Method for using GIP / GLP1 coagonist for diabetes

Abstract

To solve the problems that available treatments for obesity are particularly inadequate for patients with severe obesity, and although successful treatment of obesity is associated with mitigation or prevention of T2D, alternative treatment options are needed to induce therapeutic weight loss in patients in need of treatment.SOLUTION: A method for treating type 2 diabetes comprises: a) administering to a patient a gradually increasing dose of a GIP:GLP-1 peptide having a GIP:GLP-1 receptor agonist potency ratio of about 2.5:1 to about 10:1 as measured after 60 minutes incubation using a casein cAMP assay normalized to GIP and GLP-1, for a minimum of about two weeks; and then b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a GIP:GLP-1 receptor agonist having a GIP to GLP-1 ratio of about 2.5 to about 10:1. GIP / GLP-1 coagonist compounds with a high agonist potency ratio (hereafter, GIP:GLP A method for treating type 2 diabetes (T2D) using a novel dosing regimen of LP-1 peptide Further, the present invention provides a GI drug having a GIP to GLP-1 ratio of about 2.5:1 to about 5:1. Novel Dosing of GIP:GLP-1 Peptides with P:GLP-1 Receptor Agonist Potency Ratios The present invention also provides a method for treating T2D using the GIP:GLP- The present invention provides a method for inducing remission of T2D using a novel dosing regimen of one peptide. also describes a method for treating obesity using a novel dosing regimen of GIP:GLP-1 peptide. provide. [Background technology]

[0002] The prevalence of diabetes has been increasing for the past several decades. T2DM accounts for approximately 90% of all diabetes cases. % of all diabetes mellitus patients. T2DM is primarily associated with insulin resistance. T2D is characterized by high blood sugar levels that are associated with high blood sugar levels. T2D is widespread. The long-term effects of T2D are significant. This leads to human suffering and economic costs, but also to long-term microvascular and neuropathic complications. Much of the associated morbidity can be significantly reduced with interventions that achieve blood glucose levels closer to the non-diabetic range. New classes of drugs and many combinations have been shown to lower blood glucose. Although evidence has been shown that modern management generally does not provide optimal medical outcomes for people with diabetes, The Medical Journal has reported that patients with pulmonary embolism are unable to achieve and maintain maximal blood glucose levels. Management of Hyperglycemia in Type 2 Di abetes:A Consensus Algorithm for the Ini tiation and Adjustment of Therapy,DIABET ES CARE,VOLUME 32:193-203;,NUMBER 1,JANU ARY 2009. American Diabetes Assoc The guidelines for the National Institute of Diabetes Care (NIHC) recommend a prediabetic level of 5.7-6.1% (39- It is recommended to use an HbA1c range of 39-47mmol / mol. 7mmol / mol). American Diabetes Association ,Diabetes Care.2018 January;41 (Suppleme nt 1):S55-S64. Treatments that can help people with T2D achieve their glycemic goals There is a great need for a method.

[0003] It is well known that GLP1 treatment is associated with nausea, vomiting, and / or diarrhea. For example, one study found that all GLP-1 receptor agonist regimens were associated with low rates of gastrointestinal adverse events. Diabetes Technol The r.2015 Jan;17(1):35-42.

[0004] Endogenous GIP exerts potent insulinotropic effects in healthy subjects, but GIP severely reduced insulinotropic action of and GIP-dependent enhancement of postprandial glucagon response have hindered the development of GIP-based therapies for T2D. .al.,GIP and GLP-1,the two incretin horm ones:Similarities and differences;Journa l of Diabetes Investigation,Volume 1 Iss ue 1 / 2(February / April 2010)(8-23)p 16.

[0005] Also a GIP / GLP1 coagonist with balanced GIP / GLP1 potency The compound has been preclinical tested and tolerability at high doses is limited by gastrointestinal adverse events It was found that Portron, A. et al. cs,pharmacokinetics,safety and tolerabil ity of the novel dual glucose-dependent insulinotropic polypeptide / glucagon-like peptide-1 agonist RG7697 after single s ubcutaneous administration in healthy su bjects.”Diabetes Obes.Metab.2017;19:1446 -1453. Finan, B. et al. “Unimolecular dual i ncretins maximize metabolic benefits in rodents,monkeys,and humans.”Sci Trans Me d.2013;5(209):209ra151. Dose limitations related to gastrointestinal adverse events were , which may prevent dosing to the desired effective amount and may reduce patient compliance with treatment. These may impair the patient's ability to heal and limit the effectiveness of treatment regimens.

[0006] Treatment for T2D includes GLP-1 receptor agonists, but currently, no GIP / GLP receptor agonists are used. There are no approved T2D treatments that report receptor coagonism. The ratio of GIP to GLP-1 receptor agonist potency for There is no available treatment that has

[0007] One GIP / GLP-1 receptor with a GIP:GLP-1 potency ratio of approximately 3.6:1 The co-agonist is known as tirzepatide. In Phase II clinical trials, Treatment with tirzepatide using weekly subcutaneous dosing containing the drug dramatically reduced HbA1c. After just 26 weeks, many patients had diabetes remission and dramatically improved weight control. .

[0008] Obesity is a complex medical disorder that leads to the excessive accumulation of adipose tissue mass. Today, obesity is It is a global public health concern associated with adverse health outcomes and morbidity. The preferred treatment for patients with obesity involves reducing excess body weight, reducing obesity-related comorbidities, and The aim of the study is to improve obesity by reducing the risk of developing obesity, and to maintain weight loss in the long term. Successful treatment of obesity has implications for mitigating or preventing T2D. There is a need for alternative treatment options to induce therapeutic weight loss in patients who need treatment. The ratio of GIP receptor agonist potency to GLP-1 receptor agonist potency is approximately 2. Compounds having a ratio of .5:1 to about 10:1 are useful for significantly improving weight management and may prevent the onset of T2D in previously obese patients susceptible to T2D.

[0009] WO 2016 / 111971 describes a compound that is said to have GLP-1 and GIP activity. WO 2013 / 164483 also describes peptides that inhibit GLP-1 and and discloses compounds that are said to have GIP activity. The present invention describes compositions containing GIP / GLP1 coagonists administered by parenteral routes. and generally discloses a wide range of dosages up to about 30 mg / person / week. 74780 is a GIP / GLP1 coactivator for the treatment of diabetes, obesity, and other conditions. US9474780 describes and discloses the use of tirzepatide. Assert. Summary of the Invention

[0010] The present invention relates to the aforementioned therapies (glycemic control To provide a novel dosing regimen of GIP:GLP-1 peptide for use in diabetes, obesity, More specifically, the present invention provides novel dosing regimens, including titration and maintenance doses. The titration dose is approximately 50% of the maintenance dose and is administered approximately once a week for a minimum of approximately 2 weeks prior to administration of the maintenance dose. In another embodiment, the dosing regimen is a first dose about 25% of the maintenance dose and a second dose about 25% of the maintenance dose. Three titration doses, one of which was approximately 50% of the maintenance dose and the third was approximately 75% of the maintenance dose, and a maintenance Each titration dose, including the maintenance dose, should be administered approximately once a week for a minimum of approximately 2 weeks before administering the next higher dose. In yet a third embodiment, the dosing regimen comprises a first dose of about 17% of the maintenance dose and , the second is about 33% of the maintenance dose, the third is about 50% of the maintenance dose, and the fourth is about 50% of the maintenance dose. The first is about 66% of the initial dose and the fifth is about 83% of the maintenance dose, The dose is administered about once a week for a minimum of about two weeks prior to administration of the next higher dose. The dosage form is such that each titration dose is administered approximately once a week for approximately four weeks before the next higher dose is initiated. The dosing regimen given is as described above.

[0011] In one embodiment, the GIP:GLP-1 peptide of the invention is a peptide that is a mixture of GIP and GLP- Incubation for 60 min using the casein cAMP assay normalized to 1 When measured after administration, the GIP to GLP-1 ratio ranged from about 2.5:1 to about 10:1. In one embodiment, the GIP:GLP-1 peptide of the present invention has a potency ratio of 60 using the casein cAMP assay normalized to GIP and GLP-1 The ratio of GIP to GLP-1 was approximately 2.5:1 to approximately 2.5:1 when measured after 2 min of incubation. In one embodiment, the GIP:GL of the present invention has a receptor agonist potency ratio of 5:1. P-1 peptide inhibited casein cAMP upregulation normalized to GIP and GLP-1 GIP vs. GLP-1 as measured after 60 min of incubation using has a receptor agonist potency ratio of about 2.5:1 to about 3.5:1. The GIP:GLP-1 peptides of the present invention are normalized to GIP and GLP-1. The cAMP concentration was measured after 60 min of incubation using a casein cAMP assay. and has a receptor agonist potency ratio of GIP to GLP-1 of about 2.5:1 to about 10:1. In one embodiment, the GIP:GLP-1 peptide of the present invention comprises GIP and GLP- Using the casein cAMP assay normalized to 1, the in vitro assay was performed at 37°C for 60 min. When measured after incubation, the ratio of GIP to GLP-1 ranged from about 2.5:1 to about 10:1. It has a receptor agonist potency ratio.

[0012] Thus, the present invention provides a method for treating type 2 diabetes in a patient in need thereof. This involves administering titrated doses of the GIP:GLP-1 peptide for approximately two weeks, followed by IP: Administering a maintenance dose of GLP-1 peptide, the titration dose being Approximately 50% of the GIP:GLP-1 peptide is normal to GIP and GLP-1. Measured after 60 min incubation using a modified casein cAMP assay When administered intravenously, the GIP to GLP-1 ratio is about 2.5:1 to about 10:1. The ratio is:

[0013] The present invention further provides a method for improving glycemic control in a patient in need thereof. This involves administering titrated doses of the GIP:GLP-1 peptide for approximately two weeks, followed by IP: Administering a maintenance dose of GLP-1 peptide, the titration dose being Approximately 50% of the GIP:GLP-1 peptide is normal to GIP and GLP-1. Measured after 60 min incubation using a modified casein cAMP assay When administered intravenously, the GIP to GLP-1 ratio is about 2.5:1 to about 10:1. The ratio is:

[0014] Additionally, the present invention provides a method for improving weight management in a patient in need thereof, The patients were administered titrated doses of the GIP:GLP-1 peptide for approximately 2 weeks, after which the GIP: and administering a maintenance dose of the GLP-1 peptide, the titration dose being about 50% of the maintenance dose. %, and GIP:GLP-1 peptides were normalized to GIP and GLP-1. The cAMP concentration was measured after 60 min of incubation using a casein cAMP assay. and has a receptor agonist potency ratio of GIP to GLP-1 of about 2.5:1 to about 10:1. do.

[0015] Additionally, the present invention provides a method for treating chronic kidney disease in a patient in need thereof, This involves administering titrated doses of the GIP:GLP-1 peptide for approximately 2 weeks, followed by : administering a maintenance dose of a GLP-1 peptide, the titration dose being about 5 times the maintenance dose. 0%, and the GIP:GLP-1 peptide was normalized to GIP and GLP-1. Measured after 60 min incubation using a modified casein cAMP assay When the GIP to GLP-1 receptor agonist potency ratio is about 2.5:1 to about 10:1, Yes.

[0016] Additionally, the present invention provides a method for treating atherosclerosis in a patient in need thereof. This involves administering titrating doses of the GIP:GLP-1 peptide for approximately two weeks, followed by administering a maintenance dose of the GIP:GLP-1 peptide, the titration dose being The GIP:GLP-1 peptide was approximately 50% of the dose of GIP and GLP-1. After 60 min of incubation using a casein cAMP assay normalized to When measured, the ratio of GIP to GLP-1 is about 2.5:1 to about 10:1. It has a potency ratio of 1:1.

[0017] Additionally, the present invention provides a method for treating NAFLD in a patient in need thereof, This involves administering titrated doses of the GIP:GLP-1 peptide for approximately 2 weeks, followed by : administering a maintenance dose of a GLP-1 peptide, the titration dose being about 5 times the maintenance dose. 0%, and the GIP:GLP-1 peptide was normalized to GIP and GLP-1. Measured after 60 min incubation using a modified casein cAMP assay When the GIP to GLP-1 receptor agonist potency ratio is about 2.5:1 to about 10:1, Yes.

[0018] Additionally, the present invention provides a method for treating NASH in a patient in need thereof, The patients were administered titrated doses of the GIP:GLP-1 peptide for approximately 2 weeks, after which the GIP: and administering a maintenance dose of the GLP-1 peptide, the titration dose being about 50% of the maintenance dose. %, and GIP:GLP-1 peptides were normalized to GIP and GLP-1. The cAMP concentration was measured after 60 min of incubation using a casein cAMP assay. and has a receptor agonist potency ratio of GIP to GLP-1 of about 2.5:1 to about 10:1. do.

[0019] Further, the present invention relates to a method for curing diabetes, inducing remission or regression of diabetes, or preventing the progression of diabetes. It provides a method for providing prophylaxis to patients in need thereof, including the administration of the GIP:GLP-1 peptide A titrated dose of the GIP:GLP-1 peptide is administered for approximately 2 weeks, followed by a maintenance dose of the GIP:GLP-1 peptide. The titration dose is approximately 50% of the maintenance dose, and the GIP:GLP-1 peptide is The peptides were assayed using a casein cAMP assay normalized to GIP and GLP-1. When measured after 60 min of incubation with It has a receptor agonist potency ratio that is between 5:1 and about 10:1.

[0020] A further embodiment of the invention provides three titration doses starting with a 25% dose (approximately 25% of the maintenance dose). %, ~50%, and ~75%) were administered, and each titration dose was initiated with the next higher dose. The method of claim 1, wherein the 17% Five titration doses starting with doses of approximately 17%, 33%, 50%, 66%, and 70% of the maintenance dose and approximately 83%) are administered, with each titration dose being administered for approximately 2 weeks before administration of the next higher dose. A further embodiment of the invention is a method of administering a titrated dose or doses of a compound having the same or similar properties as the next higher dose. The method according to claim 1, wherein the administration of the compound is started about four weeks before the start of administration of the compound.

