starting dose of about 20 to about 60 U, preferably about 25 to about 55 U, preferably about 30 to about 50 U, preferably about 30 U, about 31 U, about 32 U, about 33 U, about 34 U, about 35 U, about 36 U, about 37 U, about 38 U, about 39 U, about 40 U, ​​about 41 U, about 42 U, about 43 U, about 44 U, about 45 U, about 46 U, about 47 U, about 48 U, about 49 U, or about 50 U of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, to an adult insulin-naive type 2 diabetes subject who is poorly controlled with oral hypoglycemic drugs once a week;

[0053] a) After administering the initial dose for one week, administering a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, at a dose of M once a week according to the subject's blood glucose status, wherein the M administered each week is the same or different and is independently about 5-about 400 U, preferably about 5-about 350 U, preferably about 5 U-about 300 U, preferably about 5 U-about 120 U, preferably about 10-about 250 U, preferably about 10-about 200 U, preferably about 10-about 150 U, preferably about 10-about 120 U, preferably about 5-about 40 0U, preferably about 5 to about 350U, preferably about 10 to about 110U, preferably about 10 to about 100U, preferably about 10 to about 90U, preferably about 15 to about 85U, preferably about 20 to about 80U, preferably about 25 to about 75U, preferably about 30 to about 70U, preferably about 40 to about 70U, preferably about 60U, about 61U, about 62U, about 63U, about 64U, about 65U, about 66U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75U , about 76U, about 77U, about 78U, about 79U, about 80U, about 81U, about 82U, about 83U, about 84U, about 85U, about 86U, about 87U, about 88U, about 89U, about 90U, about 91U, about 92U, about 93U, about 94U, about 95U, about 96U, about 97U, about 98U, about 99U, about 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, about 200 The administered dose M is adjusted weekly according to the following rules: when the fasting blood glucose value of the subject before administration is 3.9-4.3 mmol / L, or when the lowest value or average value of the fasting peripheral blood glucose before breakfast for three consecutive times starting from 2 days before administration is 3.9-4.3 mmol / L, the administered dose M needs to be adjusted to the last administered dose minus about 9-18 U; or

[0054] b) when the subject's fasting blood glucose value is 4.4-7.2 mmol / L before administration, or when the average fasting peripheral blood glucose value before breakfast for three consecutive times starting from two days before administration is 4.4-7.2 mmol / L, the administered dose M is the last administered dose; or

[0055] c) If the subject's fasting blood glucose value before administration is 7.3-8.0 mmol / L, or if the lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 7.3-8.0 mmol / L, the administered dose M needs to be adjusted to the previous administered dose plus approximately 9-18 U; or

[0056] d) If the subject's fasting blood glucose value before administration is 8.1-9.9 mmol / L, or if the lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 8.1-9.9 mmol / L, the administered dose M needs to be adjusted to the previous dose plus approximately 18-30 U; or

[0057] e) If the subject's fasting blood glucose value before administration is ≥10.0mmol / L, or if the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is ≥10.0mmol / L, the administered dose M needs to be adjusted to the previous administered dose plus approximately 18-27U; or

[0058] f) If the subject's fasting blood glucose value is ≤3.0mmol / L before administration, or if the lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is ≤3.0mmol / L, the administered dose M needs to be adjusted to the last administered dose minus about 18-30U; or

[0059] g) When the subject's fasting blood glucose value is 3.1-3.9 mmol / L before administration, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 3.1-3.9 mmol / L, the administered dose M needs to be adjusted to the last administered dose minus approximately 9-18 U.

[0060] A third aspect of the present invention provides a method for treating or preventing type II diabetes, the method comprising administering to a subject with adult type 2 diabetes who is poorly controlled by an oral hypoglycemic agent combined with basal insulin once a week about 5-400 U, about 5-350 U, about 5-about 300 U, preferably about 10-about 250 U, preferably about 20-about 200 U, preferably about 30-about 150 U, preferably about 40-about 120 U, preferably about 50-about 110 U, preferably about 50-about 100 U, preferably about 50-about 90 U, preferably about 55-about 85 U, preferably about 60-about 80 U, preferably about 60 U, about 61 U, about 62 U, about 63 U, about 64 U, about 65 U, preferably about 66 U, about 67 U, about 68 U, about 69 U, about 70 U, about 71 U, about 72 U, about 73 U, about 74 U, about 75 U, about 76 U, about 77 U, about 78 U, about 79 U, about 80 U, about 81 U, about 82 U, about 83 U, about 84 U, about 85 U, about 86 U, about 87 U, about 88 U, about 89 U, about 90 U, about 91 U, about 92 U, about 93 U, about 94 U, about 95 U, about 96 U, about 97 U, about 98 U, about 99 U, about 10 ... U, about 66 U, about 67 U, about 68 U, about 69 U, about 70 U, about 71 U, about 72 U, about 73 U, about 74 U, about 75 U, about 76 U, about 77 U, about 78 U, about 79 U, or about 80 U of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof; or the initial dose of the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is about 2-20 times, preferably about 3-10 times, preferably about 5-7 times, preferably about 2.5 times, about 3 times, about 5 times, about 5.5 times, about 6 times, about 6.5 times, about 7 times, about 8 times, or about 9 times the previous basal insulin dose;

[0061] After one week of administration at the initial dose, the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is administered at a dose of M according to the subject's blood glucose status once a week, and the M administered each week is the same or different, and is independently about 5-about 400 U, preferably about 5-about 350 U, preferably about 5 U-about 300 U, preferably about 5 U-about 120 U, preferably about 10-about 250 U, preferably about 10-about 200 U, preferably about 10-about 150 U, preferably 10-about 120 U, preferably 5-about 400 U, preferably about 5- about 350U, preferably about 10 to about 110U, preferably about 10 to about 100U, preferably about 10 to about 90U, preferably about 15 to about 85U, preferably about 20 to about 80U, preferably about 25 to about 75U, preferably about 30 to about 70U, preferably about 40 to about 70U, preferably about 40 to about 70U, preferably about 60U, about 61U, about 62U, about 63U, about 64U, about 65U, about 66U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75 U, about 76U, about 77U, about 78U, about 79U, about 80U, about 81U, about 82U, about 83U, about 84U, about 85U, about 86U, about 87U, about 88U, about 89U, about 90U, about 91U, about 92U, about 93U, about 94U, about 95U, about 96U, about 97U, about 98U, about 99U, about 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, about 200U The administered dose M is adjusted weekly according to the following rules: a) when the fasting blood glucose value of the subject before administration is 3.9-4.3 mmol / L, or when the lowest value or average value of the fasting peripheral blood glucose before breakfast for three consecutive times starting from 2 days before administration is 3.9-4.3 mmol / L, the administered dose M needs to be adjusted to the last administered dose minus about 9-18 U; or

[0062] b) when the subject's fasting blood glucose value is 4.4-7.2 mmol / L before administration, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 4.4-7.2 mmol / L, the administered dose M is the last administered dose; or

[0063] c) If the subject's fasting blood glucose value before administration is 7.3-8.0 mmol / L, or if the lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 7.3-8.0 mmol / L, the administered dose M needs to be adjusted to the previous administered dose plus approximately 9-18 U; or

[0064] d) If the subject's fasting blood glucose value before administration is 8.1-9.9 mmol / L, or if the lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 8.1-9.9 mmol / L, the administered dose M needs to be adjusted to the previous dose plus approximately 18-30 U; or

[0065] e) If the subject's fasting blood glucose value before administration is ≥10.0mmol / L, or if the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is ≥10.0mmol / L, the administered dose M needs to be adjusted to the previous administered dose plus approximately 18-27U; or

[0066] f) If the subject's fasting blood glucose value is ≤3.0mmol / L before administration, or if the lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is ≤3.0mmol / L, the administered dose M needs to be adjusted to the last administered dose minus about 18-30U; or

[0067] g) When the subject's fasting blood glucose value is 3.1-3.9 mmol / L before administration, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 3.1-3.9 mmol / L, the administered dose M needs to be adjusted to the last administered dose minus approximately 9-18 U.

[0068] Furthermore, the method, wherein the subject

[0069] With 18.5-35kg / m 2 , preferably 18.5-35kg / m 2 BMI; and / or

[0070] having an HbA1c of 6.5%-10.0%, preferably 7.5%-10.0%; and / or

[0071] Fasting venous blood glucose ≥7.2mmol / L; and / or

[0072] Fasting blood glucose ≤ 13.9 mmol / L; and / or

[0073] have been treated with one or more oral antidiabetic medications; and / or

[0074] Received one or more basal insulins.

[0075] Furthermore, the oral antidiabetic drug is selected from metformin, DPP4 inhibitors, α-glucosidase inhibitors, SGLT2 inhibitors and glucokinase activators; and the basal insulin is selected from glargine insulin U100, detemir insulin, degludec insulin and intermediate-acting human insulin.

[0076] Furthermore, the method described,

[0077] Wherein, the subject in need is simultaneously administered with the same dose of an oral anti-diabetic drug that the subject has previously used.

[0078] Furthermore, the method, wherein the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is administered parenterally, preferably subcutaneously. Further, the method, wherein the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is administered for a period of 6 weeks or more, preferably 16 weeks or more, preferably 4 months or more, preferably 8 months or more, preferably 12 months or more, preferably 16 months or more, preferably 18 months or more, preferably 24 months or more, preferably 30 months or more.

