Methods of using GIP / GLP1 co-agonists for diabetes

Abstract

The present invention provides methods of treating type 2 diabetes (T2D) using a novel dosing regimen of a GIP: GLP-1 peptide having a GIP: GLP-1 receptor agonist potency ratio of GIP to GLP-1 of from about 2.5: 1 to about 10: 1. In addition, the present invention provides methods of treating T2D using a new dosing regimen of a GIP: GLP-1 peptide having a GIP: GLP-1 receptor agonist potency ratio of GIP to GLP-1 of from about 2.5: 1 to about 5: 1. The present invention also provides methods for eliciting T2D remission using a novel dosing regimen of a GIP: GLP-1 peptide. The invention also provides methods of treating obesity using a novel dosing regimen of the GIP: GLP-1 peptide.

Description

[0001] This application is a divisional application of PCT application PCT / US2019 / 042824, filed on July 22, 2019, with the invention name “Methods of using GIP / GLP1 co-agonists for diabetes”. The date on which the PCT application entered the Chinese national phase is January 21, 2021, and the application number is 201980048741.8.

[0002] The present invention provides methods for treating type 2 diabetes (T2D) using a new dosing regimen of a GIP / GLP-1 co-agonist compound (hereinafter referred to as a GIP:GLP-1 peptide), wherein the compound has a GIP:GLP-1 receptor agonist potency ratio of GIP to GLP-1 of about 2.5 to about 10:1. In addition, the present invention provides methods for treating T2D using a new dosing regimen of a GIP:GLP-1 peptide, wherein the peptide has a GIP:GLP-1 receptor agonist potency ratio of GIP to GLP-1 of about 2.5:1 to about 5:1. The present invention also provides methods for inducing T2D remission using a new dosing regimen of a GIP:GLP-1 peptide. The present invention also provides methods for treating obesity using a new dosing regimen of a GIP:GLP-1 peptide.

[0003] Over the past decades, the prevalence of diabetes has continued to rise. T2DM is the most common form of diabetes, accounting for approximately 90% of all diabetes. T2DM is characterized by high blood sugar levels mainly associated with insulin resistance. T2D is prevalent. The long-term outcome of T2D turns into countless people suffering from illness and economic costs; however, most of the morbidity associated with long-term microvascular complications and neuropathic complications can be significantly reduced by intervention, and the intervention achieves glucose levels close to the non-diabetic range. Although new types of drugs and numerous combinations have been shown to reduce blood sugar, it is reported that current management generally does not achieve and maintain the blood sugar level that is most likely to provide the best medical care state to the diabetic population. The Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy, DIABETES CARE, Vol. 32: 193-203; Issue 1, January 2009. American Diabetes Association guidelines recommend using an HbA1c in the range of 5.7% to 6.1% (39-47 mmol / mol) as a prediabetic level. American Diabetes Association, DiabetesCare. 2018 Jan;41(Suppl 1):S55-S64. Treatments that make it possible for patients with T2D to achieve their glycemic treatment goals are urgently needed.

[0004] It is well known that GLP1 therapy is associated with nausea, vomiting, and / or diarrhea. For example, one study reported that all GLP-1 receptor dosing regimens significantly increased the incidence of gastrointestinal adverse events. Diabetes Technol Ther. 2015 Jan; 17(1): 35-42.

[0005] Although endogenous GIP produces a strong insulinotropic effect in healthy individuals, the severely reduced insulinotropic effect of GIP and the GIP-dependent enhancement of the postprandial glucagon response have frustrated the development of GIP-based T2D therapies. Seino et al., GIP and GLP-1, the two incretin hormones: Similarities and differences; Journal of Diabetes Investigation, Vol. 1, No. 1 / 2 (February / April 2010) (8-23) p. 16.

[0006] In addition, previous clinical trials of GIP / GLP1 co-agonist compounds with balanced GIP / GLP1 potency have been conducted and found tolerability at high doses to be limited by gastrointestinal adverse events. Portron, A. et al., "Pharmacodynamics, pharmacokinetics, safety and tolerability of the novel dualglucose-dependent insulinotropic polypeptide / glucagon-like peptide-1 agonist RG7697 after single subcutaneous administration in healthy subjects." Diabetes Obes. Metab. 2017; 19: 1446-1453. Finan, B. et al., "Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans." Sci Trans Med. 2013; 5(209): 209ra151. Dose limitations associated with gastrointestinal adverse events may hinder administration to the desired effective dose, may undermine patient treatment compliance, and may limit the effectiveness of treatment regimens.