[0021] Further aspects of the present invention include the treatment of type 2 diabetes, improving glycemic control, improving weight management, For the treatment of chronic kidney disease, treatment of NAFLD, treatment of NASH, and for curing diabetes or to induce remission or regression of diabetes or to prevent diabetes. The method described above uses GIP:GLP-1 peptides that are expressed as normal peptides for GIP and GLP-1. Measured after 60 min incubation using a modified casein cAMP assay When administered intravenously, the GIP:GLP-1 receptor agonist potency ratio is about 2.5:1 to about 5:1. Further aspects of the present invention include the treatment of type 2 diabetes, improving glycemic control, weight management, and the like. for improving metabolic processes, for treating chronic kidney disease, for treating NAFLD, for treating NASH, or for to cure diabetes, induce remission or regression of diabetes, or prevent diabetes The method for the treatment of atopic dermatitis, wherein the GIP:GLP-1 peptide is a mixture of GIP and GLP-1. After 60 min of incubation using the casein cAMP assay normalized to When measured after treatment, the GIP:GLP-1 receptor ratio was about 2.5:1 to about 3.5:1. agonist efficacy ratio.

[0022] Further aspects of the invention include the treatment of type 2 diabetes, improving glycemic control, and improving weight management. for the treatment of chronic kidney disease, for the treatment of NAFLD, for the treatment of NASH, or for diabetes for curing, inducing remission or regression of diabetes, or preventing diabetes The method according to claim 1, wherein the GIP:GLP-1 peptide is a compound of SEQ ID NO:3 or Another aspect of the present invention is the use of the compound as a medicament for the treatment of type 2 diabetes, glycemic control, and the like. for improving blood flow, improving weight management, treating chronic kidney disease, treating NAFLD, treating NASH or to cure diabetes, induce remission or regression of diabetes, or improve The above method for preventing diabetes, wherein the GIP:GLP-1 peptide is represented by SEQ ID NO: No. 3 or a pharma- ceutically acceptable salt thereof, Clinically acceptable salts are casein cAMP normalized to GIP and GLP-1 Approximately 2.5:1 as measured after 60 min incubation using the assay It has a GIP:GLP-1 receptor agonist potency ratio of about 5:1. is used to treat type 2 diabetes, improve blood sugar control, improve weight management, treat chronic kidney disease, For the treatment of NAFLD, for the treatment of NASH, or to cure or alleviate diabetes The above-mentioned method for inducing resolution or regression or preventing diabetes, The GIP:GLP-1 peptide is the compound of SEQ ID NO:3 or a pharma- ceutically acceptable salt thereof. The compound of SEQ ID NO:3 or a pharma- ceutically acceptable salt thereof inhibits GIP and GLP-1 After 60 min of incubation using the casein cAMP assay normalized to When measured after treatment, the GIP:GLP-1 receptor ratio was about 2.5:1 to about 3.5:1. agonist efficacy ratio.

[0023] In embodiment 1(a), the present invention provides a method for treating type 2 diabetes in a patient in need thereof. The present invention provides a method for a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrated doses of a peptide to said patient; and thereafter b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0024] In embodiment 1(b), the present invention provides a method for treating type 2 diabetes in a patient in need thereof. The present invention provides a method for a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0025] In embodiment 1(c), the present invention provides a method for treating type 2 diabetes in a patient in need thereof. The present invention provides a method for a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering to said patient a fifth titrated dose of said GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0026] In embodiment 1(a1), the present invention provides a method for administering to a patient in need of treatment for type 2 diabetes. A method is provided for doing this, including: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after a 60-minute incubation in a 10-mL PBS-containing 10-mL PBS buffer, the results were GIP having a GIP:GLP-1 receptor agonist potency ratio of .5:1 to about 10:1. administering a titrated dose of a GLP-1 peptide subcutaneously to the patient, and then b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0027] In embodiment 1(b1), the present invention provides a method for administering to a patient in need of treatment for type 2 diabetes. A method is provided for doing this, including: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after a 60-minute incubation in a 10-mL PBS-containing 10-mL PBS buffer, the results were GIP having a GIP:GLP-1 receptor agonist potency ratio of .5:1 to about 10:1. administering a first titrated dose of a GLP-1 peptide subcutaneously to the patient; and then b) a second titrated dose of the GIP:GLP-1 peptide about once a week for a minimum of about 2 weeks. subcutaneously administering to said patient; and thereafter c) a third titrated dose of the GIP:GLP-1 peptide about once a week for a minimum of about 2 weeks. subcutaneously administering to said patient; and thereafter d) administering a maintenance dose of the GIP:GLP-1 peptide subcutaneously to the patient. Rarely, The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0028] In embodiment 1(c1), the present invention provides a method for administering to a patient in need of treatment for type 2 diabetes. A method is provided for doing this, including: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after a 60-minute incubation in a 10-mL PBS-containing 10-mL PBS buffer, the results were GIP having a GIP:GLP-1 receptor agonist potency ratio of .5:1 to about 10:1. administering a first titrated dose of a GLP-1 peptide subcutaneously to the patient; and then b) a second titrated dose of the GIP:GLP-1 peptide about once a week for a minimum of about 2 weeks. subcutaneously administering to said patient; and thereafter c) a third titrated dose of the GIP:GLP-1 peptide about once a week for a minimum of about 2 weeks. subcutaneously administering to said patient; and thereafter d) a fourth titrated dose of the GIP:GLP-1 peptide about once a week for a minimum of about two weeks. subcutaneously administering to said patient; and thereafter e) a fifth titration dose of the GIP:GLP-1 peptide about once a week for a minimum of about two weeks. subcutaneously administering to said patient; and thereafter f) administering a maintenance dose of the GIP:GLP-1 peptide subcutaneously to said patient. Rarely, The first titration dose is about 17% of the maintenance dose and the second titration dose is about 33% of the maintenance dose. %, the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. the fifth titration dose is about 66% of the maintenance dose, and the fifth titration dose is about 83% of the maintenance dose.

[0029] In embodiment 2(a), the present invention provides a method for treating a patient in need of improved glycemic control. The method for doing this is provided by: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrated doses of a peptide to said patient; and thereafter b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0030] In embodiment 2(a), the present invention provides a method for treating a patient in need of improved glycemic control. The method for doing this is provided by: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrated doses of a peptide to said patient; and thereafter b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0031] In embodiment 2(b), the present invention provides a method for treating a patient in need of improved glycemic control. The method for doing this is provided by: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0032] In embodiment 2(c), the present invention provides a method for treating a patient in need of improved glycemic control. The method for doing this is provided by: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering to said patient a fifth titrated dose of said GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0033] In embodiment 3(a), the present invention provides improved weight management for a patient in need thereof. A method is provided, comprising: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrated doses of a peptide to said patient; and thereafter b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0034] In embodiment 3(b), the present invention provides improved weight management for a patient in need thereof. A method is provided, comprising: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0035] In embodiment 3(c), the present invention provides improved weight management for a patient in need thereof. A method is provided, comprising: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering to said patient a fifth titrated dose of said GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0036] In embodiment 4(a), the present invention provides a method for treating chronic kidney disease in a patient in need thereof. The present invention provides a method for a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrated doses of a peptide to said patient; and thereafter b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0037] In embodiment 4(b), the present invention provides a method for treating chronic kidney disease in a patient in need thereof. The present invention provides a method for a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0038] In embodiment 4(c), the present invention provides a method for treating chronic kidney disease in a patient in need thereof. The present invention provides a method for a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering to said patient a fifth titrated dose of said GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0039] In embodiment 5(a), the present invention provides a method for treating NAFLD in a patient in need thereof. The present invention provides a method for a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrated doses of a peptide to said patient; and thereafter b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0040] In embodiment 5(b), the present invention provides a method for treating NAFLD in a patient in need thereof. The present invention provides a method for a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0041] In embodiment 5(c), the present invention provides a method for treating NAFLD in a patient in need thereof. The present invention provides a method for a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering to said patient a fifth titrated dose of said GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0042] In embodiment 6(a), the present invention provides a method for treating NASH in a patient in need thereof. A method is provided, comprising: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrated doses of a peptide to said patient; and thereafter b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0043] In embodiment 6(b), the present invention provides a method for treating NASH in a patient in need thereof. A method is provided, comprising: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0044] In embodiment 6(c), the present invention provides a method for treating NASH in a patient in need thereof. A method is provided, comprising: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering to said patient a fifth titrated dose of said GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0045] In embodiment 7(a), the present invention provides a method for curing diabetes, inducing remission or regression of diabetes. and providing a method for preventing the onset or development of diabetes to a patient in need thereof, the method comprising: to cure, induce remission or regression of, or prevent diabetes , a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrated doses of a peptide to said patient; and thereafter b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0046] In embodiment 7(b), the present invention relates to a method for curing diabetes, inducing remission or regression of diabetes. and providing a method for preventing the onset or development of diabetes to a patient in need thereof, the method comprising: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0047] In embodiment 7(c), the present invention relates to a method for curing diabetes, inducing remission or regression of diabetes. and providing a method for preventing the onset or development of diabetes to a patient in need thereof, the method comprising: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering to said patient a fifth titrated dose of said GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0048] In embodiment 8, embodiments 1(a) to (c), 2(a) to (c), and 3(a) to (c) ), 4(a)~(c), 5(a)~(c), 6(a)~(c), or 7(a)~(c) Each titration dose is administered for approximately four weeks before the next higher dose is initiated. Thus, for example, the present invention provides in embodiment 1(d) a method for treating type 2 diabetes. Provide patients with the means to do so, including: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation, the ratio of GIP:GLP-1 peptide with a GIP:GLP-1 receptor agonist potency ratio of 1:1. administering to the patient a first titrated dose of a vasodilator, and thereafter b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0049] The present invention therefore relates in embodiment 1(e) to a patient in need of treatment for type 2 diabetes. The present invention further provides a method for a user to do so, including: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation, the ratio of GIP:GLP-1 peptide with a GIP:GLP-1 receptor agonist potency ratio of 1:1. administering to the patient a first titrated dose of a vasodilator, and thereafter b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for about four weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for about four weeks. And then, d) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0050] The present invention therefore relates in embodiment 1(f) to a patient in need of treatment for type 2 diabetes. The present invention further provides a method for a user to do so, including: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation, the ratio of GIP:GLP-1 peptide with a GIP:GLP-1 receptor agonist potency ratio of 1:1. administering to the patient a first titrated dose of a vasodilator, and thereafter b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for about four weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for about four weeks. And then, d) administering to the patient a fourth titrated dose of the GIP:GLP-1 peptide for about four weeks. And then, e) administering to the patient a fifth titrated dose of the GIP:GLP-1 peptide for about four weeks. And then, f) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0051] In embodiment 9, embodiments 1(a) to (c), 2(a) to (c), and 3(a) to (c) ), 4(a)~(c), 5(a)~(c), 6(a)~(c), 7(a)~(c), and The GIP:GLP-1 peptide of claim 8 is a compound of SEQ ID NO:3, or a pharma- ceutically acceptable derivative thereof. Thus, for example, the present invention provides in embodiment 1(g) a salt of and providing a method for treating a patient in need thereof, the method including: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation, the ratio of GIP:GLP-1 peptide with a GIP:GLP-1 receptor agonist potency ratio of 1:1. administering to the patient a first titrated dose of a GIP:GLP-1 peptide; , a compound of SEQ ID NO: 3, and thereafter b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0052] The present invention therefore relates in embodiment 1(h) to a patient in need of treatment for type 2 diabetes. The present invention further provides a method for a user to do so, including: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation, the ratio of GIP:GLP-1 peptide with a GIP:GLP-1 receptor agonist potency ratio of 1:1. administering to the patient a first titrated dose of a GIP:GLP-1 peptide; , a compound of SEQ ID NO: 3, and thereafter b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for about four weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for about four weeks. And then, d) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0053] The present invention therefore relates in embodiment 1(i) to a patient in need of treatment for type 2 diabetes. The present invention further provides a method for a user to do so, including: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation, the ratio of GIP:GLP-1 peptide with a GIP:GLP-1 receptor agonist potency ratio of 1:1. administering to the patient a first titrated dose of a GIP:GLP-1 peptide; , a compound of SEQ ID NO: 3, and thereafter b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for about four weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for about four weeks. And then, d) administering to the patient a fourth titrated dose of the GIP:GLP-1 peptide for about four weeks. And then, e) administering to the patient a fifth titrated dose of the GIP:GLP-1 peptide for about four weeks. And then, f) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0054] In embodiment 10, embodiments 1(a) to (c), 2(a) to (c), 3(a) to ( c), 4(a)~(c), 5(a)~(c), 6(a)~(c), 7(a)~(c), 8 or 9 GIP:GLP-1 peptides, with a GIP to GLP-1 ratio ranging from 2.5:1 to about 5: It has a receptor agonist potency ratio that is 1.

[0055] In embodiment 11, embodiments 1(a) to (c), 2(a) to (c), 3(a) to ( c), 4(a)~(c), 5(a)~(c), 6(a)~(c), 7(a)~(c), 8 , 9, or 10 GIP:GLP-1 peptides provide a GIP to GLP-1 ratio of 2.5:1 to It has a receptor agonist potency ratio of approximately 3.5:1.