[0079] Further, the method, wherein the subject is able to achieve a reduction in glycated hemoglobin of 0.1% or more, preferably 0.2% or more, preferably 0.3% or more, preferably 0.4% or more, preferably 0.5% or more, preferably 0.5%-30%, preferably 0.6%-25%, preferably 0.62%, 0.76%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 6.5%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 13.5%, 14%, 15%, 16%, 17%, 18%, 18.6%, 19%, or 20% after administering the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof; preferably, the subject A reduction in glycated hemoglobin of 0.1% or more, preferably 0.2% or more, preferably 0.3% or more, preferably 0.4% or more, preferably 0.5% or more, preferably 0.5%-30%, preferably 0.6%-25%, preferably 0.62%, 0.76%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 6.5%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 13.5%, 14%, 15%, 16%, 17%, 18%, 18.6%, 19%, or 20% can be achieved after 6 weeks, 20 weeks, 25 weeks, 30 weeks, or 35 weeks of administration of a compound of formula (I) or a pharmaceutically acceptable salt, amide, or ester thereof.Further, the method, the method, wherein the subject can achieve a reduction of fasting blood glucose by more than 1 mM, preferably more than 1.2 mM, preferably more than 1.3 mM, preferably more than 1.4 mM, preferably more than 1.5 mM, preferably 1 mM-10 mM, preferably 1.1 mM-9.8 mM, preferably 1.2 mM, 1.3 mM, 1.37 mM, 1.4 mM, 1.5 mM, ... .57mM, 1.6mM, 1.7mM, 1.77mM, 1.8mM, 1.9mM, 1.97mM, 2mM, 2.1mM, 2.2mM, 2.3mM, 2.4mM, 2.5mM, 2.6mM, 2 .7mM, 2.8mM, 2.9mM, 3mM, 3.5mM, 4mM, 4.5mM, 5mM, 5.5mM, 6mM, 6.5mM, 7mM, 7.5mM, 8mM, 8.5mM, or 9mM; preferably, The subject can achieve a reduction in fasting blood glucose of 1 mM or more, preferably 1.2 mM or more, preferably 1.3 mM or more, preferably 1.4 mM or more, preferably 1.5 mM or more, preferably 1 mM-10 mM, preferably 1.1 mM-9.8 mM, preferably 1.2 mM, 1.3 mM, 1.37 mM, 1.4 mM, 1.5 mM or more, compared to the baseline after 6 weeks, 20 weeks, 25 weeks, 30 weeks or 35 weeks of administration of the compound of formula (I) or a pharmaceutically acceptable salt, amide or ester thereof. 1mM, 1.57mM, 1.6mM, 1.7mM, 1.77mM, 1.8mM, 1.9mM, 1.97mM, 2mM, 2.1mM, 2.2mM, 2.3mM, 2.4mM, 2.5mM, 2.6mM, 2.7mM, 2.8mM, 2.9mM, 3mM, 3.5mM, 4mM, 4.5mM, 5mM, 5.5mM, 6mM, 6.5mM, 7mM, 7.5mM, 8mM, 8.5mM or 9mM. Further, described method, described method, wherein, described experimenter is injected into abdomen, upper arm deltoid region and / or thigh of experimenter in the form of subcutaneous injection when administering formula (I) compound, or its pharmaceutically acceptable salt, amide or ester. A fourth aspect of the present invention protects a kind of medicine box, it comprises:

[0080] A compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof,

[0081] packaging materials, and

[0082] A label or package insert contained within the packaging material, the label or package insert indicating that the subject receiving treatment with a compound of formula (I), or a pharmaceutically acceptable salt, amide, or ester thereof, can be treated by the method of any one of claims 1-22. BRIEF DESCRIPTION OF THE DRAWINGS

[0083] FIG1 shows the weekly insulin dosage (U / week) of Group A1 and Group A2 from Week 1 to Week 15 in Example 3.

[0084] FIG2 shows the weekly insulin dosage (U / week) of Group B1 and Group B2 from Week 1 to Week 15 in Example 4.

[0085] definition

[0086] For a better understanding of the present invention, definitions and explanations of relevant terms are provided below.

[0087] As used herein and unless otherwise specified, the terms "comprising", "including", "having" include their grammatical equivalents and are generally understood to be open-ended and non-restrictive, e.g., not excluding other unrecited elements or steps. The term "basal insulin" means an insulin having a longer duration of action than normal or normal human insulin.

[0088] The term "insulin" includes naturally occurring insulin, such as human insulin, as well as insulin analogs and insulin derivatives thereof. The present invention also protects analogs and derivatives of acylated insulin that are equivalent to the compound represented by formula (I).

[0089] The term "insulin analogue" comprises such polypeptide, which has a molecular structure that can be derived from the structure of naturally occurring insulin (e.g., human insulin) by formally disappearing and / or replacing one or more amino acid residues and / or adding one or more amino acid residues that exist in native insulin. The amino acid residue that adds and / or replaces can be a codable amino acid residue or other naturally occurring amino acid residue or a purely synthetic amino acid residue. Preferably, the amino acid residue that adds and / or replaces is a codable amino acid residue.

[0090] As used herein, the term "insulin derivative" refers to naturally occurring insulin or insulin analogs that have been chemically modified. Such modifications may include, for example, the introduction of side chains at one or more positions on the insulin backbone, oxidation or reduction of amino acid residues on the insulin, conversion of free carboxyl groups to ester groups, or acylation of free amino or hydroxyl groups. The acylated insulins of the present invention are insulin derivatives.

[0091] The term "insulin parent" refers to the insulin portion of an insulin derivative or acylated insulin (also referred to herein as parent insulin), for example, in the present invention, the portion of an insulin derivative or acylated insulin without a side chain attached or an acyl group attached. The insulin parent can be a naturally occurring insulin, such as human insulin or porcine insulin. Alternatively, the parent insulin can be an insulin analog.

[0092] Here, the term "amino acid residue" includes amino acids from which hydrogen atoms have been removed from amino groups and / or hydroxyl groups have been removed from carboxyl groups and / or hydrogen atoms have been removed from sulfhydryl groups. Inaccurately, amino acid residues may be referred to as amino acids.

[0093] Unless otherwise specified, all amino acids mentioned herein are L-amino acids.

[0094] The term "hypoglycemic event" is determined based on the lowest value of the subject's fasting peripheral blood glucose before breakfast for three consecutive times (including the day of the visit) from 2 days before administration. If the lowest value of the subject's fasting peripheral blood glucose before breakfast for three consecutive times (including the day of the visit) from 2 days before administration is ≥3.9mmol / L, the subject is judged as not having a hypoglycemic event. Conversely, if the lowest value of the subject's fasting peripheral blood glucose before breakfast for three consecutive times (including the day of the visit) from 2 days before administration is <3.9mmol / L, the subject is judged as having a hypoglycemic event.

[0095] The term "treatment" includes therapeutic treatment, prophylactic treatment, and use in reducing the risk of a subject developing a disease or other risk factors. Treatment includes, but is not limited to, complete cure of the disease, as well as alleviation of symptoms or mitigation of potential risks.

[0096] The term "metabolic syndrome" as used herein is a recognized clinical term used to describe a condition that includes a combination of type 2 diabetes, impaired glucose tolerance, insulin resistance, hypertension, obesity, increased abdominal girth, hypertriglyceridemia, low HDL, hyperuricemia, hypercoagulability, and / or microalbuminuria.

[0097] The term "type II diabetes" (also known as "type 2 diabetes" and formerly "non-insulin-dependent diabetes" or "adult-onset diabetes") accounts for 90-95% of all diabetes and encompasses individuals who are insulin-resistant and usually relatively (rather than absolutely) insulin-deficient.

[0098] "Antidiabetic treatment" for type 2 diabetes includes:

[0099] Metformin: Metformin is often the first medication prescribed for type 2 diabetes. It works by increasing the sensitivity of body tissues to insulin, allowing the body to use it more efficiently. Metformin also reduces glucose production in the liver. Metformin itself may not lower blood sugar.

[0100] α-Glucosidase inhibitors: α-Glucosidase inhibitors inhibit α-glucosidase in the brush border of the small intestinal mucosa, thereby delaying carbohydrate absorption and reducing postprandial hyperglycemia. Key benefits include stable blood sugar reduction, a high safety profile, and reduced incidence of cardiovascular complications. They are one of the few oral hypoglycemic agents that can address impaired glucose tolerance. Commonly used α-glucosidase inhibitors include acarbose and voglibose.

[0101] Dipeptidyl peptidase-4 (DPP-4) inhibitors: These drugs also lower blood sugar levels. They do not cause weight gain. Examples of these drugs are sitagliptin, saxagliptin, vildagliptin, and linagliptin.

[0102] Sulfonylureas: These medications help the body produce more insulin. Examples of these medications include glyburide, glipizide, and glimepiride. Possible side effects include low blood sugar and weight gain.

[0103] Thiazolidinediones: Like metformin, these drugs make the body's tissues more sensitive to insulin. This class of drugs is associated with weight gain and other more serious side effects, such as an increased risk of heart failure and fractures. Because of these risks, these drugs are usually not the first choice of treatment. Pioglitazone is an example of a thiazolidinedione.

[0104] SGLT2 inhibitors: These are the newest diabetes medications on the market. They work by preventing the kidneys from reabsorbing sugar into the blood. Instead, the sugar is excreted in the urine. Examples include canagliflozin and dapagliflozin.

[0105] As used herein, the term "about" when referring to a specifically recited value or range of values ​​generally means within 20%, preferably within 10%, and more preferably within 5% of the given value or range.

[0106] The term "compound" is used herein to refer to a molecular entity and, therefore, a "compound" may have different structural elements beyond the minimum elements defined for each compound or group of compounds. The term "compound" is intended to encompass pharmaceutically relevant forms thereof, i.e., the present invention relates to a compound as defined herein or a pharmaceutically acceptable salt, amide or ester thereof.

[0107] The term "pharmaceutically acceptable" refers to those compounds, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0108] The salt may be a basic salt, an acidic salt, or it may be neither (ie, a neutral salt). In water, basic salts produce hydroxide ions and acidic salts produce hydronium ions.

[0109] Salts of the derivatives of the invention may be formed by added cations or anions which react with anionic or cationic groups, respectively. These groups may be located in the peptide portion and / or in the side chains of the derivatives of the invention.

[0110] The limiting examples of the anionic group of derivatives of the present invention are included in the side chain (if any) and in the free carboxyl group in the peptide portion. The peptide portion usually comprises a free carboxyl group at the C-terminus, and it can also comprise a free carboxyl group at internal acidic amino acid residues such as Asp and Glu.

[0111] Non-limiting examples of cationic groups in the peptide portion include the free amino group at the N-terminus (if present), and any free amino groups of internal basic amino acid residues such as His, Arg, and Lys.

[0112] Esters of the derivatives according to the invention can be formed, for example, by reaction of a free carboxylic acid group with an alcohol or a phenol, which reaction results in the replacement of at least one hydroxyl group by an alkoxy or aryloxy group.

[0113] Ester formation may involve the free carboxyl group at the C-terminus of the peptide, and / or any free carboxyl group in the side chain.

[0114] Amides of the derivatives according to the invention can be formed, for example, by reaction of a free carboxylic acid group in activated form with an amine or substituted amine, or by reaction of a free or substituted amino group with a carboxylic acid in activated form.

[0115] Amide formation can involve the free carboxyl group at the C-terminus of the peptide, any free carboxyl group in a side chain, the free amino group at the N-terminus of the peptide, and / or any free or substituted amino group of the peptide in the peptide and / or side chains.

[0116] In a specific embodiment, the peptide or derivative is in the form of a pharmaceutically acceptable salt. In another specific embodiment, the derivative is in the form of a pharmaceutically acceptable amide, preferably with an amide group at the C-terminus of the peptide. In a further specific embodiment, the peptide or derivative is in the form of a pharmaceutically acceptable ester.