[0007] Although T2D treatments include GLP-1 receptor agonists, there are currently no approved T2D treatments that report GIP / GLP receptor co-agonism. Furthermore, there are no available therapies for treating T2D that have a GIP to GLP-1 receptor agonist potency ratio of about 2.5:1 to about 10:1.

[0008] A GIP / GLP-1 receptor co-agonist with a potency ratio of GIP:GLP-1 of about 3.6:1 is called tirzepatide. In a Phase II clinical trial, treatment with tirzepatide, including a 15 mg dose administered subcutaneously once weekly, resulted in a substantial reduction in HbA1c, remission of diabetes in many patients after 26 weeks, and substantial improvement in weight control.

[0009] Obesity is a complex medical condition that results in excessive accumulation of adipose tissue mass. Today, obesity is a global public health problem associated with adverse health outcomes and morbidity. The required treatment for obese patients is dedicated to reducing excess body weight, improving obesity-related comorbidities, and maintaining long-term weight loss. Currently available obesity therapies are particularly unsatisfactory for severely obese patients. Successful obesity therapies are associated with reducing or preventing T2D. Alternative therapy options that cause therapeutic weight loss in patients in need of such treatment are needed. Compounds having a ratio of GIP receptor agonist potency to GLP-1 receptor agonist potency of about 2.5:1 to about 10:1 can be used to significantly improve weight management and can prevent T2D manifestations in pre-obese patients susceptible to T2D.

[0010] WO2016 / 111971 describes peptides allegedly having GLP-1 and GIP activity. WO2013 / 164483 also discloses compounds allegedly having GLP-1 and GIP activity. US9474780 generally describes compositions containing GIP / GLP1 co-agonists administered by parenteral routes, and generally discloses a broad dosage range of up to about 30 mg per person per week. US9474780 discloses the use of GIP / GLP1 co-agonists to treat diabetes, obesity and other conditions. US9474780 describes and claims tirzepatide.

[0011] The present invention provides a new dosing regimen of GIP:GLP-1 peptides for use in the aforementioned treatments (glycemic control / diabetes, obesity), the dosing regimen comprising one or more titration doses and a maintenance dose. More specifically, the present invention provides a new dosing regimen comprising a titration dose and a maintenance dose, wherein the titration dose is about 50% of the maintenance dose and is administered about once a week for a minimum of about 2 weeks, followed by a maintenance dose. In another aspect, the dosing regimen comprises three titration doses: the first titration dose is about 25% of the maintenance dose, the second titration dose is about 50% of the maintenance dose, and the third titration dose is about 75% of the maintenance dose; and a maintenance dose, wherein each titration dose is administered about once a week for a minimum of about 2 weeks, followed by the next higher dose. In another third embodiment, the dosing regimen comprises five titration doses: the first titration dose is about 17% of the maintenance dose, the second titration dose is about 33% of the maintenance dose, the third titration dose is about 50% of the maintenance dose, the fourth titration dose is about 66% of the maintenance dose, and the fifth titration dose is about 83% of the maintenance dose, wherein each titration dose is administered about once a week for a minimum of about 2 weeks before the next higher dose is administered. Other embodiments are dosing regimens as above, wherein each titration dose is administered about once a week for about 4 weeks before the next higher dose is initiated.

[0012] In one embodiment, the GIP:GLP-1 peptides of the invention have a receptor agonist potency ratio of GIP to GLP-1 of about 2.5:1 to about 10:1 measured after 60 minutes incubation using a casein cAMP assay normalized to GIP and GLP-1. In one embodiment, the GIP:GLP-1 peptides of the invention have a receptor agonist potency ratio of GIP to GLP-1 of about 2.5:1 to about 5:1 measured after 60 minutes incubation using a casein cAMP assay normalized to GIP and GLP-1. In one embodiment, the GIP:GLP-1 peptides of the invention have a receptor agonist potency ratio of GIP to GLP-1 of about 2.5:1 to about 3.5:1 measured after 60 minutes incubation using a casein cAMP assay normalized to GIP and GLP-1. In one embodiment, the GIP:GLP-1 peptides of the invention have a receptor agonist potency ratio of GIP to GLP-1 of about 2.5:1 to about 10:1 measured after 60 minutes incubation using a casein cAMP assay normalized to GIP and GLP-1. In one embodiment, the GIP:GLP-1 peptides of the invention have a receptor agonist potency ratio of GIP to GLP-1 of about 2.5:1 to about 10:1 measured after 60 minutes incubation at 37°C using a casein cAMP assay normalized to GIP and GLP-1.