[0056] In embodiment 12(a), the present invention provides a method for administering to a patient in need of treatment for type 2 diabetes. The present invention relates to a method for the treatment of atopic dermatitis, comprising administering to a subject a drug comprising administering to said subject a GIP:GLP-1 peptide or a pharma- ceutical acceptable salt thereof, The present invention provides for the use of salts which a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrated doses of a peptide to said patient; and thereafter b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0057] In embodiment 12(b), the present invention provides a method for administering to a patient in need of treatment for type 2 diabetes. The present invention relates to a method for the treatment of atopic dermatitis, comprising administering to a subject a drug comprising administering to said subject a GIP:GLP-1 peptide or a pharma- ceutical acceptable salt thereof, The present invention provides a method for the preparation of a salt comprising the steps of: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0058] In embodiment 12(c), the present invention provides a method for administering to a patient in need of treatment for type 2 diabetes. The present invention relates to a method for the treatment of atopic dermatitis, comprising administering to a subject a drug comprising administering to said subject a GIP:GLP-1 peptide or a pharma- ceutical acceptable salt thereof, The present invention provides for the use of salts which a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering to said patient a fifth titrated dose of said GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0059] In embodiment 13(a), the present invention provides a method for treating a patient in need of improved glycemic control. and the like. In the manufacture of a medicament for doing so, The use of acceptable salts is provided, including: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrated doses of a peptide to said patient; and thereafter b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0060] In embodiment 13(b), the present invention provides a method for treating a patient in need of improved glycemic control. and the like. In the manufacture of a medicament for doing so, The use of acceptable salts is provided, including: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0061] In embodiment 13(c), the present invention provides a method for treating a patient in need of improved glycemic control. and the like. In the manufacture of a medicament for doing so, The use of acceptable salts is provided, including: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering to said patient a fifth titrated dose of said GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0062] In embodiment 14(a), the present invention provides improved weight management for a patient in need thereof. The present invention relates to a method for the treatment of atopic dermatitis, comprising administering to a patient a therapeutically effective amount of a GIP:GLP-1 peptide or a pharma- ceutical The present invention provides a method for the preparation of a salt comprising the steps of: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrated doses of a peptide to said patient; and thereafter b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0063] In embodiment 14(b), the present invention provides improved weight management for a patient in need thereof. The present invention relates to a method for the treatment of atopic dermatitis, comprising administering to a patient a therapeutically effective amount of a GIP:GLP-1 peptide or a pharma- ceutical The present invention provides a method for the preparation of a salt comprising the steps of: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0064] In embodiment 14(c), the present invention provides improved weight management for a patient in need thereof. The present invention relates to a method for the treatment of atopic dermatitis, comprising administering to a patient a therapeutically effective amount of a GIP:GLP-1 peptide or a pharma- ceutical The present invention provides a method for the preparation of a salt comprising the steps of: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering to said patient a fifth titrated dose of said GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0065] In embodiment 15(a), the present invention provides a method for administering to a patient in need of treatment for chronic kidney disease. The present invention relates to a method for the treatment of atopic dermatitis, comprising administering to a subject a drug comprising administering to said subject a GIP:GLP-1 peptide or a pharma- ceutical acceptable salt thereof, The present invention provides a method for the preparation of a salt comprising the steps of: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrated doses of a peptide to said patient; and thereafter b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0066] In embodiment 15(b), the present invention provides a method for administering to a patient in need of treatment for chronic kidney disease. The present invention relates to a method for the treatment of atopic dermatitis, comprising administering to a subject a drug comprising administering to said subject a GIP:GLP-1 peptide or a pharma- ceutical acceptable salt thereof, The present invention provides a method for the preparation of a salt comprising the steps of: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0067] In embodiment 15(c), the present invention provides a method for administering to a patient in need of treatment for chronic kidney disease. The present invention relates to a method for the treatment of atopic dermatitis, comprising administering to a subject a drug comprising administering to said subject a GIP:GLP-1 peptide or a pharma- ceutical acceptable salt thereof, The present invention provides a method for the preparation of a salt comprising the steps of: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering to said patient a fifth titrated dose of said GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0068] In embodiment 16(a), the present invention provides a method for administering to a patient in need of treatment for NAFLD. The present invention relates to a method for the treatment of atopic dermatitis, comprising administering to a subject a drug comprising administering to said subject a GIP:GLP-1 peptide or a pharma- ceutical acceptable salt thereof, The present invention provides a method for the preparation of a salt comprising the steps of: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrated doses of a peptide to said patient; and thereafter b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0069] In embodiment 16(b), the present invention provides a method for administering to a patient in need of treatment for NAFLD. The present invention relates to a method for the treatment of atopic dermatitis, comprising administering to a subject a drug comprising administering to said subject a GIP:GLP-1 peptide or a pharma- ceutical acceptable salt thereof, The present invention provides a method for the preparation of a salt comprising the steps of: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0070] In embodiment 16(c), the present invention provides a method for administering to a patient in need of treatment for NAFLD. The present invention relates to a method for the treatment of atopic dermatitis, comprising administering to a subject a drug comprising administering to said subject a GIP:GLP-1 peptide or a pharma- ceutical acceptable salt thereof, The present invention provides a method for the preparation of a salt comprising the steps of: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering to said patient a fifth titrated dose of said GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0071] In embodiment 17(a), the present invention provides a method for treating NASH in a patient in need thereof. The present invention relates to a method for the treatment of atopic dermatitis, comprising administering to a patient a therapeutically effective amount of a GIP:GLP-1 peptide or a pharma- ceutical The present invention provides a method for the preparation of a salt comprising the steps of: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrated doses of a peptide to said patient; and thereafter b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0072] In embodiment 17(b), the present invention provides a method for treating NASH in a patient in need thereof. The present invention relates to a method for the treatment of atopic dermatitis, comprising administering to a patient a therapeutically effective amount of a GIP:GLP-1 peptide or a pharma- ceutical The present invention provides a method for the preparation of a salt comprising the steps of: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0073] In embodiment 17(c), the present invention provides a method for treating NASH in a patient in need thereof. The present invention relates to a method for the treatment of atopic dermatitis, comprising administering to a patient a therapeutically effective amount of a GIP:GLP-1 peptide or a pharma- ceutical The present invention provides a method for the preparation of a salt comprising the steps of: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering to said patient a fifth titrated dose of said GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0074] In embodiment 18(a), the present invention provides a method for inducing remission or regression of diabetes, or for preventing diabetes. GIP:GLP- in the manufacture of medicines to prevent diabetes in patients who need it The present invention provides a use of a peptide or a pharma- ceutically acceptable salt thereof, comprising: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrated doses of a peptide to said patient; and thereafter b) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The titration dose is approximately 50% of the maintenance dose.

[0075] In embodiment 18(b), the present invention relates to a method for inducing remission or regression of diabetes, or for preventing diabetes. GIP:GLP- in the manufacture of medicines to prevent diabetes in patients who need it The present invention provides a use of a peptide or a pharma- ceutically acceptable salt thereof, comprising: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0076] In embodiment 18(c), the present invention provides a method for inducing remission or regression of diabetes, or for preventing diabetes. GIP:GLP- in the manufacture of medicines to prevent diabetes in patients who need it The present invention provides a use of a peptide or a pharma- ceutically acceptable salt thereof, comprising: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first titrated dose of a peptide; and then b) administering to the patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering to the patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, d) administering to the patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering to said patient a fifth titrated dose of said GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering to the patient a maintenance dose of the GIP:GLP-1 peptide. , The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0077] In embodiment 19, embodiments 12(a) to (c), 13(a) to (c), and 14(a )~(c), 15(a)~(c), 16(a)~(c), 17(a)~(c), or 1 Any titration dose of 8(a)-(c) should be started before the next higher dose is started. Each is administered for approximately four weeks.

[0078] In embodiment 20, embodiments 12(a) to (c), 13(a) to (c), and 14(a )~(c), 15(a)~(c), 16(a)~(c), 17(a)~(c), 18(a ) to (c), or any of the 19 GIP:GLP-1 peptides is a peptide of SEQ ID NO:3. tide, or a pharma- ceutically acceptable salt thereof. In embodiment 21, embodiments 12(a) to (c), 13(a) to (c), and 14(a) ~(c), 15(a)~(c), 16(a)~(c), 17(a)~(c), 18(a) ~(c) Either GIP:GLP-1 peptide 19 or 20 P-1 has a receptor agonist potency ratio of 2.5:1 to about 5:1.

[0079] In embodiment 22, embodiments 12(a) to (c), 13(a) to (c), and 14(a )~(c), 15(a)~(c), 16(a)~(c), 17(a)~(c), 18(a )–(c), 19, or 20 of the GIP:GLP-1 peptides were LP-1 has a receptor agonist potency ratio of 2.5:1 to about 3.5:1.

[0080] In embodiment 23(a), the present invention provides a method for administering to a patient in need of treatment for type 2 diabetes. and a pharmacopoietin for use in administering the same to a subject. The use of the salt provides: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrating doses of the peptide, and then b) administering a maintenance dose of the GIP:GLP-1 peptide; The titration dose is approximately 50% of the maintenance dose.

[0081] In embodiment 23(b), the present invention provides a method for administering to a patient in need of treatment for type 2 diabetes. and a pharmacopoietin for use in administering the same to a subject. The use of the salt provides: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering a first titrated dose of a peptide, and then b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about 2 weeks. And then, d) administering a maintenance dose of the GIP:GLP-1 peptide; The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0082] In embodiment 23(c), the present invention provides a method for administering to a patient in need of treatment for type 2 diabetes. and a pharmacopoietin for use in administering the same to a subject. The use of the salt provides: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering a first titrated dose of a peptide, and then b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about 2 weeks. And then, d) administering a fourth titrating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering a fifth titrating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering a maintenance dose of the GIP:GLP-1 peptide; The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0083] In embodiment 24(a), the present invention provides a method for treating a patient in need of improved glycemic control. For use in doing so, a GIP:GLP-1 peptide, or a pharma- ceutical acceptable salt thereof, The use of the salt is a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrating doses of the peptide, and then b) administering a maintenance dose of the GIP:GLP-1 peptide; The titration dose is approximately 50% of the maintenance dose.

[0084] In embodiment 24(b), the present invention provides a method for treating a patient in need of improved glycemic control. For use in doing so, a GIP:GLP-1 peptide, or a pharma- ceutical acceptable salt thereof, The use of the salt is a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering a first titrated dose of a peptide, and then b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about 2 weeks. And then, d) administering a maintenance dose of the GIP:GLP-1 peptide; The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0085] In embodiment 24(c), the present invention provides a method for treating a patient in need of improved glycemic control. For use in doing so, a GIP:GLP-1 peptide, or a pharma- ceutical acceptable salt thereof, The use of the salt is a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering a first titrated dose of a peptide, and then b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about 2 weeks. And then, d) administering a fourth titrating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering a fifth titrating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering a maintenance dose of the GIP:GLP-1 peptide; The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0086] In embodiment 25(a), the present invention provides improved weight management for a patient in need thereof. GIP:GLP-1 peptide, or a pharma- ceutical acceptable salt thereof, for use in This use provides: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrating doses of the peptide, and then b) administering a maintenance dose of the GIP:GLP-1 peptide; The titration dose is approximately 50% of the maintenance dose.

[0087] In embodiment 25(b), the present invention provides improved weight management for a patient in need thereof. GIP:GLP-1 peptide, or a pharma- ceutical acceptable salt thereof, for use in This use provides: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering a first titrated dose of a peptide, and then b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about 2 weeks. And then, d) administering a maintenance dose of the GIP:GLP-1 peptide; The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0088] In embodiment 25(c), the present invention provides improved weight management for a patient in need thereof. GIP:GLP-1 peptide, or a pharma- ceutical acceptable salt thereof, for use in This use provides: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering a first titrated dose of a peptide, and then b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about 2 weeks. And then, d) administering a fourth titrating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering a fifth titrating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering a maintenance dose of the GIP:GLP-1 peptide; The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0089] In embodiment 26(a), the present invention provides a method for administering to a patient in need of treatment for chronic kidney disease. and a pharmacopoietin for use in administering the same to a subject. The use of the salt provides: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrating doses of the peptide, and then b) administering a maintenance dose of the GIP:GLP-1 peptide; The titration dose is approximately 50% of the maintenance dose.

[0090] In embodiment 26(b), the present invention provides a method for administering to a patient in need of treatment for chronic kidney disease. and a pharmacopoietin for use in administering the same to a subject. The use of the salt provides: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering a first titrated dose of a peptide, and then b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about 2 weeks. And then, d) administering a maintenance dose of the GIP:GLP-1 peptide; The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0091] In embodiment 26(c), the present invention provides a method for administering to a patient in need of treatment for chronic kidney disease. and a pharmacopoietin for use in administering the same to a subject. The use of the salt provides: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering a first titrated dose of a peptide, and then b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about 2 weeks. And then, d) administering a fourth titrating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering a fifth titrating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering a maintenance dose of the GIP:GLP-1 peptide; The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0092] In embodiment 27(a), the present invention provides a method for administering to a patient in need of treatment for NAFLD. and a pharmacopoietin for use in administering the same to a subject. The use of the salt provides: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrating doses of the peptide, and then b) administering a maintenance dose of the GIP:GLP-1 peptide; The titration dose is approximately 50% of the maintenance dose.

[0093] In embodiment 27(b), the present invention provides a method for administering to a patient in need of treatment for NAFLD. and a pharmacopoietin for use in administering the same to a subject. The use of the salt provides: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering a first titrated dose of a peptide, and then b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about 2 weeks. And then, d) administering a maintenance dose of the GIP:GLP-1 peptide; The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0094] In embodiment 27(c), the present invention provides a method for administering to a patient in need of treatment for NAFLD. and a pharmacopoietin for use in administering the same to a subject. The use of the salt is a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering a first titrated dose of a peptide, and then b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about 2 weeks. And then, d) administering a fourth titrating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering a fifth titrating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering a maintenance dose of the GIP:GLP-1 peptide; The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0095] In embodiment 28(a), the present invention provides a method for treating NASH in a patient in need thereof. GIP:GLP-1 peptide, or a pharma- ceutical acceptable salt thereof, for use in This use provides: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrating doses of the peptide, and then b) administering a maintenance dose of the GIP:GLP-1 peptide; The titration dose is approximately 50% of the maintenance dose.