[0117] In this article, HbA1C refers to glycated hemoglobin. The glycated hemoglobin control target follows the patient-centered individualized principle. Currently, most diabetes guidelines recommend that the HbA1c target value for general adult T2DM patients be <7.0%. DETAILED DESCRIPTION

[0118] The embodiments of the present invention will be described in detail below with reference to the examples, but it will be understood by those skilled in the art that the following examples are only intended to illustrate the present invention and should not be construed as limiting the scope of the present invention. Where specific conditions are not specified in the examples, the methods were performed according to conventional conditions or the conditions recommended by the manufacturer. Where the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0119] Abbreviations AE: Adverse event AESI: Adverse event of special interest AUC: Area under the drug concentration-time curve HbA1c: Glycosylated hemoglobin BMI: Body mass index N: Number of subjects FPG: Fasting venous plasma glucose SMBG: Self-monitoring blood glucose TIR: Time in therapeutic range GMI: Glucose Management Index

[0120] Example 1 Preparation of Compound (I)

[0121] A14E, B16H, B25H, B29K (N(ε)-docosandioyl-γGlu-12xOEG), desB30 human insulin (Compound (I)), the insulin parent of the compound is A14E, B16H, B25H, desB30 human insulin (SEQ ID NO: 1 and SEQ ID NO: 2, representing the A chain and B chain, respectively).

[0122] SEQ ID NO.1:

[0123] A14E, B16H, B25H, desB30 Human insulin A chain:

[0124] Gly Ile Val Glu Gln Cys Cys Thr Ser Ile Cys Ser Leu Glu Gln Leu Glu Asn Tyr Cys Asn

[0125] SEQ ID NO.2:

[0126] A14E, B16H, B25H, desB30 Human insulin B chain:

[0127] Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu His Leu Val Cys Gly Glu Arg Gly Phe His Tyr Thr Pro Lys

[0128] Compound (I) can be prepared, for example, by the method described in WO2021136296A1.

[0129] Example 2 Injection of Compound (I)

[0130] A pharmaceutical composition injection of compound (I) was prepared: 1.2 mmol / L of the compound, 4.23 mg / ml of phenol, 1.08 mg / ml of m-cresol, 1.17 mg / ml of sodium chloride, 15 mg / ml of glycerol, 0.71 mg / ml of anhydrous disodium hydrogen phosphate and 2.3 mol of zinc ion / 6 mol of compound (I), pH 7.4.

[0131] Example 3: Hypoglycemic Effect of Compound (I) in Type 2 Diabetes (Insulin-naive Type 2 Diabetes Patients Poorly Controlled by Oral Hypoglycemic Drugs)

[0132] This study is a multicenter, randomized, open-label, parallel-controlled, target-targeted phase II clinical study in patients with type 2 diabetes who are poorly controlled by oral hypoglycemic drugs and are insulin-naive. The aim is to evaluate the efficacy of compound (I) injection once a week and insulin degludec once a day. Efficacy, safety, and tolerability of the treatment in insulin-naive patients with type 2 diabetes who are inadequately controlled with oral hypoglycemic agents.

[0133] Inclusion criteria and diagnosis:

[0134] After the subjects signed the informed consent form, this study enrolled subjects aged 18 to 75 years (inclusive) who met the World Health Organization (WHO) criteria (1999) and were diagnosed with type 2 diabetes for more than 6 months using glycated hemoglobin (HbA1c). Such subjects were required to meet the following criteria: "HbA1c ≤ 7.5% ≤ 10.0% at screening, fasting venous blood glucose ≥ 7.2 mmol / L; body mass index (BMI) ≥ 18.5 kg / m 2 and ≤35kg / m 2Patients were eligible to enter this trial only if they received metformin (total daily dose ≥1.5g or maximum tolerated dose ≥1g) ±1 oral hypoglycemic drug (DPP-4 inhibitor, α-glucosidase inhibitor, SGLT-2 inhibitor) before screening and maintained a stable daily dose for ≥3 months before randomization; and had not used insulin treatment in the past, except for those who had received short-term insulin treatment (up to 14 days cumulatively) before screening and those who received insulin treatment due to gestational diabetes.

[0135] Subjects who mainly meet any of the following conditions will be excluded: diabetic ketoacidosis, diabetic lactic acidosis or hyperosmolar non-ketotic diabetic coma within 6 months before screening, or proliferative retinopathy or maculopathy that is unstable or requires treatment; history of acute heart failure within 6 months before screening, or hospitalization for coronary heart disease, myocardial infarction, unstable angina, stroke, etc. within 6 months before screening; history of chronic heart failure at screening, classified as New York Heart Association class III or IV; use of obesity-indicated drugs within 3 months before screening, or anticipated initiation or change of concomitant medications known to affect weight or glucose metabolism during the trial; severe hypoglycemia (grade 3 hypoglycemia) events within 6 months before screening, or 1 or more hypoglycemia events (blood glucose <3.9 mmol / L) within 2 months before randomization, or repeated hypoglycemia-related symptoms before randomization (once a week or more).

[0136] The test drugs and control drugs are shown in Table 1.

[0137] Table 1:

[0138] As shown in Table 2, subjects were randomized and given a starting dose (first dose) of Compound (I) injection and insulin degludec injection according to the dosing regimen in Table 2. All drugs were administered using a 3 ml disposable pen syringe. This pen syringe was the same for the administration of Compound (I) injection and insulin degludec injection.

[0139] As shown in Tables 3 and 4, when administering the second dose to a subject, it is necessary to adjust the dose based on the individual patient's needs. The dose is adjusted based on the patient's fasting blood glucose to optimize blood glucose control. The adjustment rules are shown in Tables 3 and 4.

[0140] Table 2: Experimental design: Compound (I) injection and degludec insulin injection were administered at the initial stage of the experiment

[0141] Table 3: Weekly insulin dose adjustment rules (no hypoglycemic events*) Note: *The lowest fasting capillary blood glucose value before breakfast is ≥3.9mmol / L for 3 consecutive times (including the day of the visit) starting from 2 days before administration. **The lowest fasting capillary blood glucose value is used. If the lowest blood glucose value is ≥4.4mmol / L, the average of the 3 times is used. If one or more fasting capillary blood glucose values ​​are missing, the dose should be adjusted based on the remaining SMBG (subject self-monitoring of capillary blood glucose) values. If the subject's fasting blood glucose fails to reach the predetermined treatment target, the researcher can communicate with the sponsor to individualize the insulin dose adjustment rules based on the subject's situation.

[0142] Table 4: Weekly Insulin Dose Adjustment Rules (with Hypoglycemic Events***) Note: *** refers to any one of the three consecutive times (including the visit day) before breakfast with a fasting blood glucose level of <3.9 mmol / L from 2 days before administration.

[0143] If a subject experiences fasting hypoglycemia 1-4 days after dosing, the investigator can develop individualized insulin dose adjustment rules based on the subject's condition after consultation with the sponsor. In principle, the insulin dose for that injection should not be increased. Unless there is a clear explanation for the minimum value, such as a missed meal, the specific insulin dosage for 15 weeks of dosing is shown in Figure 1.

[0144] The study duration for each subject in this study is approximately 22 weeks at most: including a screening period of up to 17 days (W-2-W-1), a treatment period of 16 weeks (W0-W15), and a 4-week safety follow-up period (W16-W20).

[0145] Statistical methods:

[0146] The primary efficacy indicator was the change in HbA1c (%) compared with baseline at week 16.

[0147] FAS: includes all subjects who underwent randomization.

[0148] PPS: All subjects without major protocol violations were included, and subjects had to have received insulin therapy for at least 12 weeks.

[0149] Main Estimates—Primary Analysis: For the FAS, the change in HbA1c values ​​from baseline at W16 was calculated using an analysis of covariance model, with group and stratification as fixed effects and age and baseline HbA1c values ​​as covariates. Changes, 95% confidence intervals, and P values ​​were calculated.

[0150] result:

[0151] Subject distribution

[0152] A total of 42 subjects were randomly enrolled in the Compound (I)-A group, all of whom received the trial drug, and 40 subjects (95.2%) completed the trial. A total of 41 subjects were randomly enrolled in the Degludec Insulin-A group, all of whom received the control drug, and 38 subjects (92.7%) completed the trial.

[0153] Baseline characteristics

[0154] The demographic information of the Compound (I)-A group and the Degludec insulin-A group was basically balanced.

[0155] Medication adherence outcomes

[0156] The compliance of the trial drugs and background drugs was good. The compliance of 82 subjects (98.8%) with the trial drugs was within the range of 80% to 120%.

[0157] 3.1 Efficacy

[0158] Insulin-naive T2DM (type 2 diabetes) subjects whose blood sugar levels were poorly controlled by oral hypoglycemic drugs were given compound (I) injection once a week and insulin degludec once a day for 16 consecutive weeks. The results showed that compound (I) injection once a week could effectively reduce the subjects' HbA1c and improve blood sugar control, and was generally safe and well tolerated.

[0159] (1) Overall, compared with the baseline, HbA1c in both groups A1 and A2 decreased significantly, with similar decreases, and the two groups had similar glucose-lowering efficacy.

[0160] (2) Compared with baseline, the changes in fasting plasma glucose (FPG), average level of 7-point self-monitoring blood glucose (SMBG), percentage of time in target glucose (TIR), and glucose management index (GMI) were comparable in the two treatment groups.

[0161] (3) The achievement rate of HbA1c≤6.5% in group A1 was significantly higher than that in group A2. The achievement rates of HbA1c≤6.5% in group A1 and group A2 were 38.1% and 29.3%, respectively.

[0162] (4) In the last two weeks of treatment, the mean (SD) weekly insulin doses of group A1 and group A2 were 80.6 U and 165.8 U, respectively. There was a significant statistical difference between the two groups (P < 0.001). The mean weekly insulin dose of compound (I) injection was significantly lower than that of degludec insulin injection, which was about half of that of degludec insulin.

[0163] HbA1c indicator

[0164] The primary efficacy indicator of this study was the change in HbA1c measured value compared with baseline after 16 weeks. The analysis of the primary efficacy indicators based on FAS analysis is summarized in Table 5 below.

[0165] Table 5 Analysis of changes in W16 glycosylated hemoglobin relative to baseline (FAS)

[0166] As shown in Table 5, the mean (SD) changes in HbA1c from baseline in the two groups were -1.355 (0.8009)% and -1.297 (0.7886)%, respectively. Compared to baseline, HbA1c decreased significantly in both the Compound (I)-A group and the Insulin Degludec-A group, with similar decreases, demonstrating similar glucose-lowering efficacy. Compound (I) injection, administered once weekly, effectively lowered HbA1c and improved glycemic control in subjects.