[0013] Accordingly, the present invention provides a method for treating type 2 diabetes in a patient in need thereof, the method comprising: administering a titrated dose of a GIP:GLP-1 peptide for about two weeks and subsequently administering a maintenance dose of such a GIP:GLP-1 peptide, wherein the titrated dose is about 50% of the maintenance dose and wherein the GIP:GLP-1 peptide has a receptor agonist potency ratio of GIP to GLP-1 of about 2.5:1 to about 10:1 measured after 60 minutes incubation using a casein cAMP assay normalized for GIP and GLP-1.

[0014] The present invention also provides a method for improving glycemic control in a patient in need thereof, the method comprising: administering a titrated dose of a GIP:GLP-1 peptide for about two weeks and subsequently administering a maintenance dose of such a GIP:GLP-1 peptide, wherein the titrated dose is about 50% of the maintenance dose and wherein the GIP:GLP-1 peptide has a receptor agonist potency ratio of GIP to GLP-1 of about 2.5:1 to about 10:1 measured after 60 minutes of incubation using a casein cAMP assay normalized for GIP and GLP-1.

[0015] Additionally, the present invention provides a method for improving weight management in a patient in need thereof, the method comprising: administering a titration dose of a GIP:GLP-1 peptide for about two weeks and subsequently administering a maintenance dose of such a GIP:GLP-1 peptide, wherein the titration dose is about 50% of the maintenance dose and wherein the GIP:GLP-1 peptide has a receptor agonist potency ratio of GIP to GLP-1 of about 2.5:1 to about 10:1 measured after 60 minutes of incubation using a casein cAMP assay normalized for GIP and GLP-1.

[0016] Additionally, the present invention provides a method for treating chronic kidney disease in a patient in need thereof, the method comprising: administering a titrated dose of a GIP:GLP-1 peptide for about two weeks and subsequently administering a maintenance dose of such a GIP:GLP-1 peptide, wherein the titrated dose is about 50% of the maintenance dose and wherein the GIP:GLP-1 peptide has a receptor agonist potency ratio of GIP to GLP-1 of about 2.5:1 to about 10:1 as measured after 60 minutes of incubation using a casein cAMP assay normalized for GIP and GLP-1.

[0017] Additionally, the present invention provides a method of treating atherosclerosis in a patient in need thereof, the method comprising: administering a titrated dose of a GIP:GLP-1 peptide for about two weeks and subsequently administering a maintenance dose of such a GIP:GLP-1 peptide, wherein the titrated dose is about 50% of the maintenance dose and wherein the GIP:GLP-1 peptide has a receptor agonist potency ratio of GIP to GLP-1 of about 2.5:1 to about 10:1 measured after 60 minutes of incubation using a casein cAMP assay normalized for GIP and GLP-1.

[0018] In addition, the present invention provides a method for treating NAFLD in a patient in need thereof, the method comprising: administering a titrated dose of a GIP:GLP-1 peptide for about two weeks and subsequently administering a maintenance dose of such a GIP:GLP-1 peptide, wherein the titrated dose is about 50% of the maintenance dose and wherein the GIP:GLP-1 peptide has a receptor agonist potency ratio of GIP to GLP-1 of about 2.5:1 to about 10:1 measured after 60 minutes of incubation using a casein cAMP assay normalized for GIP and GLP-1.

[0019] Additionally, the present invention provides a method of treating NASH in a patient in need thereof, the method comprising: administering a titration dose of a GIP:GLP-1 peptide for about two weeks and subsequently administering a maintenance dose of such a GIP:GLP-1 peptide, wherein the titration dose is about 50% of the maintenance dose and wherein the GIP:GLP-1 peptide has a receptor agonist potency ratio of GIP to GLP-1 of about 2.5:1 to about 10:1 as measured after 60 minutes of incubation using a casein cAMP assay normalized for GIP and GLP-1.