[0096] In embodiment 28(b), the present invention provides a method for treating NASH in a patient in need thereof. GIP:GLP-1 peptide, or a pharma- ceutical acceptable salt thereof, for use in This use provides: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering a first titrated dose of a peptide, and then b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about 2 weeks. And then, d) administering a maintenance dose of the GIP:GLP-1 peptide; The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0097] In embodiment 28(c), the present invention provides a method for treating NASH in a patient in need thereof. GIP:GLP-1 peptide, or a pharma- ceutical acceptable salt thereof, for use in This use provides: a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering a first titrated dose of a peptide, and then b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about 2 weeks. And then, d) administering a fourth titrating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering a fifth titrating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering a maintenance dose of the GIP:GLP-1 peptide; The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0098] In embodiment 29(a), the present invention provides a method for inducing remission or regression of diabetes, or for preventing diabetes. GIP:GLP-1 peptide for use in preventing diabetes in patients in need of it. The present invention provides a method for the treatment of a pulmonary edema, comprising administering to a subject a therapeutically effective amount of a pulmonary edema stimulant, or a pharma- ceutically acceptable salt thereof, the method ... the a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering titrating doses of the peptide, and then b) administering a maintenance dose of the GIP:GLP-1 peptide; The titration dose is approximately 50% of the maintenance dose.

[0099] In embodiment 29(b), the present invention relates to a method for inducing remission or regression of diabetes, or for preventing diabetes. GIP:GLP-1 peptide for use in preventing diabetes in patients in need of it. The present invention provides a method for the treatment of a pulmonary edema, comprising administering to a subject a therapeutically effective amount of a pulmonary edema stimulant, or a pharma- ceutically acceptable salt thereof, the method ... the a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering a first titrated dose of a peptide, and then b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about 2 weeks. And then, d) administering a maintenance dose of the GIP:GLP-1 peptide; The first titration dose is about 25% of the maintenance dose and the second titration dose is about 50% of the maintenance dose. and the third titration dose is about 75% of the maintenance dose.

[0100] In embodiment 29(c), the present invention relates to a method for inducing remission or regression of diabetes, or for preventing diabetes. GIP:GLP-1 peptide for use in preventing diabetes in patients in need of it. The present invention provides a method for the treatment of a pulmonary edema, comprising administering to a subject a therapeutically effective amount of a pulmonary edema stimulant, or a pharma- ceutically acceptable salt thereof, the method ... the a) Using a casein cAMP assay normalized to GIP and GLP-1 When measured after 60 minutes of incubation in 100 mL of 10 ... GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering a first titrated dose of a peptide, and then b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about 2 weeks. And then, d) administering a fourth titrating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, e) administering a fifth titrating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. And then, f) administering a maintenance dose of the GIP:GLP-1 peptide; The first titration dose is about 17% of the maintenance dose, and the second titration dose is about 33% of the maintenance dose. the third titration dose is about 50% of the maintenance dose, and the fourth titration dose is about 50% of the maintenance dose. The fifth titration dose is approximately 66% of the maintenance dose, and the fifth titration dose is approximately 83% of the maintenance dose.

[0101] In embodiment 30, embodiments 23(a) to (c), 24(a) to (c), and 25(a )~(c), 26(a)~(c), 27(a)~(c), 28(a)~(c), or 2 Any titration dose of 9(a)-(c) should be started before the next higher dose is started. Each is administered for approximately four weeks.

[0102] In embodiment 31, embodiments 23(a) to (c), 24(a) to (c), and 25(a )~(c), 26(a)~(c), 27(a)~(c), 28(a)~(c), 29(a ) to (c), or any of the 30 GIP:GLP-1 peptides is a peptide of SEQ ID NO:3. tide, or a pharma- ceutically acceptable salt thereof.

[0103] In embodiment 32, embodiments 23(a) to (c), 24(a) to (c), and 25(a )~(c), 26(a)~(c), 27(a)~(c), 28(a)~(c), 29(a )-(c), 30, or 31 of the GIP:GLP-1 peptides LP-1 has a receptor agonist potency ratio of 2.5:1 to about 5:1.

[0104] In embodiment 33, embodiments 23(a) to (c), 24(a) to (c), and 25(a )~(c), 26(a)~(c), 27(a)~(c), 28(a)~(c), 29(a )-(c), 30, or 31 of the GIP:GLP-1 peptides LP-1 has a receptor agonist potency ratio of 2.5:1 to about 3.5:1.

[0105] In embodiment 34, casein cA normalized to GIP and GLP-1 Approximately 2.5: as measured after 60 min incubation using the MP assay. GIP-GLP-1 receptor agonist potency ratio of 1 to about 10:1 A composition comprising a P-1 peptide and a pharma- ceutically acceptable excipient.

[0106] In embodiment 34(a), the composition is administered in ascending doses for at least two weeks. be.

[0107] In embodiment 34(a1), the composition is administered in ascending doses for at least 2 weeks. It is.

[0108] In embodiment 34(b), the composition is administered as a maintenance dose for at least two weeks. be.

[0109] In embodiment 35, the method is used to treat diabetes in a patient in need thereof. GIP-GLP-1 peptide for IL-1 expression and normalized to GIP and GLP-1 The cAMP concentration was measured after 60 min of incubation using a casein cAMP assay. The GIP:GLP-1 receptor potency ratio of the GIP-GLP-1 peptide is approximately 2.5:1. It is about 10:1.

[0110] In embodiment 35(a), the GIP-GLP-1 peptide of embodiment 35, The peptide is administered for a minimum of about two weeks.

[0111] In embodiment 35(b), the GIP-GLP-1 of embodiment 35 or 35(a) is The peptide is administered as at least one ascending dose for a period of at least about two weeks. do.

[0112] Further provided herein are methods for treating type 2 diabetes, chronic kidney disease, atherosclerosis, In the treatment of a condition selected from the group consisting of NALFD, NASH, and metformin. amines, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium glucose cotransporter, SGLT-2 inhibitor, growth differentiation factor 15 modulator (G DF15), peptide tyrosine modulators ("PYY"), modified insulin Amylin, a dual amylin calcitonin receptor agonist, and oxyntomody and one or more drugs selected from the group consisting of cyclophosphamide, ... and sequentially in combination with the GIP:GLP-1 peptide. is offering Metformin as a treatment for improving glycemic control and / or weight management. amines, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, nat sodium glucose cotransporter, SGLT-2 inhibitors, GDF15, PYY, modified insulin , amylin, dual amylin calcitonin receptor agonist, and OXM. GIP:GLP-1 peptide Also provided herein are methods of using glycerol in the treatment of diabetes. metformin, to induce remission or regression of diabetes or to prevent diabetes; Thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium Glucose cotransporters, SGLT-2 inhibitors, GDF15, PYY, modified insulin, amitriptyline 1 selected from lin, dual amylin calcitonin receptor agonist, and OXM GIP:GLP-1 peptides in combination with one or more drugs simultaneously, individually, and sequentially In one embodiment, the compounds of the present invention are Zindione, sulfonylurea, dipeptidyl peptidase 4 inhibitor, sodium glucose insulin cotransporter, SGLT-2 inhibitors, GDF15, PYY, modified insulin, amylin, dexamethasone and one or more selected from the group consisting of a dual amylin calcitonin receptor agonist, and OXM. It is provided in a fixed dose combination with the drug.

[0113] The present invention provides for the administration of titration doses about once a week for a minimum of about two weeks, followed by a maintenance dose. and providing a new dosing regimen, comprising administering a titration dose of about 50% of the maintenance dose. In certain embodiments, the titration doses may be administered for about four weeks. , titration doses should be approximately 10-20 minutes, as determined by the nurse, patient, and / or healthcare provider. It may be administered for more than 4 weeks.

[0114] As used herein, "treating" or "treating The term "to treat" includes the progression or severity of a symptom, condition, or disorder. This includes limiting, slowing, stopping, or reversing the speed.

[0115] As used herein, "normalized to GIP and GLP-1" refers to The natural peptides provided herein as SEQ ID NO:1 and SEQ ID NO:2 are As a control, casein was tested in the cAMP assay, and the peptide, GLP- The raw CPM data of the concentration curve of 1 or GIP was calculated by subtracting the nonspecific binding (unlabeled) from each CPM value. The binding of GLP-1 or GIP in excess was subtracted to determine nonspecific binding. The inhibition is calculated by dividing the signal by the total binding signal, which is corrected by subtracting the total binding signal. Data (curve maximum, curve minimum, IC 50 , Hill slope) nonlinear regression routines (Gened ata Screener, version 12.0.4, Genedata AG, Bas The data are analyzed using the ELISA kit (http: / / www.scientific.com / science / scientific / articles / 1013023 ...).

[0116] GIP, like GLP-1, is a 42-amino acid peptide also known as an incretin. SEQ ID NO:1) and stimulates insulin secretion from pancreatic beta cells in the presence of glucose GLP-1 plays a physiological role in glucose homeostasis by inhibiting the 36-amino acid It is an acid peptide, and its main biologically active fragment (GLP-1 7-36 ) is a 30 amino acid sequence. It is produced as a C-terminal amidated peptide (SEQ ID NO:2).

[0117] The compound of SEQ ID NO:3 provides the desired potency at each of the GIP and GLP-1 receptors. In one embodiment, the compound of SEQ ID NO: 3 inhibits desirable GIP and GLP receptors. The GIP agonist potency was measured by the casein cAMP assay. The potency is about 2.5:1 to about 10 times the GLP1 receptor potency, and the potency is measured on the day of the assay. The peptide is normalized to native GIP and GLP. The compounds have desirable GIP and GLP receptor activity and GIP agonist potency is Approximately 2.5:1-fold greater potency than GLP1 receptors as measured by in vivo cAMP assay Approximately 5-fold increase in potency was normalized to native GIP and GLP on the day of assay. do.

[0118] As used herein, a "maintenance dose" refers to a dose that is consistent with a side effect profile that supports chronic dosing. The term "effective amount" refers to an effective dose for treating a patient with A compound that, when administered in one or more doses, provides the desired effect in the patient being diagnosed or treated. An effective amount refers to the amount or dosage of GIP:GLP-1 peptide administered. Using the clinical trial descriptions provided in the sublicense, and observing the results obtained under similar circumstances In determining the effective amount for a subject, the The species, size, age, and general health of the dairy animal, any specific disease or disorder involved, and any illness or the extent, involvement or severity of the disorder, the response of the individual patient, the particular compound administered the mode of administration, the bioavailability characteristics of the administered formulation, the selected dosing regimen, the use of concomitant medications, Many factors will be taken into consideration, including but not limited to the use, .

[0119] As used herein, the terms "titration" or "titration dose(s)" also refer to , escalating or escalating dose(s) and may be interchangeable therewith.

[0120] As used herein, the term GIP vs. GLP-1 also refers to GIP:GLP- 1 and may be interchangeable therewith. Thus, "GIP to GLP-1 is approximately 2.5 ~10:1" or "GIP to GLP-1 ratio of about 2.5:1 to about 10:1" is used. In this case, it is also about 2.5 to about 10 GIP activity to 1 GLP-1 activity, or about 2. This means a GIP activity of 5 to about 10:GLP-1 activity of 1.

[0121] As used herein with reference to one or more of the GIP or GLP-1 receptors: "activity", "activate(s)", "activation" The terms "activating" and "activating" are used in conjunction with the in vitro assays described below. The compound binds to the receptor(s) as measured using assays known in the art, such as ELISA. Such activity refers to the ability of a protein to bind to and elicit a response in a protein. It can be measured in vivo using serum. GIP: Receptor for GLP-1 peptide The agonist potency ratio was determined by using a casein cAMP assay as described herein below. It is measured using.

[0122] Specific GIP:GLP-1 coagonists at each of the GIP and GLP-1 receptors The affinity of the host compound can be determined using methods known in the art, including, for example, those described in the Examples below. The level of receptor binding can be measured using known techniques and is typically expressed as Ki It is expressed as a value that is about 2.5 to about 10 times the receptor potency at the GLP-1 receptor. The GIP potency ratio was determined using the following casein cAMP assay.

[0123] In one embodiment, the pharmaceutical composition of the GIP:GLP-1 peptide is administered parenterally (e.g., For example, the composition is suitable for administration via a route other than the endothelial cell, such as subcutaneous, intravenous, intraperitoneal, intramuscular, or transdermal route. In some embodiments, pharmaceutical compositions of the GIP:GLP-1 peptide are administered orally (e.g., as tablets, Such pharmaceutical compositions and processes for preparing the same are suitable for use in pharmaceutical preparations such as pharmaceutical compositions ... Generally, this is well known in the art. (See, e.g., Remington: The Sc ience and Practice of Pharmacy(DBTroy, Editor,21st Edition,Lippincott,Williams (See, e.g., & Wilkins, 2006). In one embodiment of the present invention, The route is subcutaneous. In one embodiment of the invention, the route of administration is oral.

[0124] As used herein, "glycemic control" refers to the maintenance of a patient's HbA1c levels. "Improvement" of glycemic control refers to a decrease in HbA1c.

[0125] As used herein, "weight management" refers to the management of obesity in an individual. "Improvement" in this case refers to weight loss.

[0126] As used herein, "HbA1c" refers to the amount of hemoglobin that binds to glucose in the blood. The HbA1c level is the level of glycated hemoglobin that occurs when blood sugar levels are increased. A commonly used measure of glycemic control in people with Generally, the present invention provides improved glycemic control. results in a reduction in HbA1c. In certain embodiments, the reduction in HbA1c is For HbA1c levels resulting from treatment with lower doses of GIP:GLP-1 peptide Decreases.