[0167] Based on FAS, the results of the main analysis using the covariance analysis model showed that the least squares mean (LSMEANS) (95% CI) of the changes in HbA1c from baseline in the Compound (I)-A group and the Degludec insulin-A group at W16 were -1.50 (-1.88, -1.11)% and -1.48 (-1.86, -1.10)%, respectively. The difference in LSMEANS (95% CI) between the two groups (Compound (I)-A group and Degludec insulin-A group) was -0.02 (-0.34, 0.30)%. There was no statistically significant difference between the groups (P = 0.902). The analysis results showed that the random stratification factor effect (stratification factors: metformin + DPP4 inhibitor; metformin + SGLT-2 inhibitor; metformin + α-glucosidase inhibitor; metformin) and age effect were not significant (P>0.05), and the baseline HbA1c effect was significant (P<0.001). It can be concluded that there is no random stratification factor effect or age effect, but there is a baseline HbA1c effect.

[0168] Proportion of subjects with HbA1c ≤ 6.5% at week 16

[0169] The study analyzed the HbA1c target rate after 16 weeks of treatment based on FAS. The results are shown in Table 6.

[0170] Table 6 Proportion of subjects with W16 glycosylated hemoglobin ≤ 6.5% (FAS)

[0171] It can be seen from the data in Table 6 that after 16 weeks of treatment, the HbA1c ≤ 6.5% standard-reaching rates in the Compound (I)-A group and the Degludec insulin-A group were 38.1% and 29.3%, respectively. The HbA1c ≤ 6.5% standard-reaching rate in the Compound (I)-A group was higher than that in the Degludec insulin-A group.

[0172] During the last 2 weeks of treatment, weekly injection of compound (I) and daily injection of insulin degludec are used.

[0173] The dosage of the investigational drugs Compound (I) injection and degludec insulin injection is shown in Table 10.

[0174] Table 10 Summary of the dosage of trial drugs used in each visit from W14 to W15 (FAS / PPS)

[0175] The results in Table 10 show that, based on FAS, in the last two weeks of treatment, the average (SD) actual average administered dose of Group (I)-A during W14-W15 was 80.6 (45.97) U, and the average (SD) actual average administered dose of Group (I)-A during W14-W15 was 165.8 (100.28) U. The average weekly insulin dose of Compound (I) was significantly less than half of that of Insulin Degludec.

[0176] There was a significant statistical difference between the two groups (P<0.001). The trends of PPS and FAS were consistent.

[0177] The study also found that compared with baseline, the changes in fasting plasma glucose (FPG), average 7-point self-monitoring blood glucose (SMBG) levels, time in therapeutic range (TIR) ​​and glucose management index (GMI) were comparable in the two treatment groups.

[0178] 3.2 Security

[0179] No adverse events leading to death, SUSAR, or severe hypoglycemia occurred in this trial. According to the CTCAE (Common Criteria for Adverse Events) classification, most TEAEs that occurred were grade 1-2 (98.14%).

[0180] There were no significant differences in the blood routine, blood biochemistry, coagulation function, urine routine, urine biochemistry, 12-lead electrocardiogram, vital signs, physical examination, and fundus examination of the subjects in the compound (I)-A group of the present disclosure.

[0181] After 16 weeks of treatment, the total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides in the compound (I)-A group of the present disclosure did not change much compared with the baseline.

[0182] Example 4: Hypoglycemic Effect of Compound (I) in Type 2 Diabetes (Adult Type 2 Diabetes Patients Poorly Controlled by Oral Hypoglycemic Agents Combined with Basal Insulin)

[0183] This study is a multicenter, randomized, open-label, parallel-controlled, treat-to-target Phase II clinical study in patients with type 2 diabetes who are poorly controlled with oral hypoglycemic agents combined with basal insulin. The study aims to evaluate the efficacy and safety of once-weekly Compound (I) injection versus once-daily insulin degludec in patients with type 2 diabetes who are poorly controlled with oral hypoglycemic agents combined with basal insulin. The experimental materials are shown in Table 1 in Example 3.

[0184] Inclusion criteria and diagnosis:

[0185] After the subjects signed the informed consent form, this study enrolled subjects aged 18 to 75 years (inclusive) who met the World Health Organization (WHO) criteria (1999) and were diagnosed with type 2 diabetes for more than 6 months using glycated hemoglobin (HbA1c). Such subjects were required to meet the following criteria: "HbA1c ≤ 7.5% ≤ 10.0% at screening, fasting venous blood glucose ≥ 7.2 mmol / L; body mass index (BMI) ≥ 18.5 kg / m 2 and ≤35kg / m 2 Patients were eligible for this trial if they received metformin (total daily dose ≥1.5 g or maximum tolerated dose ≥1 g) ± 1 oral hypoglycemic drug (dipeptidyl peptidase-4 [DPP-4] inhibitor, α-glucosidase inhibitor, sodium-glucose cotransporter-2 [SGLT-2] inhibitor, glucokinase activator), and 1 basal insulin (glargine U100, detemir, degludec, or NPH) before screening, with 10 U ≤ basal insulin dosage ≤ 50 U / day, and the basal insulin and stable dose oral hypoglycemic drug treatment regimen remained unchanged for ≥3 months before randomization, and the basal insulin (of any type) was administered once daily (QD) or twice daily (BID).

[0186] Subjects who mainly meet any of the following conditions will be excluded: diabetic ketoacidosis, diabetic lactic acidosis or hyperosmolar non-ketotic diabetic coma within 6 months before screening, or proliferative retinopathy or maculopathy that is unstable or requires treatment; history of acute heart failure within 6 months before screening, or hospitalization for coronary heart disease, myocardial infarction, unstable angina, stroke, etc. within 6 months before screening; history of chronic heart failure at screening, classified as New York Heart Association class III or IV; use of obesity-indicated drugs within 3 months before screening, or anticipated initiation or change of concomitant medications known to affect weight or glucose metabolism during the trial; severe hypoglycemia (grade 3 hypoglycemia) events within 6 months before screening, or 1 or more hypoglycemia events (blood glucose <3.9 mmol / L) within 2 months before randomization, or repeated hypoglycemia-related symptoms before randomization (once a week or more). As shown in Table 11, subjects were randomized and given a starting dose (first dose) of Compound (I) injection and insulin degludec injection according to the dosing regimen in Table 11. All drugs were administered using a 3 ml disposable pen syringe. This pen syringe was the same for the administration of Compound (I) injection and insulin degludec injection.

[0187] Table 11: Experimental design: Compound (I) injection and degludec insulin injection were administered at the initial stage of the experiment

[0188] As shown in Tables 3 and 4 in Example 3, when administering the second dose to a subject, it is determined based on the individual patient's needs. The dose is adjusted based on the patient's fasting blood glucose to optimize blood glucose control, and the adjustment rules are shown in Tables 3 and 4 in Example 3.

[0189] During the trial, the injections were administered on the same day of the week, and the specific insulin dosages for 16 weeks are shown in Figure 2.

[0190] The study duration for each subject was approximately 22 weeks at most: including a screening period of up to 17 days (W-2-W-1), a treatment period of 16 weeks (W0-W15), and a 4-week safety follow-up period (W16-W20).

[0191] Statistical methods:

[0192] The primary efficacy endpoint of this study was the change in HbA1c (%) from baseline at week 16. Assuming an estimated error of 0.4% for the difference between the two group means, the standard deviation of the change in HbA1c (%) from baseline at week 16 was 0.89% for both the experimental and control groups. PASS (version 21.0) software was used for calculations.

[0193] In this study, all statistical analyses except pharmacokinetics were performed using SAS version 9.4 statistical software.

[0194] FAS: includes all subjects who underwent randomization.

[0195] PPS: All subjects without major protocol violations were included, and subjects had to have received insulin therapy for at least 12 weeks.

[0196] Main Estimates—Primary Analysis: For the FAS, the change in HbA1c values ​​from baseline at W16 was calculated using an analysis of covariance model, with group and stratification as fixed effects and age and baseline HbA1c values ​​as covariates. Changes, 95% confidence intervals, and P values ​​were calculated.

[0197] Test results:

[0198] Subject distribution

[0199] A total of 48 subjects were randomly enrolled in the Compound (I)-B group, all of whom received the experimental drug Compound (I) injection treatment, and 46 subjects (95.8%) completed the trial.

[0200] A total of 48 subjects were randomly enrolled in the degludec insulin-B group, all of whom received the control drug degludec insulin injection. 46 subjects (95.8%) completed the trial.

[0201] A total of 96 subjects (100.0%) were included in the full analysis set (FAS) and safety analysis set (SS), including 48 subjects (100.0%) in the Compound (I)-B group and 48 subjects (100.0%) in the degludec insulin-B group. A total of 87 subjects (90.6%) were included in the per-protocol set (PPS), including 43 subjects (89.6%) in the Compound (I)-B group and 44 subjects (91.7%) in the degludec insulin-B group.

[0202] Baseline characteristics

[0203] The demographic information of the Compound (I)-B group and the Degludec insulin-B group was basically balanced.

[0204] Medication adherence outcomes

[0205] Compliance with trial drugs and background medications was good during the treatment period.

[0206] The compliance of 96 subjects (100.0%) with the trial drugs was within the range of 80% to 120%.

[0207] 4.1 Efficacy

[0208] (1) The least squares mean (LSMEANS) (95% CI) of the changes in HbA1c compared with baseline in group B1 and group B2 after 16 weeks of treatment were -1.26 (-1.46, -1.06)% and -0.87 (-1.07, -0.68)%, respectively. The difference in LSMEANS between the two groups (95% CI) was -0.38 (-0.66, -0.11)%. There was a significant statistical difference between the two groups (P = 0.007).

[0209] (2) After 16 weeks of treatment, the achievement rates of HbA1c < 7% and HbA1c ≤ 6.5% in group B1 were significantly higher than those in group B2 (Table 7).

[0210] (3) Compared with baseline, the changes in FPG, 7-point SMBG mean level, TIR and GMI were comparable in the two treatment groups.

[0211] (4) In the last two weeks of treatment, the mean (SD) weekly insulin doses of group B1 and group B2 were 88.65 U and 218.15 U, respectively. There was a significant statistical difference between the two groups (P < 0.001). The mean weekly insulin dose of compound (I) injection was significantly lower than that of degludec injection, and compound (I) injection was approximately 0.4 times that of degludec injection.

[0212] (5) The time (median) for the first reaching of the titration target [average fasting peripheral blood glucose level before breakfast for three consecutive times between 4.4-7.2 mmol / L (including the cut-off value)] in group B1 and group B2 was 1.14 weeks and 3.29 weeks, respectively. The Kaplan-Meier analysis showed significant statistical differences between the two groups (P < 0.001).

[0213] HbA1c indicator

[0214] The primary efficacy indicator of this study was the change in HbA1c measured value compared with baseline after 16 weeks. The primary efficacy based on FAS analysis is shown in Table 12 below.

[0215] Table 12 Analysis of changes in W16 glycosylated hemoglobin relative to baseline (FAS)

[0216] As shown in Table 12, after 16 weeks of treatment, the mean (SD) changes in HbA1c compared to baseline in the two groups were -1.269 (0.7856)% and -0.889 (0.8209)%, respectively. Compared to baseline, HbA1c decreased significantly in both the Compound (I)-B group and the Insulin Degludec-B group, with the magnitude of decrease in the Compound (I)-B group being greater than that in the Insulin Degludec-B group. Compound (I) exhibited superior glucose-lowering efficacy to Insulin Degludec.