[0020] In addition, the present invention provides a method for curing diabetes, causing remission or regression of diabetes, or preventing diabetes in a patient in need thereof, the method comprising: administering a titrated dose of a GIP:GLP-1 peptide for about two weeks and subsequently administering a maintenance dose of such a GIP:GLP-1 peptide, wherein the titrated dose is about 50% of the maintenance dose and wherein the GIP:GLP-1 peptide has a receptor agonist potency ratio of GIP to GLP-1 of about 2.5:1 to about 10:1 measured after 60 minutes of incubation using a casein cAMP assay normalized for GIP and GLP-1.

[0021] Another embodiment of the present invention is the above method, wherein three titration doses (about 25%, about 50%, and about 75% of the maintenance dose) are administered, starting with the 25% dose and wherein each titration dose is administered for about two weeks before the next higher dose is initiated. Another embodiment of the present invention is the above method, wherein five titration doses (about 17%, about 33%, about 50%, about 66%, and about 83% of the maintenance dose) are administered, starting with the 17% dose and wherein each titration dose is administered for about two weeks before the next higher dose is initiated. Another embodiment of the present invention is the above method, wherein the titration dose or multiple titration doses are administered for about four weeks before the next higher dose is initiated.

[0022] Another aspect of the invention is the above method for treating type 2 diabetes, improving glycemic control, improving weight management, treating chronic kidney disease, treating NAFLD, treating NASH and curing diabetes, causing diabetes remission or regression, or preventing diabetes, wherein the GIP:GLP-1 peptide has a GIP:GLP-1 receptor agonist potency ratio of about 2.5:1 to about 5:1 measured using a casein cAMP assay normalized to GIP and GLP-1 after 60 minutes of incubation. Another aspect of the invention is the above method for treating type 2 diabetes, improving glycemic control, improving weight management, treating chronic kidney disease, treating NAFLD, treating NASH or curing diabetes, causing diabetes remission or regression, or preventing diabetes, wherein the GIP:GLP-1 peptide has a GIP:GLP-1 receptor agonist potency ratio of about 2.5:1 to about 3.5:1 measured using a casein cAMP assay normalized to GIP and GLP-1 after 60 minutes of incubation.

[0023] Another aspect of the present invention is the above method for treating type 2 diabetes, improving glycemic control, improving weight management, treating chronic kidney disease, treating NAFLD, treating NASH or curing diabetes, causing diabetes remission or regression, or preventing diabetes, wherein the GIP:GLP-1 peptide is a compound of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof. Another aspect of the present invention is the above method for treating type 2 diabetes, improving glycemic control, improving weight management, treating chronic kidney disease, treating NAFLD, treating NASH or curing diabetes, causing diabetes remission or regression, or preventing diabetes, wherein the GIP:GLP-1 peptide is a compound of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof, and wherein the compound of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof has a GIP:GLP-1 receptor agonist potency ratio of about 2.5: 1 to about 5: 1 measured using a casein cAMP assay normalized for GIP and GLP-1 after 60 minutes of incubation. Another aspect of the invention is the above method for treating type 2 diabetes, improving glycemic control, improving weight management, treating chronic kidney disease, treating NAFLD, treating NASH or curing diabetes, causing diabetes remission or regression, or preventing diabetes, wherein the GIP:GLP-1 peptide is a compound of SEQ ID NO:3 or a pharmaceutically acceptable salt thereof, and wherein the compound of SEQ ID NO:3 or a pharmaceutically acceptable salt thereof has a GIP:GLP-1 receptor agonist potency ratio of about 2.5:1 to about 3.5:1 measured using a casein cAMP assay normalized to GIP and GLP-1 after 60 minutes of incubation.

[0024] In embodiment 1(a), the present invention provides a method of treating type 2 diabetes in a patient in need thereof, the method comprising:

[0025] a) administering to said patient titrated doses 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 subsequently

[0026] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0027] The titration dose is approximately 50% of the maintenance dose.

[0028] In embodiment 1(b), the present invention provides a method of treating type 2 diabetes in a patient in need thereof, the method comprising:

[0029] a) administering to said patient a first titrated 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 subsequently

[0030] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0031] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0032] d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0033] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0034] In embodiment 1(c), the present invention provides a method of treating type 2 diabetes in a patient in need thereof, the method comprising:

[0035] a) administering to said patient a first titrated 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 subsequently

[0036] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0037] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0038] d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0039] e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0040] f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0041] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0042] In one embodiment 1(a1), the present invention provides a method of treating type 2 diabetes in a patient in need thereof, the method comprising:

[0043] a) administering subcutaneously to said patient about once a week for a minimum of about two weeks a titrated 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; and subsequently

[0044] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0045] The titration dose is approximately 50% of the maintenance dose.