[0127] As used herein, the term "administer" refers to a medical device, such as a nurse, a healthcare provider, a patient, or administration by any other individual, including self-administration under the direction of a physician. , including not only delivery into the body, but also prescribing, dispensing, or in any way assisting in delivery .

[0128] As used herein, "treatment" and "treat" refer to The terms "treatment," "treating," and the like refer to the delay in the progression of a disease or disorder. This term is intended to include the retardation or attenuation of a disorder or condition. alleviate or ameliorate one or more symptoms of a disorder or condition, even if the condition is not cured The term includes prevention of symptoms.

[0129] As used herein, "diabetes remission" refers to the use of GIP:GLP-1 peptide in the treatment of diabetes. This means that patients taking the drug achieve their glycemic control treatment goals.

[0130] As used herein, the term GIP:GLP-1 peptide refers to a ratio of approximately 2.5:1 A compound having a GIP:GLP agonist potency ratio of about 10:1 or a pharma- ceutical acceptable salt thereof. GIP:GLP-1 peptide therapy to cure diabetes is thus To prevent, reduce the severity of, or induce remission of diabetes in patients with In one embodiment, the GIP:GLP-1 peptide can be used to treat diabetes. Patients using this drug are more likely to achieve and maintain glycemic control treatment goals. In one embodiment, GIP:G is used to treat diabetes. Patients using LP-1 peptides achieved at least their glycemic control treatment goals. The goal of treatment is to achieve a cure using GIP:GLP-1 peptides and all other diabetes medications. In one embodiment, the GIP:GLP-1 peptide is used to treat diabetes. Patients taking tido-tide achieved at least their glycemic control treatment goals, which were Discontinue treatment with GIP:GLP-1 peptides and all other diabetes medications. In one embodiment, the GIP:GL Patients using P-1 peptide achieved at least their glycemic control treatment goals, The goal of treatment is to treat with GIP:GLP-1 peptides and all other diabetes medications. In one embodiment, the patient is maintained on GIP: Failure to achieve glycemic goals prior to GLP-1 peptide treatment. In one embodiment, The patient has been unable to achieve glycemic goals using oral diabetes medications. In the study, patients were unable to achieve glycemic goals using metformin treatment. In one embodiment, the patient's glycemic goal is less than about 5.7%.

[0131] As used herein, a "patient(s)" refers to a person in need of treatment for a condition or disorder. In one embodiment, the patient receives about 2.5:1 to about 10:1 GIP: From treatment with GIP:GLP-1 peptides with GLP-1 receptor agonist potency ratios A human having a disease or condition that would benefit.

[0132] As used herein, "EDTA" means ethylenediaminetetraacetic acid. As used herein, "DMSO" means dimethylsulfoxide. As used herein, "CPM" means counts per minute. When used herein, "IBMX" means 3-isobutyl-1-methylxanthine. As used in this publication, "LC / MS" means liquid chromatography / mass spectrometry. As used herein, "HTRF" means homogeneous time resolved fluorescence. As used herein, "BSA" means bovine serum albumin.

[0133] Cure diabetes, induce remission or regression of diabetes, or prevent diabetes Despite advances in the treatment of diabetes, many patients receiving such treatments have glycemic control. The present invention is directed to a method for treating GIP: Patients Treated for Diabetes with GLP1 Peptides Achieve HbA1c Goals and that such patients can maintain HbA1c goals even after discontinuation of GIP:GLP1 peptide therapy. In one embodiment, the present invention provides a method for treating diabetes that maintains the GIP:GLP1 Patients receiving peptide therapy approved for use in glycemic control or the treatment of diabetes Maintain HbA1c goals even after discontinuation of all currently administered medications. In this case, terms such as "diabetes medication" and "diabetes medication" are used to describe glycemic control or type II diabetes. In one embodiment, the term "medicinal agent" refers to an agent that has been approved by an appropriate regulatory agency for use in the treatment of a disease. In Japan, the HbA1c measurement for patients receiving treatment for diabetes is approximately 5.9% or less. In an embodiment, the patient receives at least one dose of GIP:GLP1 peptide without further administration. In one embodiment, the GIP:G Patients previously treated for diabetes with LP1 peptides were treated with additional GIP:GLP 1) Hb for at least one month without administration of peptide or any other diabetes medication In one embodiment, the patient receives additional GIP:GLP1 peptide. HbA1 for at least 6 months without administration of peptides or any other diabetes medications c Maintain target levels.

[0134] As used herein, the term "amino acid" refers to naturally occurring amino acids, and The term refers to both natural and unnatural amino acids. Amino acids are usually designated by their standard one-letter codes (e.g. , L=leucine), and alpha-methyl substituted residues of natural amino acids (e.g., α-methyl α-methyl-lysine, or αMeL, and α-methyl-lysine, or αMeK, Aminoisobutyric acid, or other specific It is illustrated using unnatural amino acids, the structures of which are shown below: [ka] [ka]

[0135] As used herein, "Orn" means ornithine. When used herein, "4Pal" means 3-(4-pyridyl)-L-alanine. As used herein, "αMeF(2F)" means alpha-methyl 2-Fl-phenylalanine. As used herein, "αMeY", "αMeK", and "αMeK" refer to MeL" stands for alpha-methyl-tyrosine, alpha-methyl-lysine, and alpha-methyl-lysine, respectively. As used herein, "e" and "D-Glu" refer to , meaning D-glutamic acid.

[0136] As used herein, "C 16 -C 22 The term "amino acid bound to a fatty acid" is attached to the fatty acid via a direct bond to the fatty acid or, preferably, via a linker This refers to any natural or unnatural amino acid having a functional group that has been chemically modified in such a way. Examples of such functional groups include an amino group, a carboxyl group, a chloro group, a bromo group, and an iodo group. , azide groups, alkynyl groups, alkenyl groups, and thiol groups. Examples of natural amino acids that contain functional groups include K (amino), C (thiol), E (carboxyl), and In one embodiment, the linked amino The acid is K.

[0137] As used herein, "C 16 -C 22 The term "fatty acid" refers to a group of fatty acids with 16 to 22 amino acids. In one embodiment, the term "carboxylic acid" is used herein to refer to a carboxylic acid having carbon atoms. C 16 -C 22 The fatty acid may be a saturated dibasic acid. In one embodiment, the fatty acid is C 20 -C 22 is 。 In one embodiment, q is selected from the group consisting of 14, 16, 18, and 20. In one embodiment, q is selected from the group consisting of: In an embodiment, q is 18. In one embodiment, q is 20.

[0138] In one embodiment, the compounds disclosed herein and specific saturated C 16 -C 22 Fatty acids include hexadecanedioic acid (C 16 diacid), heptadecanedioic acid (C 17 diacid), octadecanedioic acid (C 18 diacid), nonadecanedioic acid (C 19 diacid), eicosane Diacid (C 20 diacid), heneicosanedioic acid (C 21 diacid), docosanedioic acid (C 22 Diacid)( including branched and substituted derivatives thereof.

[0139] In one embodiment, C 16 -C 22 Fatty acids are saturated C 18 Diacid, saturated C 19 diacid, saturated Japanese C 20 In one embodiment, the compound is selected from the group consisting of diacids, and branched and substituted derivatives thereof. In terms of form, C16 -C 22 The fatty acids are stearic acid, arachidonic acid, and eicosapentaenoic acid. In one embodiment, the compound is selected from the group consisting of C 16 -C 22 Fatty acids are It is quidonic acid.

[0140] As used herein, "time extension technology" refers to peptide time extension technology, e.g. , recombinant human serum albumin ("rHSA"), polymeric sequences of amino acids ("XTEN") ), non-sulfated heparin-like carbohydrate polymers, rimer ("HEP"), hydroxyethyl starch ("HES"), llama heavy chain antibody fragment ( "VHH"), PEGylated, Fc-linked, bovine serum albumin ("BSA") (Sl eep,D.Epert Opin Drug Del (2015)12,793-8 12, Podust VN et.al.J Control.Release,201 5;ePUB, Hey, T.et.al.in: R. Kontermann (Ed.) ,Therapeutic Proteins:Strategies to Modu late their Plasma Half-Lives, Wiley-VCH V erlag Gmbh & Co. KGaA, Weinheim, Germany, 20 12, pp117-140, DeAngelis, PL, Drug Dev Deliv. ery(2013)January,12 / 31 / 2012. In one embodiment, the time The extension technique is applied using a linker group. In one embodiment, the extension technique is It is applied using 0, 1, 2, or 3 amino acids as anchors.

[0141] Has a GIP potency that is about 2.5 to about 10 times the receptor potency at the GLP-1 receptor The compounds may be used in peptide time extension technology, e.g., recombinant human serum albumin ("rHSA") ), a polymeric sequence of amino acids ("XTEN"), or peptide linkages, non-sulfated heparin-like carbohydrate polymers ("HEP"), and hydroxyl It can be further modified using ethyl starch ("HES").

[0142] In one embodiment, the formula: R1X1X2X3GTX6TSDX 10 X 11 X 12 X 13 X 14 DX 16 X 17 AX 19 X 20 X 21 X 22 X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 GIP:GLP-1 peptide of (SEQ ID NO:3) (In the formula, R1 is a modification of the N-terminal amino group, the modification being selected from the group consisting of Ac and absence , X1 is selected from the group consisting of Y, H, D-Tyr, F, desH, and desY. , X2 is selected from the group consisting of Aib, αMeP, A, P, and D-Ala; or X1 and X2 combine to form desH-ψ[NHCO]-Aib, X3 is selected from the group consisting of E, N, Aad, and cTA; X6 is selected from the group consisting of F, αMeF, and αMeF(2F); X10 are A, L, H, 3Pal, 4Pal, V, Y, E, αMeF, αMeF(2F ), I, αMeY, Q, D-His, D-Tyr, cTA, and K(2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q COH; X 11 is selected from the group consisting of S, αMeS, and D-Ser; X 12 are I, S, D-Ile, and K(2-[2-(2-amino-ethoxy)- from the group consisting of 2-(γ-Glu)-CO-(CH2)qCO2H Selected, X 13 Nle, Aib, L, αMeL, and K(2-[2-(2-amino-ethoxy) 2-(γ-Glu)-CO-(CH2)qCO2H is selected from the group consisting of X 14 is selected from the group consisting of L and K, where K is C 16 -C 22 Binds to fatty acids wherein the fatty acid is optionally linked to the K via a linker; X 16 K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, R, and and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Gl u) -CO-(CH2)qCO2H; X 17 are K, Q, I, and C 16 -C 22 A group of amino acids that bind to fatty acids wherein said fatty acid is optionally linked to said amino acid via a linker; X 19 Q, A, and K (2-[2-(2-amino-ethoxy)-ethoxy]-a cetyl)2-(γ-Glu)-CO—(CH2)qCO2H; X 20 Aib, Q, H, R, K, αMeK, and K(2-[2-(2-amino- Ethoxy]-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H is selected from the group consisting of X 21 H, Aad, D, Aib, T, A, E, I, and K(2-[2-(2-A 2-(γ-Glu)-CO-(CH2)qC OH; X 22 is selected from the group consisting of F and αMeF; X 23 are I, L, A, G, F, H, E, V, and K (2-[2-(2-amino- 2-(γ-Glu)-CO-(CH2)qCO2H is selected from the group consisting of X 24 S, Aad, D-Glu, E, Aib, H, V, A, Q, D, P, and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)- CO-(CH2)qCO2H; X 25 is selected from the group consisting of Y and αMeY; X 26 L, αMeL, and K(2-[2-(2-amino-ethoxy)-ethoxy ]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H R, X 27 are L, I, and K (2-[2-(2-amino-ethoxy)-ethoxy]-amino cetyl)2-(γ-Glu)-CO—(CH2)qCO2H; X 28are E, A, S, D-Glu, and K(2-[2-(2-amino-ethoxy) -ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)qCO2H is selected from X 29 Aib, G, A, and K (2-[2-(2-amino-ethoxy)-ethoxy] Selected from the group consisting of: 2-(γ-Glu)-CO-(CH2)qCO2H And, X 30 are C, G, G-R2 and K(2-[2-(2-amino-ethoxy)-ethoxy] [gamma-Glu]-CO-(CH2)q-CO2H Selected, X 31 is absent or PX 32 X 33 X 34 -R2 (SEQ ID NO: 4), PX 32 X3 3X 34 X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 5), PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R2 (SEQ ID NO: 6), K[(2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH2)q -CO2H]X 32 X 33 X 34 -R2 (SEQ ID NO: 7), K[(2-[2-(2-amino -ethoxy]-ethoxy]-acetyl)2-(γ-Glu)-CO-(CH)q-CO 2H]X 32 X 33 X 34X 35 X 36 X 37 X 38 X 39 -R2 (SEQ ID NO: 8), and and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γ-Gly u)-CO-(CH2)q-CO2H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 - R2 (SEQ ID NO: 9), (In the formula, X 32 is S, or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetate Chill) 2- (γ-Glu)-CO-(CH2)q-CO2H], X 33 is S, or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetate Chill) 2- (γ-Glu)-CO-(CH2)q-CO2H], X 34 are G, C, and K [(2-[2-(2-amino-ethoxy)-ethoxy]- acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H] R, X 35 A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetate Chill) 2- (γ-Glu)-CO-(CH2)q-CO2H], X 36 is P, or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetate Chill) 2- (γ-Glu)-CO-(CH2)q-CO2H], X 37is P, or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetate Chill) 2- (γ-Glu)-CO-(CH2)q-CO2H], X 38 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl L) 2- (γ-Glu)-CO-(CH2)q-CO2H], X 39 are C, S, and K[(2-[2-(2-amino-ethoxy)-ethoxy]- acetyl)2-(γ-Glu)-CO-(CH2)q-CO2H] R, X 40 C and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl] (γ-Glu)-CO-(CH)q-COH) , q is selected from the group consisting of 14, 15, 16, 17, 18, 19, and 20; R2 is a modification of the C-terminus (wherein the modification is NH2 or absent); or a pharma- ceutically acceptable salt thereof; X 30 If G-R2, then X 31 is absent, X 10 , X 12 , X 13 , X 14 , X 16 , X 17 , X 19 , X 20 , X 21 , X 23 , X 24 , X 26 , X 27 , X 28 , X 29 , X 30 , X 31 , X 32 , X 33 , X 34 , X 35 , X 36 , X 37 , X 38 , X 39 , and X 40 Among them, fatty acid-containing There can be no more than one substituting base, X 30 , X 34 , X 39 , and X 40 Of these, at most one is C, X 30 , X 34 , X 39 , and X 40 If one of is C, then X 10 , X 12 , X1 3. X 14 , X 16 , X 17 , X 19 , X 20 , X 21 , X 23 , X 24 , X 26 , X2 7. X 28 , X 29 , X 30 , X 31 , X 32 , X 33 , X 34 , X 35 , X 36 , X3 7. X 38 , X 39 , and X 40 None of the substituents contain fatty acids, GIP:GLP-1 peptides have receptor agonist efficacies ranging from about 2.5:1 to about 10:1. It has a force ratio.