[0217] Based on FAS, the main analysis results using the covariance analysis model showed that the least squares means (LSMEANS) (95% CI) of the changes in HbA1c from baseline in the Compound (I)-B group and the Degludec insulin-B group at W16 were -1.26 (-1.46, -1.06)% and -0.87 (-1.07, -0.68)%, respectively. The difference in LSMEANS (95% CI) between the two groups (Compound (I)-B group and Degludec insulin-B group) was -0.38 (-0.66, -0.11)%, and the inter-group comparison had a significant statistical difference (P=0.007), that is, the change from baseline in the Compound (I)-B group was significantly greater than that in the Degludec insulin-B group. The analysis results showed that the effect of random stratification factors (stratification factors: glargine U100 / degludec / detemir insulin + glycated hemoglobin ≥8.5%, glargine U100 / degludec / detemir insulin + glycated hemoglobin <8.5%, NPH + glycated hemoglobin ≥8.5%, NPH + glycated hemoglobin <8.5%) was not significant (P=0.475), which means that there was no random stratification factor effect; the effects of group, age, and baseline HbA1c were all significant (P<0.05), which means that there were group effects, age effects, and baseline HbA1c effects.

[0218] The compliance rate of HbA1c < 7% and HbA1c ≤ 6.5%

[0219] The study analyzed the HbA1c target rate after 16 weeks of treatment based on FAS, and the results are shown in Table 13.

[0220] Table 13 Proportion of subjects with W16 glycosylated hemoglobin <7% and ≤6.5% (FAS)

[0221] As shown in Table 13, after 16 weeks of treatment, the achievement rates of HbA1c <7% in the Compound (I)-B group and the insulin degludec group were 52.1% and 29.2%, respectively, and the achievement rates of HbA1c ≤6.5% in the Compound (I)-B group and the insulin degludec group were 25.0% and 10.4%, respectively. The achievement rates of HbA1c <7% and HbA1c ≤6.5% in the Compound (I)-B group were significantly higher than those in the insulin degludec group.

[0222] During the last 2 weeks of treatment, weekly injection of compound (I) and daily injection of insulin degludec are used.

[0223] The dosage of the experimental drug compound (I) injection and insulin degludec injection was studied. The results are shown in Table 17:

[0224] Table 17 Summary of the dosage of trial drugs used in each visit from W14 to W15 (FAS / PPS)

[0225] As shown in Table 17, during the final two weeks of treatment, the mean (SD) weekly insulin doses for the Compound (I)-B group and the Insulin Degludec-B group were 88.65 (34.645) U and 218.15 (92.603) U, respectively, with statistically significant differences between the groups (P < 0.001). The mean weekly insulin dose for Compound (I) was significantly lower than that for Insulin Degludec, approximately half that for Insulin Degludec.

[0226] The study also found that the changes in fasting blood glucose (FPG), average levels of 7-point self-monitoring blood glucose (SMBG), time in therapeutic range (TIR) ​​and glucose management index (GMI) were similar in the two treatment groups.

[0227] 4.2 Security

[0228] Few subjects experienced hypoglycemic events at around 70 units, so the starting dose was around 70 units.

[0229] No adverse events leading to death, SUSAR, or severe hypoglycemia occurred in this trial. According to the CTCAE (Common Criteria for Adverse Events) classification, most TEAEs that occurred were grade 1-2 (97.6%).

[0230] There were no significant differences in the blood routine, blood biochemistry, coagulation function, urine routine, urine biochemistry, 12-lead electrocardiogram, vital signs, physical examination, and fundus examination of the subjects in the compound (I)-B group of the present disclosure.

[0231] After 16 weeks of treatment, the total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides in the compound (I)-B group of the present disclosure did not change much compared with the baseline.

[0232] The present invention has been described through the above-described embodiments. However, it should be understood that the above-described embodiments are for illustrative and illustrative purposes only and are not intended to limit the present invention to the described embodiments. Furthermore, it will be understood by those skilled in the art that the present invention is not limited to the above-described embodiments and that further variations and modifications may be made based on the teachings of the present invention, all of which fall within the scope of the present invention. The scope of protection of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for treating or preventing metabolic syndrome, the method comprising administering to a subject in need thereof about 5-about 400 U, preferably about 5-about 120 U, of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof; preferably, the method comprises administering to a subject in need thereof about 5-about 400 U, preferably about 5-120 U, of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, once every 3 days, twice a week, once every 4 days, once every 5 days, once a week or less, wherein each dose administered is independently the same or different, Preferably, the metabolic syndrome is diabetes; Preferably, the diabetes is type II diabetes (type 2 diabetes); Preferably, the subject is an insulin-naive type 2 diabetes patient who is poorly controlled by oral hypoglycemic drugs; Preferably, the subject is a patient with type 2 diabetes who is poorly controlled by oral hypoglycemic drugs combined with basal insulin.

2. The method according to claim 1, wherein the method comprises administering to a subject in need thereof about 5 to about 400 U, about 5 to about 350 U, about 5 to about 300 U, preferably about 10 to about 250 U, preferably about 10 to about 200 U, preferably about 10 to about 150 U, preferably about 10 to about 120 U, preferably about 10 to about 110 U, preferably about 15 to about 105 U, preferably about 20 to about 100 U, preferably about 30 to about 100 U, preferably about 31 to about 100 U, Preferably about 31-9 about 7U, preferably about 35-about 95U, preferably about 38-about 90U, preferably about 40-about 90U, preferably about 40-about 88U, preferably about 45-about 88U, preferably about 48-about 85U, preferably about 49-about 80U, preferably about 49-about 79U, preferably about 49-about 70U, preferably about 40-about 70U of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof; preferably, the method comprises administering to a subject in need thereof 3 times per day About 5 to about 400 U, about 5 to about 350 U, about 5 to about 300 U, preferably about 10 to about 250 U, preferably about 10 to about 200 U, preferably about 10 to about 150 U, preferably about 10 to about 120 U, preferably about 10 to about 110 U, preferably about 15 to about 105 U, preferably about 20 to about 100 U, preferably about 30 to about 100 U, preferably about 31 to about 100 U, Preferably about 31-about 97 U, preferably about 35-about 95 U, preferably about 38-about 90 U, preferably about 40-about 90 U, preferably about 40-about 88 U, preferably about 45-about 88 U, preferably about 48-about 85 U, preferably about 49-about 80 U, preferably about 49-about 79 U, preferably about 49-about 70 U, preferably about 40-about 70 U of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, wherein the dose administered each time is independently the same or different.

3. The method according to claim 1 or 2, wherein: The method comprises administering to a subject in need thereof about 5 to about 300 U, preferably about 10 to about 250 U, preferably about 10 to about 200 U, preferably about 10 to about 150 U, preferably about 10 to about 120 U, preferably about 10 to about 110 U, preferably about 15 to about 105 U, preferably about 20 to about 100 U, preferably about 30 to about 100 U, preferably about 31 to about 100 U, preferably about 31 to about 97 U, preferably about 35 to about 95 The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is administered at a dose of about 38 to about 90 U, preferably about 40 to about 90 U, preferably about 40 to about 88 U, preferably about 45 to about 88 U, preferably about 48 to about 85 U, preferably about 49 to about 80 U, preferably about 49 to about 79 U, preferably about 49 to about 70 U, preferably about 40 to about 70 U, and preferably the weekly administered doses are independently the same or different.

4. The method according to any one of claims 1 to 3, wherein: The method comprises administering to a subject in need thereof a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, at a weekly administration dose of about 5 U, about 6 U, about 7 U, about 8 U, about 9 U, about 10 U, about 11 U, about 12 U, about 13 U, about 14 U, about 15 U, about 16 U, about 17 U, about 18 U, about 19 U, about 20 U, about 21 U, about 22 U, about 23 U, about 24 U, about 25 U, about 26 U, about 27 U, about 28 U, about 29U, about 30U, about 31U, about 32U, about 33U, about 34U, about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U, about 48U, about 49U, about 50U, about 51U, about 52U, about 53U, about 54U, about 55U, about 56U, about 57U, about 58U, about 59U, about 60U, about 61U, about 62U , about 63U, about 64U, about 65U, about 66U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, about 80U, about 81U, about 82U, about 83U, about 84U, about 85U, about 86U, about 87U, about 88U, about 89U, about 90U, about 91U, about 92U, about 93U, about 94U, about 95U, about 96U 6U, about 97U, about 98U, about 99U, about 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, about 200U, about 210U, about 220U, about 230U, about 240U, about 250U, about 260U, about 270U, ​​about 280U, about 290U, or about 300U, preferably, the weekly administration doses are independently the same or different.