[0046] In embodiment 1(b1), the present invention provides a method of treating type 2 diabetes in a patient in need thereof, the method comprising:

[0047] a) administering to said patient subcutaneously about once a week for a minimum of about two weeks a first titrated 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; and subsequently

[0048] b) administering to said patient subcutaneously a second titrated dose of said GIP:GLP-1 peptide approximately once a week for a minimum of about two weeks; and thereafter

[0049] c) administering to said patient a third titrated dose of said GIP:GLP-1 peptide subcutaneously about once a week for a minimum of about two weeks; and thereafter

[0050] d) subcutaneously administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0051] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0052] In embodiment 1(c1), the present invention provides a method of treating type 2 diabetes in a patient in need thereof, the method comprising:

[0053] a) administering to said patient subcutaneously about once a week for a minimum of about two weeks a first titrated 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; and subsequently

[0054] b) administering to said patient subcutaneously a second titrated dose of said GIP:GLP-1 peptide approximately once a week for a minimum of about two weeks; and thereafter

[0055] c) administering to said patient a third titrated dose of said GIP:GLP-1 peptide subcutaneously about once a week for a minimum of about two weeks; and thereafter

[0056] d) administering to said patient subcutaneously a fourth titrated dose of the GIP:GLP-1 peptide approximately once a week for a minimum of about two weeks; and thereafter

[0057] e) administering to said patient subcutaneously a fifth titrated dose of the GIP:GLP-1 peptide approximately once a week for a minimum of about two weeks; and thereafter

[0058] f) subcutaneously administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0059] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0060] In embodiment 2(a), the present invention provides a method for improving glycemic control in a patient in need thereof, the method comprising:

[0061] a) administering to said patient titrated doses 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 subsequently

[0062] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0063] The titration dose is approximately 50% of the maintenance dose.

[0064] In one embodiment 2(a), the present invention provides a method of improving glycemic control in a patient in need thereof, the method comprising:

[0065] a) administering to said patient titrated doses 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 subsequently

[0066] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0067] The titration dose is approximately 50% of the maintenance dose.

[0068] In embodiment 2(b), the present invention provides a method for improving glycemic control in a patient in need thereof, the method comprising:

[0069] a) administering to said patient a first titrated 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 subsequently

[0070] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0071] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0072] d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0073] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0074] In embodiment 2(c), the present invention provides a method for improving glycemic control in a patient in need thereof, the method comprising:

[0075] a) administering to said patient a first titrated 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 subsequently

[0076] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0077] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0078] d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0079] e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0080] f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0081] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0082] In embodiment 3(a), the present invention provides a method of improving weight management in a patient in need thereof, the method comprising:

[0083] a) administering to said patient titrated doses 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 subsequently

[0084] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0085] The titration dose is approximately 50% of the maintenance dose.

[0086] In embodiment 3(b), the present invention provides a method of improving weight management in a patient in need thereof, the method comprising:

[0087] a) administering to said patient a first titrated 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 subsequently

[0088] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0089] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0090] d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0091] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0092] In embodiment 3(c), the present invention provides a method of improving weight management in a patient in need thereof, the method comprising:

[0093] a) administering to said patient a first titrated 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 subsequently

[0094] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0095] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0096] d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0097] e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0098] f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0099] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0100] In embodiment 4(a), the present invention provides a method of treating chronic kidney disease in a patient in need thereof, the method comprising:

[0101] a) administering to said patient titrated doses 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 subsequently

[0102] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0103] The titration dose is approximately 50% of the maintenance dose.

[0104] In embodiment 4(b), the present invention provides a method of treating chronic kidney disease in a patient in need thereof, the method comprising:

[0105] a) administering to said patient a first titrated 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 subsequently

[0106] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0107] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0108] d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0109] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0110] In embodiment 4(c), the present invention provides a method of treating chronic kidney disease in a patient in need thereof, the method comprising:

[0111] a) administering to said patient a first titrated 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 subsequently

[0112] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0113] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0114] d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0115] e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0116] f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0117] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0118] In embodiment 5(a), the present invention provides a method of treating NAFLD in a patient in need thereof, the method comprising:

[0119] a) administering to said patient titrated doses 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 subsequently

[0120] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0121] The titration dose is approximately 50% of the maintenance dose.