[0143] A further embodiment provides a novel GIP:GLP-1 peptide of SEQ ID NO:3, The GLP-1 peptide has a GIP:GLP-1 receptor antagonist ratio of about 2.5:1 to about 5:1. A further embodiment of the present invention is a novel GIP:GLP having the same potency ratio as SEQ ID NO:3. The ratio of GIP:GLP-1 peptide is about 2.5:1 to about 3.5:1. It has a GIP:GLP-1 receptor agonist potency ratio similar to that of

[0144] The present invention uses a cAMP casein assay to measure receptor potency at the GLP-1 receptor. and the following compounds exhibiting desirable GIP potency ratios of about 2.5:1 to about 10 times greater than those of the However, these exemplary peptides are not to be construed as limiting.

[0145] Peptide synthesis - Peptide 1 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LDEK((2-[ 2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)-CO-(C H2) 18 -CO2H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSG APPPS-NH2 (sequence number 10). The structure of SEQ ID NO:10 is shown below using the standard one-letter amino acid code. Residues Aib2, αMeF(2F)6, and αMeL13, in which the structure of amino acid residues is extended; Exceptions are K17, Aib20, D-Glu24, and Ser39. [ka]

[0146] The peptide backbone of peptide 1 is fluorenylmethyloxycarbonyl (Fmoc) / t Using ert-butyl (t-Bu) chemistry, the peptides were synthesized using a Symphony X peptide synthesizer ( Synthesized by Gyros Protein Technologies, Tucson, AZ will be done.

[0147] The resin was 1% DVB cross-linked polystyrene (Fmoc- Rink-MBHA Low Loading Resin, 100-200 Mesh, EMD Millipore). Standard side chain protecting groups were used. Fmoc-Lys( Mtt)-OH is used for lysine at position 17, and Boc-Tyr(tBu)-OH) is used for lysine at position 1 Each coupling step (7 min x 2) was preceded by DMF The Fmoc group is removed using 20% ​​piperidine in 100% methanol. All the tags were prepared using Fmoc amino acids (0.3 mM), diisopropylcarbodiimide (0.9 Equimolar ratios of 0.1 mM DMSO (0.01 mM) and Oxyma (0.9 mM) were used to theoretically load The reaction is carried out at a 9-fold molar excess over the primary amine for 1 hour and the secondary amine for 3 hours. The peptide was then coupled for 3 h to a Cα-methylated amino acid. After the synthesis of the backbone is complete, the resin is thoroughly washed six times with DCM to remove any residual DMF. The Mtt protecting group of lysine 17 was removed by cleavage in DCM with 30% hexafluoroisopropanol. (Oakwood Chemicals) treatment was performed twice (40 minutes treatment x 2 times), and peptidase The tetrahydrofuran is selectively removed from the chitosan resin.

[0148] Subsequent attachment of the fatty acid linker moiety is accomplished by the use of 2-[2-(2-Fmoc-amino-ethoxy )-ethoxy]-acetic acid (Fmoc-AEEA-OH, ChemPep, Inc.), Fm oc-Glutamic acid α-t-butyl ester (Fmoc-Glu-OtBu, Ark P harm, Inc.), and eicosanedioic acid (WuXi AppTec, Shanghai, China). ai, China) in a three-fold excess of reagent (AA:PyAO P:DIPEA = 1:1:1 mol / mol) was used for each coupling of 1 hour duration. will be done.

[0149] Once synthesis is complete, wash the peptide resin with DCM and air dry thoroughly. , and incubated at room temperature for 2 h in 10 mL of cleavage cocktail (trifluoroacetic acid:water:triisopropyl The resin was filtered off and each was treated with 2 mL of free Water T ’ The combined filtrate was washed twice with FA and then diluted with a 5-fold excess of cold diethyl ether (-20°C). The crude peptide is precipitated by treatment with ether at 3500 r. Centrifuge at 400 nm for 2 min to form a solid pellet, decant the supernatant, and add the solid pellet to ether. The crude peptide is triturated twice more with 20% acetonitrile / 20 Luna 5, solubilized in 100% acetic acid / 60% water with a linear gradient of 100% acetonitrile μm phenyl-hexyl preparative column (21x250mm, Phenomenex), and and 0.1% TFA / water buffer system (30–50% acetonitrile in 60 min), R The purity of the peptides was assessed using analytical RP-HPLC. The pooling criteria are >95%. The purity of the main pool of compound 1 is 98.0%. The final main product pool was then freeze-dried, resulting in a lyophilized peptide. The molecular weight was determined by LC-MS (actual: M+3=16 57.2, calculation: M+3=1657.0).

[0150] Peptide 2 to Peptide 265 Peptide 2 (SEQ ID NO: 11) to Peptide 265 (SEQ ID NO: 14) shown in Table 1 below Compounds according to 5) are prepared essentially as described by the procedure for peptide 1.

[0151] Binding assays Glucagon (also called Gcg) is manufactured by Eli Lilly and Company. The standard sample prepared was GLP-1,7-36-NH2 (also called GLP-1). , CPC Scientific (Sunnyvale, CA, 97.2% purity, 100 100 μM aliquots in 100% DMSO. GIP1-42 (referred to as GIP ) was synthesized using peptide synthesis and HPLC chromatography as described above. Prepared at Ly Research Laboratories (purity >80%, 10 100 μM aliquots in 0% DMSO). 125 I] radiolabeled Gcg, GLP- 1, or GIP, 125 It was prepared using [I]-lactoperoxidase and Obtained from rkin Elmer (Boston, MA).

[0152] Stably transformed cell lines were constructed by subcloning the receptor cDNA into the pcDNA3 expression plasmid. Cloned and cloned into human embryonic kidney (HEK) 293 (hGcgR and hGLP-1R) or Chinese hamster ovary (CHO) (hGIPR) cells, and then Geneticin (hGLP-1R and hGIPR) or hygromycin B (hGcgR ) is prepared by selecting

[0153] Two methods are used to prepare crude cell membranes. Method 1: 50 mM Tris HCl (pH 7.5) and Roche Complete Frozen cells in hypotonic buffer containing te™ protease inhibitors (containing EDTA) The pellet is thawed on ice. Using a Ter-Elvehjem homogenizer, vortex the cell suspension 25 times. The homogenate is centrifuged at 1100 x g for 10 minutes at 4°C. The supernatant is collected and stored on ice. While storing, the pellet is resuspended in homogenization buffer and rehomogenized as above. The homogenate is centrifuged at 1100 x g for 10 minutes. The second supernatant is combined with the first. The mixture is then centrifuged at 35,000×g for 1 hour at 4° C. The resulting membrane pellet is separated into approximately 1-3 Resuspend in homogenization buffer containing protease inhibitors at 10 mg / mL and freeze in liquid nitrogen. Freeze and store in aliquots in a -80°C freezer until use.

[0154] Method 2: 50 mM Tris HCl (pH 7.5), 1 mM MgCl2, Roch e Complete™ EDTA-free protease inhibitors, and 25 units / ml Frozen cell pellets were incubated in a hypotonic buffer containing 100 mL of DNAse I (Invitrogen). Thaw the solution on ice. Using an Elvehjem homogenizer, vortex the cell suspension 20-25 times. The homogenate is centrifuged at 1800 x g for 15 minutes at 4°C. The supernatant is collected and stored on ice. While storing, the pellet was resuspended in homogenization buffer (DNAse I-free) and purified as described above. Rehomogenize. Centrifuge the homogenate at 1800 x g for 15 minutes. The supernatant is combined with the first supernatant and centrifuged for an additional 15 minutes at 1800×g. The cells are centrifuged at 25,000 x g for 30 minutes at 4°C. The resulting membrane pellet is separated by centrifugation at approximately 1-20°C. Resuspend in homogenization buffer (DNAse I-free) containing protease inhibitors at 3 mg / mL. The solution is then thawed and stored in aliquots at -80°C in a freezer until use.

[0155] Connection determination method Equilibrium binding dissociation constants (K d )teeth,[ 125 I]S Due to the high propanol content of the stock material, the results of the homologous competitive binding analysis rather than saturation binding were not consistent. The K determined for the receptor preparation d The values ​​were as follows: hGcgR( 3.9 nM), hGLP-1R (1.2 nM), and hGIPR (0.14 nM).

[0156] [ 125 I]-glucagon binding Scintillation with wheat germ agglutinin (WGA) beads (Perkin Elmer) The human Gcg receptor binding assay is performed using a selective proximity assay (SPA) format. The binding buffer was 25 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonyl HEPES pH 7.4, 2.5 mM CaCl2, 1 mM MgCl2, 0.1 % (w / v) bacitracin (Research Products), 0.003% ( (w / v) Polyoxyethylene sorbitan monolaurate (TWEEN®-20 ), and EDTA-free Roche Complete™ protease inhibitors. Thaw the peptide and Gcg and serially dilute them three-fold (10 Then, 45 μL of assay binding buffer or unlabeled Gcg counter-injection were added. Containing a control (non-specific binding or NSB, 1 μM final), Corning® Transfer 5 μL of serially diluted compounds or DMSO to a 3632 clear bottom assay plate. Next, add 50 μL of [ 125 I]-Gcg (0.15 nM final), 50 μL of human Gc gR membrane (1.5 μg / well), and 50 μL of WGA SPA beads (80–150 Add 10 μg / well of 10000 ng ... Seal, mix for 1 minute on a plate shaker (setting 6), and incubate at room temperature for 12 hours. After standing, PerkinElmer Trilux MicroBeta (registered trademark) The plate is read in a scintillation counter. Response curves show the activity of the peptides tested. Final assay concentration range is typically 1150 nM to 0.058 nM, with control Gcg at 1000 nM to 0.05 nM.

[0157] [ 125 I]-GLP-1 binding The human GLP-1 receptor binding assay was performed using a SPA format with WGA beads. The binding buffer is 25 mM HEPES, pH 7.4, 2.5 mM C aCl2, 1 mM MgCl2, 0.1% (w / v) bacitracin, 0.003% (w / v) TWEEN®-20, and EDTA-free Roche Complete Contains protease inhibitors. Peptides and GLP-1 were thawed and diluted in 100% D Serially dilute 3-fold in MSO (10-point concentration-response curve). Then, add 45 μL of the assay Binding buffer or unlabeled GLP-1 control (nonspecific binding or NSB, 0.25 μM Final) into a Corning® 3632 clear bottom assay plate containing Transfer 5 μL of serially diluted compound or DMSO. Next, transfer 50 μL of 125 I]-G LP-1 (0.15 nM final), 50 μL of human GLP-1R membrane (0.5 μg / well) , and 50 μL of WGA SPA beads (100–150 μg / well) in Biote Add with Multiflo dispenser. Seal plate and place on plate shaker. Mix for 1 minute on the plate (setting 6), incubate at room temperature for 5-12 hours, then rinse with water. KinElmer Trilux MicroBeta® Scintillation Counter The final assay concentration range of peptides tested in the response curve is , usually 1150nM-0.058nM, and the control GLP-1 is 250nM-0.013nM It is.

[0158] [125I]-GIP bond The human GIP receptor binding assay uses an SPA format with WGA beads. The binding buffer is 25 mM HEPES, pH 7.4, 2.5 mM CaCl l2, 1 mM MgCl2, 0.1% (w / v) bacitracin, 0.003% (w / v ) TWEEN®-20, and EDTA-free Roche Complete ( The peptide and GIP were thawed and diluted in 100% DMSO. Serially dilute 3-fold in 10-point concentration-response curve. Then, add 45 μL of Assay Binding Include buffer or unlabeled GIP controls (nonspecific binding or NSB, 0.25 μM final). 5 μL of each of the 5 μL plates were placed in a Corning® 3632 clear bottom assay plate. Transfer the serially diluted compound or DMSO to 50 μL of 125 I]-GIP(0. 0.75–0.15 nM final), 50 µL of human GIPR membrane (3 µg / well), and 5 Add 100 μL of WGA SPA beads (100–150 μg / well) to a Biotek Multiplate reader. Add with tiflo dispenser. Seal plate and place on plate shaker for 1 min. Mix (setting 6) and incubate at room temperature for 2.5-12 hours, then add Perkin in an Elmer Trilux MicroBeta® scintillation counter. Read the plate. The final assay concentration range of peptides tested in the response curve is typically 1150nM~0.058nM or 115nM~0.0058nM, and the control GIP was 2 50nM~0.013nM.