5. The method according to any one of claims 1 to 4, wherein: The method comprises administering a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, to a subject in need thereof once every 3 days, twice a week, once every 4 days, once every 5 days, once a week or less, preferably the dosages administered each time are independently the same or different; Preferably, the method comprises administering to a subject in need thereof once a week a dose of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof: about 5 U, about 6 U, about 7 U, about 8 U, about 9 U, about 10 U, about 11 U, about 12 U, about 13 U, about 14 U, about 15 U, about 16 U, about 17 U, about 18 U, about 19 U, about 20 U, about 21 U, about 22 U, about 23 U, about 24 U, about 25 U, about 26 U, about 27 U, about 28 U, about 29 U, about 30 U, about 31 U, about 32 U, about 33 U, about 34 U, about 35 U, about 36 U, about 37 U, about 38 U, about 39 U, about 40 U, ​​about 41 U, about 42 U, about 43 U, about 44 U, about 45 U, about 46 U, about 47 U, about 48 U, about 49 U, about 50 U, about 51 U, about 52 U, about 53 U, about 54 U, about 55 U, about 56 U, about 57 U, about 58 U, about 59 U, about 60 U, about 61 U, about 62 U, about 63 U, about 64 U, about 65 U, about 66 U, about 67 U, about 68 U, about 69 U, about 70 U, about 71 U, about 72 U, about 73 U, about 74 U 28U, about 29U, about 30U, about 31U, about 32U, about 33U, about 34U, about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U, about 48U, about 49U, about 50U, about 51U, about 52U, about 53U, about 54U, about 55U, about 56U, about 57U, about 58U, about 59U, about 60U, about 61U, about 62U, about 63U, about 64U, about 65U, about 66U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, about 80U, about 81U, about 82U, about 83U, about 84U, about 85U, about 86U, about 87U, about 88U, about 89U, about 90U, about 91U, about 92U, about 93U, about 94U, about 95U, about about 96U, about 97U, about 98U, about 99U, about 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, about 200U, about 210U, about 220U, about 230U, about 240U, about 250U, about 260U, about 270U, ​​about 280U, about 290U, or about 300U, wherein the weekly administration doses are each independently the same or different; Preferably, the method comprises administering to a subject in need thereof once a week a fixed dose of: About 6-12 nmol / kg, preferably about 6 nmol / kg, about 7 nmol / kg, about 8 nmol / kg, about 9 nmol / kg, about 10 nmol / kg, about 11 nmol / kg, or about 12 nmol / kg of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof; or About 1 U / kg-6 U / kg, preferably 1 U / kg-3 U / kg, preferably about 1 U / kg-2 U / kg, preferably about 1 U / kg, about 1.3 U / kg, about 1.5 U / kg or about 2 U / kg of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof; Preferably, for subjects who previously administered once-a-day or twice-a-day basal insulin, when switching to administration of the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, the dose of each administration of the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is about 2-20 times, preferably about 2-10 times, preferably about 2-7 times, preferably about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, about 4.5 times, about 5 times, about 5 times, about 6 times, about 7 times, about 8 times, about 9 times, about 10 times, about 11 times, about 12 times, about 13 times, about 14 times, about 15 times, about 16 times, about 17 times, about 18 times, about 19 times, about 20 times, about 21 times, about 22 times, about 23 times, about 24 times, about 25 times, about 26 times, about 27 times, about 28 times, about 29 times, about 30 times, about 31 times, about 32 times, about 33 times, about 34 times, about 35 times, about 36 times, about 37 times, about 38 times, about 39 times, about 40 times, about 41 times, about 42 times, about 43 times, about 44 times, about 45 times, about 46 times, about 47 times, about 48 times, about 49 times, about 50 times, about 51 times, about 52 times, about 53 times, about 54 times, about 56 times, about 57 times, about 58 times, about 59 times, about 60 times, about 61 times, about 61 times, about 62 times, about 63 times, about 64 times, about 65 times, about 66 times, .5 times, about 6 times, about 6.5 times, about 7 times, about 8 times, or about 9 times, preferably, the dose of the compound of formula (I) or its pharmaceutically acceptable salt, amide or ester for the first or each administration is independently about 2-20 times, preferably about 2-10 times, preferably about 2-7 times, preferably about 2 times, about 2.5 times, about 3 times, about 3.5 times, about 4 times, about 4.5 times, about 5 times, about 5.5 times, about 6 times, about 6.5 times, about 7 times, about 8 times, or about 9 times the dose of the previous basal insulin.

6. The method according to any one of claims 1 to 5, wherein: The method comprises administering a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, to a subject in need thereof at a starting dose of about 5 to about 400 U, preferably about 5 to about 350 U, preferably about 5 to about 300 U, preferably about 10 to about 250 U, preferably about 10 to about 200 U, preferably about 10 to about 150 U, preferably about 10 to about 120 U, preferably about 10 to about 110 U, preferably about 10 to about 100 U, preferably about 10 to about 90 U, preferably about 15 to about 85 U, preferably about 20 to about 80 U, preferably about 20 to about 75 U, preferably about 25 to about 75 U, preferably about 30 to about 70 U, preferably about 40 to about 70 U; preferably about 10 to about 40 U; preferably about 20 to about 40 U Preferably, the method comprises administering a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, to a subject in need thereof at a starting dose of about 5 U, about 6 U, about 7 U, about 8 U, about 9 U, about 10 U, about 11 U, about 12 U, about 13 U, about 14 U, about 15 U, about 16 U, about 17 U, about 18 U, about 19 U, about 20 U, about 21 U, about 22 U, about 23 U, about 24 U, about 25 U, about 26 U, about about 47U, about 48U, about 49U, about 50U, about 51U, about 52U, about 53U, about 54U, about 55U, about 56U, about 57U, about 58U, about 59U, about 60U, about 61U, about 62U, about 63U, about 64U, about 65U, about 66U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, about 80U, about 81U, about 82U, about 83U, about 84U about 60U, about 61U, about 62U, about 63U, about 64U, about 65U, about 66U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, about 80U, about 81U, about 82U, about 83U, about 84U, about 85U, about 86U, about 87U, about 88U, about 89U, about 90U, about 91U, about 92U About 90U, about 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, about 200U, about 210U, about 220U, about 230U, about 240U, about 250U, about 260U, about 270U, ​​about 280U, about 290U, or about 300U.

7. The method according to claim 6, wherein: The method further comprises administering the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, to a subject in need thereof at the starting dose, and then administering the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, once every 3 days, twice a week, once every 4 days, once every 5 days, once a week or less frequently. The dose administered each time may be the same as or different from the starting dose. Preferably, the dose administered each time is determined according to the individual condition of the subject.

8. The method according to any one of claims 1 to 7, wherein: The method comprises administering to a subject in need thereof a starting dose of about 5 to about 400 U, preferably about 5 to about 350 U, preferably about 5 to about 300 U, preferably about 10 to about 250 U, preferably about 10 to about 200 U, preferably about 10 to about 150 U, preferably about 10 to about 120 U, preferably about 10 to about 110 U, preferably about 10 to about 100 U, preferably about 10 to about 90 U, preferably about 15 to about 85 U, preferably about 20 to about 80 U, preferably about 25 to about 75 U, preferably about 30 to about 70 U, preferably about 40 to about 70 U, preferably about 20 to about 40 U of a compound of formula (I), or a pharmaceutical preparation thereof, once a week. Preferably, the method comprises administering to a subject in need thereof a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, at a starting dose of about 5 U, about 6 U, about 7 U, about 8 U, about 9 U, about 10 U, about 11 U, about 12 U, about 13 U, about 14 U, about 15 U, about 16 U, about 17 U, about 18 U, about 19 U, about 20 U, about 21 U, about 22 U, about 23 U, about 24 U, about 25 U, about 26 U, about 27 U, about 28 U, about 29 U, about 30 U, about 31 U, about 32 U, about 33 U, about 34 U, about 35 U, about 36 U U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U, about 48U, about 49U, about 50U, about 51U, about 52U, about 53U, about 54U, about 55U, about 56U, about 57U, about 58U, about 59U, about 60U, about 61U, about 62U, about 63U, about 64U, about 65U, about 66U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, about 80U, about 81 U, about 82 U, about 83 U, about 84 U, about 85 U, about 86 U, about 87 U, about 88 U, about 89 U, about 90 U, about 91 U, about 92 U, about 93 U, about 94 U, about 95 U, about 96 U, about 97 U, about 98 U, about 99 U, about 100 U, about 110 U, about 120 U, about 130 U, about 140 U, ​​about 150 U, about 160 U, about 170 U, about 180 U, about 190 U, about 200 U, about 210 U, about 220 U, about 230 U, about 240 U, ​​about 250 U, about 260 U, about 270 U, about 280 U, about 290 U, or about 300 U;Preferably, for subjects who previously administered once-a-day or twice-a-day basal insulin, when switching to administration of the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, the initial dose of the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is about 2-20 times, preferably about 3-10 times, preferably about 5-7 times, preferably about 5 times, about 5.5 times, about 6 times, about 6.5 times, about 7 times, about 8 times, or about 9 times the dose of the previous basal insulin; After one week of administration at the initial dose, a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is administered once a week according to the subject's blood sugar condition. The dose M administered each week is the same or different, and each is independently about 5-about 400U, preferably about 5-about 350U, preferably about 5U-about 300U, preferably about 5U-about 120U, preferably about 10-about 250U, preferably about 10-about 200U, preferably about 10-about 150U, preferably about 10-about 120U, preferably about 5-about 400U, preferably about 5-about 350U, preferably about 10-about 110U, preferably about 10-about 100U, preferably about 10-about 90U, preferably about 15-about 85U, preferably about 20-about 80U, preferably about 25-about 75U, preferably about 30-about 70U, preferably about 40-about 70U; preferably, the dose M administered per week is each independently about 5U, about 6U, about 7U, about 8U, about 9U, about 10U, about 11U, about 12U, about 13U, about 14U, about 15U, about 16U , about 17U, about 18U, about 19U, about 20U, about 21U, about 22U, about 23U, about 24U, about 25U, about 26U, about 27U, about 28U, about 29U, about 30U, about 31U, about 32U, about 33U, about 34U, about 35U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U, about 48U, about 49U, about 50U, about 51U, about 52U , about 53U, about 54U, about 55U, about 56U, about 57U, about 58U, about 59U, about 60U, about 61U, about 62U, about 63U, about 64U, about 65U, about 66U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, about 80U, about 81U, about 82U, about 83U, about 84U, about 85U, about 86U, about 87U, about 88U, About 89U, about 90U, about 91U, about 92U, about 93U, about 94U, about 95U, about 96U, about 97U, about 98U, about 99U, about 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, about 200U, about 210U, about 220U, about 230U, about 240U, about 250U, about 260U, about 270U, ​​about 280U, about 290U, or about 300U.

9. The method according to claim 8, wherein: The dosage M is adjusted weekly according to the following rules: a) When the fasting blood glucose value of the subject before administration is 3.9-4.3mmol / L, or when the lowest value or average value of the fasting peripheral blood glucose before breakfast for three consecutive times starting from 2 days before administration is 3.9-4.3mmol / L, the administered dose M needs to be adjusted to a dose reduced by about 1-30U, preferably by about 1-20U, preferably by about 3-18U, preferably by about 5-10U; or b) When the subject's fasting blood glucose value before administration is 4.4-7.2mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 4.4-7.2mmol / L, the administered dose M is the last administered dose; or c) When the fasting blood glucose value of the subject before administration is 7.3-8.0mmol / L, or when the lowest value or average value of the fasting peripheral blood glucose before breakfast for three consecutive times starting from 2 days before administration is 7.3-8.0mmol / L, the administered dose M needs to be adjusted to the last administered dose plus about 1-about 30U, preferably about 1-about 20U, preferably about 3-18U, preferably about 5-about 10U; or d) When the fasting blood glucose value of the subject before administration is 8.1-9.9 mmol / L, or when the lowest value or average value of the fasting peripheral blood glucose before breakfast for three consecutive times starting from 2 days before administration is 8.1-9.9 mmol / L, the administered dose M needs to be adjusted to the last administered dose plus about 5-about 30 U, preferably about 15-about 20 U, preferably about 15-18 U; or e) When the fasting blood glucose value of the subject before administration is ≥10.0mmol / L, or when the lowest or average value of the fasting peripheral blood glucose before breakfast for three consecutive times starting from 2 days before administration is ≥10.0mmol / L, the administered dose M needs to be adjusted to the last administered dose plus about 10-40U, preferably about 25-30U, preferably about 15-18U; or f) When the fasting blood glucose value of the subject before administration is ≤3.0mmol / L, or when the lowest or average value of the fasting peripheral blood glucose before breakfast for three consecutive times starting from 2 days before administration is ≤3.0mmol / L, the administered dose needs to be adjusted to the last administered dose minus about 5 to about 30U, preferably minus about 15 to about 20U; or g) When the fasting blood glucose value of the subject before administration is 3.1-3.9mmol / L, or when the lowest or average value of the fasting peripheral blood glucose before breakfast for three consecutive times starting from 2 days before administration is 3.1-3.9mmol / L, the dosage should be adjusted to the last dosage minus about 1-about 20U, preferably minus about 5-10U; or h) When the subject's fasting blood glucose value before administration is less than 4.4mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is less than 4.4mmol / L, the administered dose needs to be adjusted to the last administered dose minus about 5-20U, preferably minus about 10-18U; i) When the fasting blood glucose value of the subject before administration is greater than about 7.2 mmol / L, or when the lowest value or average value of the fasting peripheral blood glucose of the subject before breakfast for three consecutive times starting from 2 days before administration is greater than about 7.2 mmol / L, the administered dose M needs to be adjusted to the last administered dose plus about 1-about 30 U, preferably about 1-20 U, and preferably about 3-18 U.