[0122] In embodiment 5(b), the present invention provides a method of treating NAFLD in a patient in need thereof, the method comprising:

[0123] a) administering to said patient a first titrated 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 subsequently

[0124] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0125] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0126] d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0127] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0128] In embodiment 5(c), the present invention provides a method of treating NAFLD in a patient in need thereof, the method comprising:

[0129] a) administering to said patient a first titrated 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 subsequently

[0130] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0131] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0132] d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0133] e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0134] f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0135] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0136] In embodiment 6(a), the present invention provides a method of treating NASH in a patient in need thereof, the method comprising:

[0137] a) administering to said patient titrated doses 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 subsequently

[0138] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0139] The titration dose is approximately 50% of the maintenance dose.

[0140] In embodiment 6(b), the present invention provides a method of treating NASH in a patient in need thereof, the method comprising:

[0141] a) administering to said patient a first titrated 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 subsequently

[0142] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0143] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0144] d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0145] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0146] In embodiment 6(c), the present invention provides a method of treating NASH in a patient in need thereof, the method comprising:

[0147] a) administering to said patient a first titrated 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 subsequently

[0148] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0149] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0150] d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0151] e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0152] f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0153] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0154] In embodiment 7(a), the present invention provides a method for curing diabetes, causing remission or regression of diabetes, or preventing diabetes in a patient in need thereof, the method comprising: in order to cure diabetes, cause remission or regression of diabetes, or prevent diabetes,

[0155] a) administering to said patient titrated doses 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 subsequently

[0156] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0157] The titration dose is approximately 50% of the maintenance dose.

[0158] In embodiment 7(b), the present invention provides a method of curing diabetes, causing remission or regression of diabetes, or preventing diabetes in a patient in need thereof, the method comprising:

[0159] a) administering to said patient a first titrated 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 subsequently

[0160] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0161] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0162] d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0163] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0164] In embodiment 7(c), the present invention provides a method of curing diabetes, causing remission or regression of diabetes, or preventing diabetes in a patient in need thereof, the method comprising:

[0165] a) administering to said patient a first titrated 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 subsequently

[0166] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0167] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0168] d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0169] e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0170] f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0171] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0172] In Embodiment 8, the titrated doses of Embodiments 1(a)-(c), 2(a)-(c), 3(a)-(c), 4(a)-(c), 5(a)-(c), 6(a)-(c), or 7(a)-(c) are each administered for about four weeks before administration of the next higher dose is initiated. Thus, for example, in Embodiment 1(d), the invention provides a method of treating type 2 diabetes in a patient in need thereof, the method comprising:

[0173] a) administering to said patient a first titrated 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 about four weeks; and subsequently

[0174] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0175] The titration dose is approximately 50% of the maintenance dose.

[0176] In embodiment 1(e), the present invention therefore also provides a method of treating type 2 diabetes in a patient in need thereof, the method comprising:

[0177] a) administering to said patient a first titrated 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 about four weeks; and subsequently

[0178] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for about four weeks; and subsequently

[0179] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for about four weeks; and subsequently

[0180] d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0181] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0182] In embodiment 1(f), the present invention therefore also provides a method of treating type 2 diabetes in a patient in need thereof, the method comprising:

[0183] a) administering to said patient a first titrated 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 about four weeks; and subsequently

[0184] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for about four weeks; and subsequently

[0185] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for about four weeks; and subsequently

[0186] d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for about four weeks; and subsequently

[0187] e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for about four weeks; and subsequently

[0188] f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0189] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0190] In embodiment 9, the GIP:GLP-1 peptide of embodiment 1(a)-(c), 2(a)-(c), 3(a)-(c), 4(a)-(c), 5(a)-(c), 6(a)-(c), 7(a)-(c) or 8 is a compound of SEQ ID NO: 3 or a pharmaceutically acceptable salt thereof. Thus, for example, in embodiment 1(g), the present invention provides a method of treating type 2 diabetes in a patient in need thereof, the method comprising:

[0191] a) administering to said patient a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1, wherein the GIP:GLP-1 peptide is the compound of SEQ ID NO:3; and subsequently

[0192] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0193] The titration dose is approximately 50% of the maintenance dose.