[0159] Normalization of binding assay data The CPM raw data of the concentration curves of peptides, Gcg, GLP-1, or GIP were The M value indicates nonspecific binding (excessive unlabeled Gcg, GLP-1, or GIP). Subtract the binding (if the binding is positive) and divide by the total binding signal corrected for non-specific binding. The inhibition rate is calculated by 4 parameters (curve maximum, curve minimum, IC 50 , Hill Slope) Nonlinear regression routine (Genedata Screener, version 12.0 4, Genedata AG, Basal, Switzerland) The affinity constant (K i ) is the formula K i =IC 50 / (1+D / K d ) based on absolute I C 50 values, where D is the concentration of the radioligand used in the experiment and I C 50 is the concentration that causes 50% inhibition of binding, and K dis the equilibrium binding solution of the radioactive ligand is the dissociation constant (see above). K i Values ​​are reported as geometric means and errors are the standard error of the mean (SE M), where n is equal to the number of independent replicates (determined by assays performed on different days). The geometric mean is calculated as follows: Geometric mean = 10 (arithmetic mean of Log Ki values)

[0160] Ki ratios for each receptor and species (Ki of native control peptide / Ki of test compound) The Ki ratio is a rapid measure of the apparent affinity of a peptide compared to a native control peptide. A Ki ratio < 1 is an indicator of the binding of the test peptide to the receptor more strongly than the native peptide. A lower affinity (higher Ki value) indicates that the test has a higher affinity for the compound. The peptide has a higher affinity (lower Ki value) for the receptor than the native peptide. This indicates that:

[0161] Example 1 cAMP pharmacological function assay in the presence of casein One additional set of cAMP assays for human GLP-1 receptor (GLP-1R), gastric inhibition HEK293 cells expressing the peptide receptor (GIPR) and glucagon receptor (GcgR) The pharmacological activity of the hGLP1R / GIPR peptide was determined by the expression of the human GLP-1 receptor ( GLP-1R), gastric inhibitory peptide receptor (GIPR), or GLP-2 receptor (GLP -2R) in a 20 μl assay volume. , 0.1% casein (Sigma catalog no. C4765), 250 μM IBMX, 1 x GlutaMAX™ (Gibco Cat. No. 35050), and 20 mM HEPES (HyClone catalog number SH30237.01), Overexpress the cell line with the test peptide in M ​​(Gibco Cat. No. 31053) Each receptor (20 μl) was treated. After 60 min incubation at room temperature, the cells were Increase in intracellular cAMP was measured using the CisBio cAMP Dynamic 2 HTRF assay. The kit (62AM4PEJ) was used to quantitatively determine the amount of cAMP-d2 conjugate ( 20 μl) and the antibody anti-cAMP-Eu3+-cryptate (20 μl). Add lysis buffer to determine cAMP levels. Incubate at room temperature for 1 hour. Afterwards, the HTRF signal was recorded using an Envision 2104 plate reader (PerkinElmer). Detect with a 60 min and 1 h incubator for each run of the assay. The two incubation steps (6 Each of the incubation periods (0 min and 1 hr) can be carried out at about room temperature or at about 37° C. Fluorescence emission was measured at 20 nm and 665 nm, and the ratio of 620 nm and 665 nm was calculated. Calculate and convert to nM cAMP per well using a cAMP standard curve. Dose-response curves were plotted against minimum (buffer only) and maximum (maximum concentration of each control ligand) values. Plotted as percentage of stimulation normalized to 1000 s (degrees) and fitted with a variable slope Analyze using 4-parameter nonlinear regression (Genedata Screener 13 EC50 is the compound's half-maximal dose simulation in the dose-response curve. Concentration. Percentage of maximum response fitted to a four-parameter logistic equation Relative EC values ​​were calculated by nonlinear regression analysis using the concentration of peptide added versus the concentration of the peptide. 50Induce values.

[0162] Casein (serum acetate) was used as a nonspecific blocker that does not interact with the fatty acid moiety of the analyte molecule. In the presence of α-glutamin, homogeneous time-resolved fluorescence measurements were performed using the examples and Assays are performed to determine the intrinsic potency of the comparator molecules. Intracellular cAMP levels are determined by extrapolation using a standard curve. Compound dose response Curves were plotted as normalized stimulations to the minimum (buffer only) and maximum (maximum concentration of each control ligand). Plotted as a percentage of total excitation and fitted with a four-parameter nonlinear regression with variable slope. Analyze using imputation fitting (Genedata Screener 13). EC5 0 is the concentration of compound that produces half-maximal simulation of the dose-response curve. Each relative EC50 value of the mean calculation is determined from the curve fitting.

[0163] Compound concentration-response curves were plotted against minimum (buffer only) and maximum (maximum concentration of each control ligand) values. ) as a percentage of stimulation normalized to the stimuli and fitted with a variable slope. Analyze using a nonlinear regression fit of the parameters (Genedata Screener 13) EC50 is the compound that simulates the half-maximal dose in the dose-response curve. is the concentration of the compound.

[0164] EC 50 Summary statistics are calculated as follows: Geometric mean: GM=10^(log 10 The arithmetic mean of EC 50 value).

[0165] Report the standard error of the mean: SEM=geometric mean×(log 10 Standard deviation conversion of EC50 (value / square root of number of executions) x 10 log e .

[0166] Logarithmic transformation uses EC that corresponds to multiplication rather than arithmetic scale. 50 The value is taken into account.

[0167] The assay was performed daily and the test peptide plus the natural ligands GIP and GLP-1, Buffer only was performed as a baseline (minimum) for each GIP and The highest concentration of the GLP-1 standards is used as the maximum value for calculations. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13]

[0168] As shown in Table 1, data normalized to baseline and native peptides The peptides synthesized were synthesized by ELISA using the cAb binding assay from human GLP-1R and GIPR in the presence of 0.1% casein. Stimulates MPs and has a GIP potency ratio that is about 2.5 to about 10 times the potency of the GLP-1 receptor do.

[0169] In one embodiment, the peptide is a cell membrane guanosine 5'-(gamma-thio)triphosphate acid-[ 35 S] (GTPγS) binding assay for GLP-1R is a partial agonist at inhibiting β-arrestin-2 recruitment, as shown by β-arrestin-2 recruitment assays. A potent GIPR / GLP-1R dual partial agonist for GLP-1R In one embodiment, the compound is a GIP:GLP-1 coagonist compound. P: A GLP-1 coagonist compound or a pharma- ceutically acceptable salt thereof, GLP-1R HEK293 cell membrane guanosine 5'-(γ-thio)triphosphate-[ 35 In the GLP-1R-induced Gα s Stimulates activation In one embodiment, the compound inhibits the GLP-1R receptor by inhibiting the guanosine 5'-(γ -thio)triphosphate-[ 35 In the [S](GTPγS) binding assay, less than 75% It is a compound that shows selective agonism and inhibits β-arrestin recruitment in GLP-CHO cells. These compounds exhibited partial agonism of 35% or less in the agonist assay.

[0170] In one embodiment, the method comprises isolating GLP-1R from HEK293 cell membrane guanosine 5'-(γ-thio ) triphosphate-[ 35 Compounds showing 75% or less partial agonism in the [S] binding assay were included. and administering an effective amount of a compound that is a GIP agonist. In one embodiment, the present invention relates to a method for treating a disease. 5'-(γ-thio)triphosphate-[ 35 S](GTPγS) binding assay Compounds that exhibit agonism are co-administered with compounds that have GIP agonist activity. In the morphology, the GLP-1R is expressed in HEK293 cell membrane guanosine 5'-(γ-thio)triphosphate acid-[ 35 Compounds that exhibit partial agonism in the [S](GTPγS) binding assay were The active agent was administered within one week before or after administration of a compound with GIP agonist activity. In one embodiment, the method for treating diabetes includes administering to a subject a GLP-CHO cell β- Compounds that show ≤35% partial agonism in the arrestin recruitment assay were included. The effect of administration of guanosine 5'-(γ-thio) agonists on the GLP-1R in HEK293 cell membranes was examined. Triphosphate-[ 35 S](GTPγS) binding assay showed partial agonism of 75% or less. The method includes administering an effective amount of a compound that

[0171] GLP-1R HEK293 cell membrane [ 35 S]GTPγS binding assay Upon ligand-induced receptor activation, the GLP-1 receptor activates the GTP-bound Gα s Increase GLP-1R-induced Gα s activation The potency of peptides to stimulate GLP-1R was measured using purified membranes from HEK293 cells expressing human GLP-1R. The assay was performed similarly to that previously described. (Bueno et al., J. Biol. Chem., (2016) 291, 10700 and Willard et al., Mol. Pharmacol. (20 12) 82, 1066). Test peptides were solubilized in DMSO and incubated at room temperature for 30 min. 1 mM HEPES pH 7.4, 50 mM NaCl, 5 mM MgCl2, 40 μg / mL ml of saponin, 0.1% BSA, and 500 pM 35 5 in S-labeled GTPγS The reaction was performed using rabbit anti-Gα s Polyclonal antibodies and Nonidet P-40 surfactant containing 0.5 mg of anti-rabbit polyvinyl beads The mixture was allowed to develop for 30 min and centrifuged at 80 × g for 10 min. Centrifuge for 1 min and then freeze using a MicroBeta TriLux device for 1 min per well. The peptide concentration-response curves were fitted to a four-parameter logistic model. Se, E.C. 50 DMSO and DMSO were used as minimum and maximum controls for the receptor. Normalization of data to % stimulation is performed using Ca and GLP-1 (7–36). mpbell et al, Assay Guidance Manual 2017) GIPR-induced Gα s The potency of the sample peptide to stimulate activation is determined. The results showed that GLP-1R-induced Gα s Regarding activation, the part for GLP-1R Peptides that are selective agonists are identified.

[0172] GLP-1R CHO cell β-arrestin recruitment assay Activated G protein-coupled receptors bind to the β-arrestin family of signaling proteins. Peptide inhibitors for GLP-1R-induced arrestin recruitment The efficacy of PathHunter Enzyme Fragment Compleme The von Degtation method is used to determine the degree of enfeld et al.,FASEB J.,2007(14):3819-26 and Hamdouchi et al., J.Med Chem., 2016 59(2 4):10891-10916). Pro-Link tagged human GLP-1R and enzyme CHO-K1 cells expressing acceptor-tagged β-arrestin-2 were cultured using DiscoveR x and can be prepared as frozen cells for the assay. Dissolve in O and dispense using an Echo acoustic dispenser (LabCyte). Dilutions are performed. The assay medium contains 0.1% w / v hydrolyzed casein (Sigma). PathHunter Cell Assay Buffer (DiscoveRx) containing 10 0 nl of peptide was dispensed into 10 μl of assay medium in a 384-well plate and then Add 10 μl of cells in 100% medium to give 5000 cells per well. Plate 3 Incubate at 7℃ / 5% CO2 for 90 minutes, then add 10 μl of Path Add Hunter detection reagent (DiscoveRx) and incubate the plate at room temperature for 60 minutes. The peptide concentration-response curves were generated using a four-parameter logistic regression model. Fit the tick model and EC 50Calculate the potency at the minimum and maximum controls. Normalize data to % stimulation using DMSO and GLP-1 (7–36) (Campbell et al., Assay Guidance Manual al 2017). Sample peptides that stimulate GLP-1R-induced β-arrestin recruitment The assay results show that GLP-1 has a role in β-arrestin-2 recruitment. Peptides that are partial agonists for R are identified.

[0173] GIP: A clinical trial to determine the maintenance dose of GLP-1 peptide A 6-month (26-week) Phase 2 double-blind clinical trial was conducted with and without stable metformin dosing. Regardless, in patients with T2DM who have inadequate glycemic control through diet and exercise, Dulaglutide 1.5 mg administered once weekly (QW) and placebo administered QW In comparison, four dose levels of the GIP:GLP-1 peptide administered by subcutaneous injection once weekly (1 mg, 5 mg, 10 mg, and 15 mg, respectively) safety, efficacy, and PK The study is designed to assess GIP:GLP / PD using the following weekly dose escalations: The peptide dose was titrated to a maintenance dose. [Table 2]

[0174] The study also has a four-week follow-up period. In addition to efficacy, efficacy endpoints included placebo and dulaglutide 1. GIP:GL on HbA1c, FBG, weight, lipids, and waist circumference compared with 5mg The study included the effects of the P-1 peptide. The study was conducted to assess gastrointestinal tolerance, hypoglycemia, hypersensitivity reactions, and the effect of GIP:GLP-1 peptides on pancreatic safety and treatment-emergent The development of anti-drug antibodies associated with the drug will also be evaluated. A model-based dose-response analysis will be performed to assess efficacy in longer studies. This is performed to predict the likelihood of significant HbA1c reduction and weight loss.

[0175] Statistical analysis: Efficacy: The primary efficacy outcome was HbA1c change from baseline to the 26-week endpoint Sexual outcomes will be analyzed using a Bayesian dose-response model. Analyses will be population (mITT) analyses. The confirmation portion of the primary efficacy outcome in the mITT dataset will be The analysis was performed on subjects with a body mass index (BMI) of <30 kg / m 2 , ≧30kg / m 2 ), metformin Use, treatment, visit, and the interaction of treatment by visit as fixed effects, and Baseline HbA1c and post-baseline measurements with patients as random effects This is a model (MMRM).

[0176] Mean change in body weight from baseline at 12 and 26 weeks, and HbA1c at 12 weeks The mean changes from baseline in were analyzed using a dose-response model similar to the primary analysis. Patients with a weight loss of ≥ 5% or ≥ 10% and HbA1c target of ≤ 6.5% or The proportion of patients who achieved a survival rate of ≤7.0% or required rescue therapy was calculated based on the treatment and Logistic regression with a fixed effect for stratum, as well as baseline as a covariate Analyze: Baseline FBG (fasting blood glucose), SMBG (self-monitored blood glucose) levels, waist circumference Changes from baseline and mean percent changes in lipids from baseline to weeks 12 and 26 were compared. The data are analyzed using the same MMRM used in the next analysis.