10. The method according to any one of claims 8 to 9, wherein: The dosage M is adjusted weekly according to the following rules: a) When the fasting blood glucose value of the subject before administration is 3.9-4.3mmol / L, or when the lowest or average value of the fasting peripheral blood glucose before breakfast for three consecutive times starting from 2 days before administration is 3.9-4.3mmol / L, the administered dose M needs to be adjusted to the last administered dose minus about 9U-18U; or b) When the subject's fasting blood glucose value before administration is 4.4-7.2mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 4.4-7.2mmol / L, the administered dose M is the last administered dose; or c) When the subject's fasting blood glucose value before administration is 7.3-8.0mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 7.3-8.0mmol / L, the administered dose M needs to be adjusted to the last administered dose plus about 9-18U; or d) When the subject's fasting blood glucose value before administration is 8.1-9.9mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 8.1-9.9mmol / L, the administered dose M needs to be adjusted to the last administered dose plus about 18-30U; or e) When the subject's fasting blood glucose value before administration is ≥10.0mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for 3 consecutive times starting from 2 days before administration is ≥10.0mmol / L, the administered dose M needs to be adjusted to the last administered dose plus about 18-27U; or f) When the subject's fasting blood glucose value before administration is ≤3.0mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is ≤3.0mmol / L, the administered dose M needs to be adjusted to the last administered dose minus about 18-30U; or g) When the fasting blood glucose value of the subject before administration is 3.1-3.9mmol / L, or when the lowest or average value of the fasting peripheral blood glucose of the subject before breakfast for 3 consecutive times starting from 2 days before administration is 3.1-3.9mmol / L, the administered dose M needs to be adjusted to the last administered dose minus about 9-18U.

11. The method according to any one of claims 8 to 10, wherein: The method comprises administering about 10 to about 400 U, 10 to about 300 U, about 10 to about 100 U, about 10 to about 70 U, about 20 to about 60 U, preferably about 25 to about 55 U, preferably about 28 to about 55 U, preferably about 30 to about 50 U, preferably about 30 U, about 31 U, about 32 U, about 33 U, about 34 U, about 35 U, about 36 U, about 37 U, about 38 U, about 39 U, about 40 U, ​​about 41 U, about 42 U, about 43 U, about 44 U, about 45 U, about 46 U, about 47 U, about 48 U, about 49 U, about 50 U, about 51 U, about 52 U, about 53 U, about 54 U, about 55 U, about 56 U, about 57 U, about 58 U, about 59 U, about 60 U, about 61 U, about 62 U, about 63 U, about 64 U, about 65 U, about 67 U, about 68 U, about 69 U, about 70 U, about 71 U, about 72 U, about 73 U, about 74 U, about 75 U, about 76 U, about 77 U, about 78 U, about 79 U, about 80 U, about 81 U, about 82 U, about 83 U, about 84 U, about 85 U, about 86 U, about 87 U, about 88 U, about 89 U, about 90 U, about 91 U, about 92 U, about 36U, about 37U, about 38U, about 39U, about 40U, about 41U, about 42U, about 43U, about 44U, about 45U, about 46U, about 47U, about 48U, about 49U, about 50U, about 51U, about 52U, about 53U, about 54U, about 55U, about 56U, about 57U, about 58U, about 59U, about 60U, about 61U, about 62U, about 63U, about 64U, about 65U, about 66U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, about 80U, about 81U, about 82U, about 83U, about 84U, about 85U, about 86U, about 87U, about 88U, about 89U, about 90U, about 91U, about 92U, about 93U, about 94U, about 95U, about 96U, about 97U, about 98U, about 99U U, about 100 U, about 110 U, about 120 U, about 130 U, about 140 U, ​​about 150 U, about 160 U, about 170 U, about 180 U, about 190 U, about 200 U, about 210 U, about 220 U, about 230 U, about 240 U, ​​about 250 U, about 260 U, about 270 U, about 280 U, about 290 U, or about 300 U of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof; After one week of administration at the initial dose, a compound of formula (I) or a pharmaceutically acceptable salt, amide or ester thereof is administered at a dose of M according to the subject's blood glucose condition once a week, wherein the M administered each week is the same or different and is independently about 5U-about 300U, preferably about 10-about 250U, preferably about 10-about 200U, preferably about 10-about 150U, preferably about 5-about 120U, preferably about 10-about 120U, preferably about 10-about 110U, preferably about 10-about 100U, preferably about 10-about 100U, preferably about 10-about 100U about 30 to about 70 U, preferably about 31 to about 67 U, preferably about 31 U, about 32 U, about 33 U, about 34 U, about 35 U, about 36 U, about 37 U, about 38 U, about 39 U, about 40 U, ​​about 41 U, about 42 U, about 43 U, about 44 U, about 45 U, about 46 U, about 47 U, about 48 U, about 49 U, about 50 U, about 51 U, about 52 U, about 53 U, about 54 U, about 55 U, about 56 U, about 57 U, about 58 U, about 59 U, about 60 U, about 61 U 1U, about 62U, about 63U, about 64U, about 65U, about 66U, about 67U, about 70U, about 80U, about 90U, about 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, about 200U, about 210U, about 220U, about 230U, about 240U, about 250U, about 260U, about 270U, ​​about 280U, about 290U, or about 300U.

12. The method according to any one of claims 8 to 11, wherein: The method comprises administering about 50 to about 90 U, preferably about 50 to about 90 U, preferably 55 to about 85 U, preferably about 60 to about 80 U, preferably about 60 U, about 61 U, about 62 U, about 63 U, about 64 U, about 65 U, about 66 U, about 67 U, about 68 U, about 69 U, about 70 U, about 71 U, about 72 U, about 73 U, about 74 U, about 75 U, about 76 U, about 77 U, about 78 U, about 79 U, about 80 U, about 90 U, about 100 U, about 110 U, about 120 U, about 130 U, about 140 U, ​​about 150 U, about 160 U, about about 170U, about 180U, about 190U, about 200U, about 210U, about 220U, about 230U, about 240U, about 250U, about 260U, about 270U, ​​about 280U, about 290U, or about 300U of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof; or the initial dose of the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is about 2-20 times, preferably about 3-10 times, preferably about 5-7 times, preferably about 2.5 times, about 3 times, about 5 times, about 5.5 times, about 6 times, about 6.5 times, about 7 times, about 8 times, or about 9 times the dose of the previous basal insulin; After one week of administration at the initial dose, a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is administered at a dose of M according to the blood glucose condition of the subject once a week, wherein the M administered each week is the same or different and is independently about 5U-about 300U, preferably about 10-about 250U, preferably about 20-about 200U, preferably about 30-about 150U, preferably about 40-about 120U, preferably about 50-about 110U, preferably about 50-about 100U, preferably about 60-about 100U, preferably about 61-about 97U, preferably about 60U, about 61U, about 62U, about 63U, about 64U, about 65U, about 66U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, about 80U, about 81U, about 82U, about 83U, about 84U, about 85U, about 86U, about 87U, about 88U, about 89U, about 90U, about 91U, about 92U, about 93U, about 94U, about 95U, about 96U, about 97U, about 98U, about 99U About 100U, about 110U, about 120U, about 130U, about 140U, about 150U, about 160U, about 170U, about 180U, about 190U, about 200U, about 210U, about 220U, about 230U, about 240U, about 250U, about 260U, about 270U, ​​about 280U, about 290U, or about 300U.

13. A method for treating or preventing type II diabetes, the method comprising administering a starting dose of about 20 to about 60 U, preferably about 25 to about 55 U, preferably about 30 to about 50 U, preferably about 30 U, about 31 U, about 32 U, about 33 U, about 34 U, about 35 U, about 36 U, about 37 U, about 38 U, about 39 U, about 40 U, ​​about 41 U, about 42 U, about 43 U, about 44 U, about 45 U, about 46 U, about 47 U, about 48 U, about 49 U, or about 50 U of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, to an adult insulin-naive type 2 diabetes subject who is poorly controlled by oral hypoglycemic agents at a frequency of once per week; After one week of administration at the initial dose, a compound of formula (I) or a pharmaceutically acceptable salt, amide or ester thereof is administered at a dose of M according to the blood glucose condition of the subject once a week, wherein the M administered each week is the same or different and is independently about 5 to about 400 U, preferably about 5 to about 350 U, preferably about 5 U to about 300 U, preferably about 5 U to about 120 U, preferably about 10 to about 250 U, preferably about 10 to about 200 U, preferably about 10 to about 1 50U, preferably about 10-about 120U, preferably about 5-about 400U, preferably about 5-about 350U, preferably about 10-about 110U, preferably about 10-about 100U, preferably about 10-about 90U, preferably about 15-about 85U, preferably about 20-about 80U, preferably about 25-about 75U, preferably about 30-about 70U, preferably about 40-about 70U, preferably about 60U, about 61U, about 62U, about 63U, about 64U, about 65U U, about 66U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, about 80U, about 81U, about 82U, about 83U, about 84U, about 85U, about 86U, about 87U, about 88U, about 89U, about 90U, about 91U, about 92U, about 93U, about 94U, about 95U, about 96U, about The dosage M for administration is adjusted weekly according to the following rules: a) When the subject's fasting blood glucose value before administration is 3.9-4.3mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 3.9-4.3mmol / L, the administered dose M needs to be adjusted to the last administered dose minus about 9-18U; or b) When the subject's fasting blood glucose value before administration is 4.4-7.2mmol / L, or when the average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 4.4-7.2mmol / L, the administered dose M is the last administered dose; or c) When the subject's fasting blood glucose value before administration is 7.3-8.0mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 7.3-8.0mmol / L, the administered dose M needs to be adjusted to the last administered dose plus about 9-18U; or d) When the subject's fasting blood glucose value before administration is 8.1-9.9mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 8.1-9.9mmol / L, the administered dose M needs to be adjusted to the last administered dose plus about 18-30U; or e) When the subject's fasting blood glucose value before administration is ≥10.0mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for 3 consecutive times starting from 2 days before administration is ≥10.0mmol / L, the administered dose M needs to be adjusted to the last administered dose plus about 18-27U; or f) When the subject's fasting blood glucose value before administration is ≤3.0mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is ≤3.0mmol / L, the administered dose M needs to be adjusted to the last administered dose minus about 18-30U; or g) When the fasting blood glucose value of the subject before administration is 3.1-3.9mmol / L, or when the lowest or average value of the fasting peripheral blood glucose of the subject before breakfast for 3 consecutive times starting from 2 days before administration is 3.1-3.9mmol / L, the administered dose M needs to be adjusted to the last administered dose minus about 9-18U.