[0194] In embodiment 1(h), the present invention therefore also provides a method of treating type 2 diabetes in a patient in need thereof, the method comprising:

[0195] a) administering to said patient a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1, wherein the GIP:GLP-1 peptide is the compound of SEQ ID NO:3; and subsequently

[0196] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for about four weeks; and subsequently

[0197] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for about four weeks; and subsequently

[0198] d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0199] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0200] In embodiment 1(i), the present invention therefore also provides a method of treating type 2 diabetes in a patient in need thereof, the method comprising:

[0201] a) administering to said patient a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1, wherein the GIP:GLP-1 peptide is the compound of SEQ ID NO:3; and subsequently

[0202] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for about four weeks; and subsequently

[0203] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for about four weeks; and subsequently

[0204] d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for about four weeks; and subsequently

[0205] e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for about four weeks; and subsequently

[0206] f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0207] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0208] In embodiment 10, the GIP:GLP-1 peptide of embodiment 1(a)-(c), 2(a)-(c), 3(a)-(c), 4(a)-(c), 5(a)-(c), 6(a)-(c), 7(a)-(c), 8 or 9 has a receptor agonist potency ratio of GIP to GLP-1 of 2.5:1 to about 5:1.

[0209] In embodiment 11, the GIP:GLP-1 peptide of embodiment 1(a)-(c), 2(a)-(c), 3(a)-(c), 4(a)-(c), 5(a)-(c), 6(a)-(c), 7(a)-(c), 8, 9 or 10 has a receptor agonist potency ratio of GIP to GLP-1 of 2.5:1 to about 3.5:1.

[0210] In embodiment 12(a), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating type 2 diabetes in a patient in need thereof, comprising:

[0211] a) administering to said patient titrated doses 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 subsequently

[0212] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0213] The titration dose is approximately 50% of the maintenance dose.

[0214] In embodiment 12(b), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating type 2 diabetes in a patient in need thereof, comprising:

[0215] a) administering to said patient a first titrated 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 subsequently

[0216] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0217] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0218] d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0219] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0220] In embodiment 12(c), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating type 2 diabetes in a patient in need thereof, comprising:

[0221] a) administering to said patient a first titrated 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 subsequently

[0222] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0223] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0224] d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0225] e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0226] f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0227] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0228] In embodiment 13(a), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving glycemic control in a patient in need thereof, comprising:

[0229] a) administering to said patient titrated doses 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 subsequently

[0230] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0231] The titration dose is approximately 50% of the maintenance dose.

[0232] In embodiment 13(b), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving glycemic control in a patient in need thereof, comprising:

[0233] a) administering to said patient a first titrated 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 subsequently

[0234] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0235] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0236] d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0237] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0238] In embodiment 13(c), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving glycemic control in a patient in need thereof, comprising:

[0239] a) administering to said patient a first titrated 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 subsequently

[0240] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0241] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0242] d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0243] e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0244] f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0245] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0246] In embodiment 14(a), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving weight management in a patient in need thereof, comprising:

[0247] a) administering to said patient titrated doses 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 subsequently

[0248] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0249] The titration dose is approximately 50% of the maintenance dose.

[0250] In embodiment 14(b), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving weight management in a patient in need thereof, comprising:

[0251] a) administering to said patient a first titrated 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 subsequently

[0252] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0253] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0254] d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0255] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0256] In embodiment 14(c), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for improving weight management in a patient in need thereof, comprising:

[0257] a) administering to said patient a first titrated 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 subsequently

[0258] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0259] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0260] d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0261] e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0262] f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0263] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0264] In embodiment 15(a), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating chronic kidney disease in a patient in need thereof, comprising:

[0265] a) administering to said patient titrated doses 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 subsequently

[0266] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0267] The titration dose is approximately 50% of the maintenance dose.

[0268] In embodiment 15(b), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating chronic kidney disease in a patient in need thereof, comprising:

[0269] a) administering to said patient a first titrated 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 subsequently

[0270] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0271] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0272] d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0273] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0274] In embodiment 15(c), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating chronic kidney disease in a patient in need thereof, comprising:

[0275] a) administering to said patient a first titrated 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 subsequently

[0276] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0277] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0278] d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0279] e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0280] f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0281] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0282] In embodiment 16(a), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating NAFLD in a patient in need thereof, comprising:

[0283] a) administering to said patient titrated doses 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 subsequently

[0284] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0285] The titration dose is approximately 50% of the maintenance dose.