[0177] GIP: A clinical trial to determine GLP-1 peptide titration schedules This involves a one-week screening period (Visit 1), followed by a one-week run-in period (Visit 2), followed by 12 weeks of treatment (Visits 3-10, including telephone visits) followed by 4 weeks of safety follow-up This is a 12-week treatment followed by a drop-out. This can be achieved by diet and exercise alone or metformin alone. In patients with type 2 diabetes who were inadequately controlled with stable medication, The efficacy and tolerability of once-weekly subcutaneous administration of GIP:GLP-1 peptide compared with placebo This is a Phase 2 study designed to investigate the effect of 100 mg / kg / day on the efficacy and safety of 100 mg / kg / day ... This was carried out to improve the scheme. [Table 3]

[0178] Amino acid sequence SEQ ID NO:1 GIP (human) YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNI TQ SEQ ID NO:2 GLP-1(7-36)(human) HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH2 SEQ ID NO:3 R1X1X2X3GTX6TSDX 10 X 11 X 12 X 13 X 14 DX 16 X 17 AX1 9X 20 X 21 X 22 X 23 X 24 X 25 X 26 X27 X 28 X 29 X 30 X 31 SEQ ID NO:4 PX 32 X 33 X 34 -R2 SEQ ID NO:5 PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R2 SEQ ID NO:6 PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R2 SEQ ID NO:7 K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-C O-(CH2)q-CO2H]X 32 X 33 X 34 -R2 SEQ ID NO:8 K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-C O-(CH2)q-CO2H]X 32 X 33 X 34 X 35 X 36 X 37 X3 8X 39 -R2 SEQ ID NO:9 K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-γGlu-C O-(CH2)q-CO2H]X 32 X 33 X 34 X 35 X 36 X 37 X3 8X 39 X 40 -R2

Claims

1. For patients who need treatment for type 2 diabetes, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient increasing doses of a peptide, and thereafter b) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; A method for treating type 2 diabetes, wherein the titration dose is about 50% of the maintenance dose. 。

2. For patients who need treatment for type 2 diabetes, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first escalating dose of a peptide; b) administering to said patient a second escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, c) administering to said patient a third escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. and thereafter, d) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; 1. A method for treating type 2 diabetes, comprising: The first escalating dose is about 25% of the maintenance dose, and the second escalating dose is about said third escalating dose being about 75% of said maintenance dose; Law.

3. For patients who need treatment for type 2 diabetes, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first escalating dose of a peptide; b) administering to said patient a second escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, c) administering to said patient a third escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, d) administering to said patient a fourth escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, e) administering to said patient a fifth escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. and thereafter, f) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; 1. A method for treating type 2 diabetes, comprising: The first escalating dose is about 17% of the maintenance dose and the second escalating dose is about 17% of the maintenance dose. said third escalating dose being about 50% of said maintenance dose; The fourth escalating dose is about 66% of the maintenance dose, and the fifth escalating dose is about 66% of the maintenance dose. The method of claim 1, wherein the amount of the

4. For patients who need improved glycemic control, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient increasing doses of a peptide, and thereafter b) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; 1. A method for improving glycemic control, comprising: The method, wherein the escalating dose is about 50% of the maintenance dose.

5. For patients who need improved glycemic control, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first escalating dose of a peptide; b) administering to said patient a second escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, c) administering to said patient a third escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. and thereafter, d) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; 1. A method for improving glycemic control, comprising: The first escalating dose is about 25% of the maintenance dose, and the second escalating dose is about said third escalating dose being about 75% of said maintenance dose; Law.

6. For patients who need improved glycemic control, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first escalating dose of a peptide; b) administering to said patient a second escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, c) administering to said patient a third escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, d) administering to said patient a fourth escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, e) administering to said patient a fifth escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. and thereafter, f) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; 1. A method for improving glycemic control, comprising: The first escalating dose is about 17% of the maintenance dose, and the second escalating dose is about said third escalating dose being about 50% of said maintenance dose; The fourth escalating dose is about 66% of the maintenance dose, and the fifth escalating dose is about 66% of the maintenance dose. The method is about 83% of the dose.

7. For patients who need improved weight management, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient increasing doses of a peptide, and thereafter b) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; 1. A method for improving weight management, comprising: The method, wherein the escalating dose is about 50% of the maintenance dose.

8. For patients who need improved weight management, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first escalating dose of a peptide; b) administering to said patient a second escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, c) administering to said patient a third escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. and thereafter, d) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; 1. A method for improving weight management, comprising: The first escalating dose is about 25% of the maintenance dose, and the second escalating dose is about said third escalating dose being about 75% of said maintenance dose; Law.

9. For patients who need improved weight management, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first escalating dose of a peptide; b) administering to said patient a second escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, c) administering to said patient a third escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, d) administering to said patient a fourth escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, e) administering to said patient a fifth escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. and thereafter, f) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; 1. A method for improving weight management, comprising: The first escalating dose is about 17% of the maintenance dose, and the second escalating dose is about said third escalating dose being about 50% of said maintenance dose; The fourth escalating dose is about 66% of the maintenance dose, and the fifth escalating dose is about 66% of the maintenance dose. The method is about 83% of the dose.

10. For patients who need treatment for chronic kidney disease, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient increasing doses of a peptide, and thereafter b) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; 1. A method for treating chronic kidney disease, comprising: The method, wherein the escalating dose is about 50% of the maintenance dose.

11. For patients who need treatment for chronic kidney disease, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first escalating dose of a peptide; b) administering to said patient a second escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, c) administering to said patient a third escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. and thereafter, d) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; 1. A method for treating chronic kidney disease, comprising: The first escalating dose is about 25% of the maintenance dose, and the second escalating dose is about said third escalating dose being about 75% of said maintenance dose; Law.

12. For patients who need treatment for chronic kidney disease, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first escalating dose of a peptide; b) administering to said patient a second escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, c) administering to said patient a third escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, d) administering to said patient a fourth escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, e) administering to said patient a fifth escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. and thereafter, f) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; 1. A method for treating chronic kidney disease, comprising: The first escalating dose is about 17% of the maintenance dose, and the second escalating dose is about said third escalating dose being about 50% of said maintenance dose; The fourth escalating dose is about 66% of the maintenance dose, and the fifth escalating dose is about 66% of the maintenance dose. The method is about 83% of the dose.

13. For patients who need treatment for NAFLD, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient increasing doses of a peptide, and thereafter b) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; 1. A method for treating NAFLD, comprising: The method, wherein the escalating dose is about 50% of the maintenance dose.

14. For patients who need treatment for NAFLD, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first escalating dose of a peptide; b) administering to said patient a second escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. After that, c) administering to said patient a third escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. and thereafter, d) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; 1. A method for treating NAFLD, comprising: The first escalating dose is about 25% of the maintenance dose, and the second escalating dose is about said third escalating dose being about 75% of said maintenance dose; Law.

15. For patients who need treatment for NAFLD, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first escalating dose of a peptide; b) administering to said patient a second escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, c) administering to said patient a third escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, d) administering to said patient a fourth escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, e) administering to said patient a fifth escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. and thereafter, f) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; 1. A method for treating NAFLD, comprising: The first escalating dose is about 17% of the maintenance dose, and the second escalating dose is about said third escalating dose being about 50% of said maintenance dose; The fourth escalating dose is about 66% of the maintenance dose, and the fifth escalating dose is about 66% of the maintenance dose. The method is about 83% of the dose.

16. For patients who need treatment for NASH, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient increasing doses of a peptide, and thereafter b) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; 1. A method for treating NASH, comprising: The method, wherein the escalating dose is about 50% of the maintenance dose.

17. For patients who need treatment for NASH, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first escalating dose of a peptide; b) administering to said patient a second escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, c) administering to said patient a third escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. and thereafter, d) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; 1. A method for treating NASH, comprising: The first escalating dose is about 25% of the maintenance dose, and the second escalating dose is about said third escalating dose being about 75% of said maintenance dose; Law.

18. For patients who need treatment for NASH, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first escalating dose of a peptide; b) administering to said patient a second escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, c) administering to said patient a third escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, d) administering to said patient a fourth escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, e) administering to said patient a fifth escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. and thereafter, f) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; 1. A method for treating NASH, comprising: The first escalating dose is about 17% of the maintenance dose, and the second escalating dose is about said third escalating dose being about 50% of said maintenance dose; The fourth escalating dose is about 66% of the maintenance dose, and the fifth escalating dose is about 66% of the maintenance dose. The method is about 83% of the dose.

19. Patients in need of a cure for diabetes, induction of remission or regression of diabetes, or prevention of diabetes To those, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient increasing doses of a peptide, and thereafter b) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; Methods for curing, inducing remission or regression of, or preventing diabetes And, The method, wherein the escalating dose is about 50% of the maintenance dose.

20. Patients in need of a cure for diabetes, induction of remission or regression of diabetes, or prevention of diabetes To those, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first escalating dose of a peptide; b) administering to said patient a second escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, c) administering to said patient a third escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. and thereafter, d) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; Methods for curing, inducing remission or regression of, or preventing diabetes And, The first escalating dose is about 25% of the maintenance dose, and the second escalating dose is about said third escalating dose being about 75% of said maintenance dose; Law.

21. Patients in need of a cure for diabetes, induction of remission or regression of diabetes, or prevention of diabetes To those, a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering to said patient a first escalating dose of a peptide; b) administering to said patient a second escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, c) administering to said patient a third escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, d) administering to said patient a fourth escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. Then, e) administering to said patient a fifth escalating dose of said GIP:GLP-1 peptide for a minimum of about two weeks. and thereafter, f) administering to said patient a maintenance dose of the GIP:GLP-1 peptide; Methods for curing, inducing remission or regression of, or preventing diabetes And, The first escalating dose is about 17% of the maintenance dose, and the second escalating dose is about said third escalating dose being about 50% of said maintenance dose; The fourth escalating dose is about 66% of the maintenance dose, and the fifth escalating dose is about 66% of the maintenance dose. The method is about 83% of the dose.

22. The escalating doses are each administered for about four weeks before the administration of the next higher dose begins. The method according to any one of claims 1 to 21, wherein

23. The GIP:GLP-1 peptide is a compound of SEQ ID NO:3, or a pharma- ceutically acceptable derivative thereof. The method according to any one of claims 1 to 22, wherein the compound is a salt thereof.

24. The GIP:GLP-1 peptide is from 2.5:1 to about 5:1 GIP to GLP-1. The method of any one of claims 1 to 23, wherein the receptor agonist potency ratio is

25. The GIP:GLP-1 peptide is from 2.5:1 to about 3.5:1 of GIP to GLP-1.

24. The method of any one of claims 1 to 23, having a receptor agonist potency ratio which is:

26. GIP:GLP-1 peptide for use in the treatment of type 2 diabetes in a patient in need thereof; or a pharma- ceutically acceptable salt thereof, wherein said use comprises a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering increasing doses of the peptide, and thereafter b) administering a maintenance dose of the GIP:GLP-1 peptide; the escalating dose being about 50% of the maintenance dose; or and pharma- ceutically acceptable salts thereof.

27. GIP:GLP-1 peptide for use in the treatment of type 2 diabetes in a patient in need thereof; or a pharma- ceutically acceptable salt thereof, wherein said use comprises a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering a first escalating dose of a peptide; thereafter b) administering a second escalating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. ,after that, c) administering a third escalating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. , and then, d) administering a maintenance dose of the GIP:GLP-1 peptide; The first escalating dose is about 25% of the maintenance dose, and the second escalating dose is about G. The third escalating dose is about 75% of the maintenance dose. IP: A GLP-1 peptide, or a pharma- ceutically acceptable salt thereof.

28. GIP:GLP-1 peptide for use in the treatment of type 2 diabetes in a patient in need thereof; or a pharma- ceutically acceptable salt thereof, wherein said use comprises a) Using a casein cAMP assay normalized to GIP and GLP-1 and a 60 minute incubation for at least about two weeks. GIP:GLP-1 with a GIP:GLP-1 receptor agonist potency ratio of 10:1 administering a first escalating dose of a peptide; thereafter b) administering a second escalating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. ,after that, c) administering a third escalating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. ,after that, d) administering a fourth escalating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. ,after that, e) administering a fifth escalating dose of the GIP:GLP-1 peptide for a minimum of about two weeks. , and then, f) administering a maintenance dose of the GIP:GLP-1 peptide; The first escalating dose is about 17% of the maintenance dose, and the second escalating dose is about said third escalating dose being about 50% of said maintenance dose; The fourth escalating dose is about 66% of the maintenance dose, and the fifth escalating dose is about 66% of the maintenance dose. 83% of the dose of the GIP:GLP-1 peptide, or a pharma- ceutically acceptable salt thereof. 。

28. 6 using a casein cAMP assay normalized to GIP and GLP-1 A GI of about 2.5:1 to about 10:1 when measured after 0 minutes of incubation. GIP:GLP-1 peptides having a GIP:GLP-1 receptor agonist potency ratio and pharmaceutical and an excipient acceptable thereto.

29. 29. The composition of claim 28, wherein the composition is administered in escalating doses for at least two weeks. thing.

30. 30. The method of claim 28 or 29, wherein the composition is administered in escalating doses for at least 4 weeks. The composition described.

31. 31. The method of claim 28, wherein the composition is administered as a maintenance dose for at least two weeks. The composition according to any one of claims 1 to 4.

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