14. A method for treating or preventing type II diabetes, the method comprising administering about 5-400 U, about 5-350 U, about 5-about 300 U, preferably about 10-about 250 U, preferably about 20-about 200 U, preferably about 30-about 150 U, preferably about 40-about 120 U, preferably about 50-about 110 U, preferably about 50-about 100 U, preferably about 50-about 90 U, preferably about 55-about 85 U, preferably about 60-about 80 U, preferably about 60 U, about 61 U, about 62 U, about 63 U, about 64 U, about 65 U, about 66 U about 6U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, or about 80U of a compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof; or the starting dose of the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is about 2-20 times, preferably about 3-10 times, preferably about 5-7 times, preferably about 2.5 times, about 3 times, about 5 times, about 5.5 times, about 6 times, about 6.5 times, about 7 times, about 8 times, or about 9 times the dose of the previous basal insulin; After one week of administration at the initial dose, a compound of formula (I) or a pharmaceutically acceptable salt, amide or ester thereof is administered once a week according to the subject's blood sugar condition. The M administered each week is the same or different, and each is independently about 5-about 400U, preferably about 5-about 350U, preferably about 5U-about 300U, preferably about 5U-about 120U, preferably about 10-about 250U, preferably about 10-about 200U, preferably about 10-about 150U , preferably 10-about 120U, preferably 5-about 400U, preferably about 5-about 350U, preferably about 10-about 110U, preferably about 10-about 100U, preferably about 10-about 90U, preferably about 15-about 85U, preferably about 20-about 80U, preferably about 25-about 75U, preferably about 30-about 70U, preferably about 40-about 70U, preferably about 40-about 70U, preferably about 60U, about 61U, about 62U, about 63U, about 64U , about 65U, about 66U, about 67U, about 68U, about 69U, about 70U, about 71U, about 72U, about 73U, about 74U, about 75U, about 76U, about 77U, about 78U, about 79U, about 80U, about 81U, about 82U, about 83U, about 84U, about 85U, about 86U, about 87U, about 88U, about 89U, about 90U, about 91U, about 92U, about 93U, about 94U, about 95U, about 96U , about 97 U, about 98 U, about 99 U, about 100 U, about 110 U, about 120 U, about 130 U, about 140 U, ​​about 150 U, about 160 U, about 170 U, about 180 U, about 190 U, about 200 U, about 210 U, about 220 U, about 230 U, about 240 U, ​​about 250 U, about 260 U, about 270 U, about 280 U, about 290 U, or about 300 U. The dose M is adjusted weekly according to the following rules: a) When the subject's fasting blood glucose value before administration is 3.9-4.3mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 3.9-4.3mmol / L, the administered dose M needs to be adjusted to the last administered dose minus about 9-18U; or b) When the subject's fasting blood glucose value before administration is 4.4-7.2mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 4.4-7.2mmol / L, the administered dose M is the last administered dose; or c) When the subject's fasting blood glucose value before administration is 7.3-8.0mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 7.3-8.0mmol / L, the administered dose M needs to be adjusted to the last administered dose plus about 9-18U; or d) When the subject's fasting blood glucose value before administration is 8.1-9.9mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is 8.1-9.9mmol / L, the administered dose M needs to be adjusted to the last administered dose plus about 18-30U; or e) When the subject's fasting blood glucose value before administration is ≥10.0mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for 3 consecutive times starting from 2 days before administration is ≥10.0mmol / L, the administered dose M needs to be adjusted to the last administered dose plus about 18-27U; or f) When the subject's fasting blood glucose value before administration is ≤3.0mmol / L, or when the subject's lowest or average fasting peripheral blood glucose value before breakfast for three consecutive times starting from 2 days before administration is ≤3.0mmol / L, the administered dose M needs to be adjusted to the last administered dose minus about 18-30U; or g) When the fasting blood glucose value of the subject before administration is 3.1-3.9mmol / L, or when the lowest or average value of the fasting peripheral blood glucose of the subject before breakfast for 3 consecutive times starting from 2 days before administration is 3.1-3.9mmol / L, the administered dose M needs to be adjusted to the last administered dose minus about 9-18U.

15. The method according to any one of claims 1 to 14, wherein the subject With 18.5-35kg / m 2 , preferably 18.5-35kg / m 2 BMI; and / or having an HbA1c of 6.5%-10.0%, preferably 7.5%-10.0%; and / or Fasting venous blood glucose ≥7.2mmol / L; and / or Fasting blood glucose ≤ 13.9mmol / L; and / or Have been treated with one or more oral antidiabetic medications; and / or Received one or more basal insulins.

16. The method according to claim 15, wherein the oral antidiabetic drug is selected from metformin, DPP4 inhibitors, α-glucosidase inhibitors, SGLT2 inhibitors and glucokinase activators; and the basal insulin is selected from glargine insulin U100, detemir insulin, degludec insulin and intermediate-acting human insulin.

17. The method according to any one of claims 1 to 16, wherein: The subject in need thereof is simultaneously administered the same dose of oral antidiabetic drugs that the subject has been using previously.

18. The method according to any one of claims 1 to 17, wherein: The compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is administered parenterally, preferably subcutaneously.

19. The method according to any one of claims 1 to 18, wherein: The administration period of the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, is 6 weeks or more, preferably 16 weeks or more, preferably 4 months or more, preferably 8 months or more, preferably 12 months or more, preferably 16 months or more, preferably 18 months or more, preferably 24 months or more, preferably 30 months or more.

20. The method according to any one of claims 1 to 19, wherein: The subject can achieve a reduction of 0.1% or more in glycated hemoglobin after administration of the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, preferably 0.2% or more, preferably 0.3% or more, preferably 0.4% or more, preferably 0.5% or more, preferably 0.5%-30%, preferably 0.6%-25%, preferably 0.62%, 0.76%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 6.5%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 13.5%, 14%, 15%, 16%, 17%, 18%, 18.6%, 19%, or 20%; preferably, the ... The compound or its pharmaceutically acceptable salt, amide or ester can achieve a reduction of glycosylated hemoglobin by 0.1% or more, preferably 0.2% or more, preferably 0.3% or more, preferably 0.4% or more, preferably 0.5% or more, preferably 0.5%-30%, preferably 0.6%-25%, preferably 0.62%, 0.76%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 6.5%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 13.5%, 14%, 15%, 16%, 17%, 18%, 18.6%, 19%, or 20% after 6 weeks, 20 weeks, 25 weeks, 30 weeks or 35 weeks.

21. The method according to any one of claims 1 to 19, wherein: The subject can achieve a decrease in fasting blood glucose of more than 1 mM, preferably more than 1.2 mM, preferably more than 1.3 mM, preferably more than 1.4 mM, preferably more than 1.5 mM, preferably 1 mM-10 mM, preferably 1.1 mM-9.8 mM, preferably 1.2 mM, 1.3 mM, 1.37 mM, 1.4 mM, 1.5 mM, 1.57 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, 3.1 mM, 3.2 mM, 3.3 mM, 3.4 mM, 3.5 mM, 3.6 mM, 3.7 mM, 3.8 mM, 3.9 mM, 4.1 mM, 4.2 mM, 4.3 mM, 4.4 mM, 4.5 mM, 4.6 mM, 4.7 mM, 4.8 mM, 4.9 mM, 4.9 mM, 4.1 mM, 4.2 mM, 4.3 mM, 4.4 mM, 4.5 mM, 4.6 mM, 4.7 mM, 1.77mM, 1.8mM, 1.9mM, 1.97mM, 2mM, 2.1mM, 2.2mM, 2.3mM, 2.4mM, 2.5mM, 2.6mM, 2.7mM, 2.8mM, 2.9mM, 3mM, 3.5mM, 4mM, 4.5mM, 5mM, 5.5mM, 6mM, 6.5mM, 7mM, 7.5mM, 8mM, 8.5mM, or 9mM; preferably, the subject is administered formula (I) The compound or its pharmaceutically acceptable salt, amide or ester can achieve a decrease in fasting blood glucose of 1 mM or more, preferably 1.2 mM or more, preferably 1.3 mM or more, preferably 1.4 mM or more, preferably 1.5 mM or more, preferably 1 mM-10 mM, preferably 1.1 mM-9.8 mM, preferably 1.2 mM, 1.3 mM, 1.37 mM, 1.4 mM, 1.5 mM, 1.6 mM, 1.7 mM, 1.8 mM, 1.9 mM, 2.1 mM, 2.2 mM, 2.3 mM, 2.4 mM, 2.5 mM, 2.6 mM, 2.7 mM, 2.8 mM, 2.9 mM, 3.9 mM, 4.1 mM, 4.2 mM, 4.3 mM, 4.4 mM, 4.5 mM, 4.6 mM, 4.7 mM, 4.8 mM, 4.9 mM, 5.9 mM, 6.9 mM, 7.1 mM, 7.2 mM, 7.3 mM, 7.4 mM, 7.5 mM, 7.6 mM, 7.7 mM, 7.8 mM, 7.9 mM, 8. 57mM, 1.6mM, 1.7mM, 1.77mM, 1.8mM, 1.9mM, 1.97mM, 2mM, 2.1mM, 2.2mM, 2.3mM, 2.4mM, 2.5mM, 2.6mM, 2.7mM, 2.8mM, 2.9mM, 3mM, 3.5mM, 4mM, 4.5mM, 5mM, 5.5mM, 6mM, 6.5mM, 7mM, 7.5mM, 8mM, 8.5mM, or 9mM.

22. The method according to any one of claims 1 to 21, wherein: When administering the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, the subject is injected subcutaneously into the abdomen, deltoid region of the upper arm and / or thigh of the subject.

23. A medicine kit comprising: A compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, Packaging materials, and A label or package insert contained within the packaging material, the label or package insert indicating that the subject receiving treatment with the compound of formula (I), or a pharmaceutically acceptable salt, amide or ester thereof, can be treated by the method of any one of claims 1-22.

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