[0286] In embodiment 16(b), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating NAFLD in a patient in need thereof, comprising:

[0287] a) administering to said patient a first titrated 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 subsequently

[0288] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0289] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0290] d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0291] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0292] In embodiment 16(c), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating NAFLD in a patient in need thereof, comprising:

[0293] a) administering to said patient a first titrated 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 subsequently

[0294] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0295] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0296] d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0297] e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0298] f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0299] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0300] In embodiment 17(a), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating NASH in a patient in need thereof, comprising:

[0301] a) administering to said patient titrated doses 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 subsequently

[0302] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0303] The titration dose is approximately 50% of the maintenance dose.

[0304] In embodiment 17(b), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating NASH in a patient in need thereof, comprising:

[0305] a) administering to said patient a first titrated 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 subsequently

[0306] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0307] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0308] d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0309] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0310] In embodiment 17(c), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating NASH in a patient in need thereof, comprising:

[0311] a) administering to said patient a first titrated 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 subsequently

[0312] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0313] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0314] d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0315] e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0316] f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0317] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0318] In embodiment 18(a), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing remission or regression of diabetes or preventing diabetes in a patient in need thereof, comprising:

[0319] a) administering to said patient titrated doses 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 subsequently

[0320] b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0321] The titration dose is approximately 50% of the maintenance dose.

[0322] In embodiment 18(b), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing remission or regression of diabetes or preventing diabetes in a patient in need thereof, comprising:

[0323] a) administering to said patient a first titrated 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 subsequently

[0324] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0325] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0326] d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0327] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0328] In embodiment 18(c), the present invention provides the use of a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inducing remission or regression of diabetes or preventing diabetes in a patient in need thereof, comprising:

[0329] a) administering to said patient a first titrated 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 subsequently

[0330] b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0331] c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0332] d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0333] e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0334] f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient;

[0335] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0336] In embodiment 19, titrated doses of any of embodiments 12(a)-(c), 13(a)-(c), 14(a)-(c), 15(a)-(c), 16(a)-(c), 17(a)-(c), or 18(a)-(c) are each administered for about four weeks before administration of the next higher dose is initiated.

[0337] In embodiment 20, the GIP:GLP-1 peptide of any one of embodiments 12(a)-(c), 13(a)-(c), 14(a)-(c), 15(a)-(c), 16(a)-(c), 17(a)-(c), 18(a)-(c), or 19 is a peptide of SEQ ID NO:3 or a pharmaceutically acceptable salt thereof.

[0338] In embodiment 21, the GIP:GLP-1 peptide of any one of embodiments 12(a)-(c), 13(a)-(c), 14(a)-(c), 15(a)-(c), 16(a)-(c), 17(a)-(c), 18(a)-(c), 19 or 20 has a receptor agonist potency ratio of GIP to GLP-1 of 2.5:1 to about 5:1.

[0339] In embodiment 22, the GIP:GLP-1 peptide of any of embodiments 12(a)-(c), 13(a)-(c), 14(a)-(c), 15(a)-(c), 16(a)-(c), 17(a)-(c), 18(a)-(c), 19 or 20 has a receptor agonist potency ratio of GIP to GLP-1 of 2.5:1 to about 3.5:1.

[0340] In embodiment 23(a), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in treating type 2 diabetes in a patient in need thereof, wherein the use comprises:

[0341] a) administering titrated doses of a GIP:GLP-1 peptide for a minimum of about two weeks, the 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; and subsequently

[0342] b) administering a maintenance dose of the GIP:GLP-1 peptide;

[0343] The titration dose is approximately 50% of the maintenance dose.

[0344] In embodiment 23(b), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in treating type 2 diabetes in a patient in need thereof, wherein the use comprises:

[0345] a) administering a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1 for a minimum of about two weeks; and subsequently

[0346] b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0347] c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0348] d) administering a maintenance dose of the GIP:GLP-1 peptide;

[0349] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0350] In embodiment 23(c), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in treating type 2 diabetes in a patient in need thereof, wherein the use comprises:

[0351] a) administering a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1 for a minimum of about two weeks; and subsequently

[0352] b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0353] c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0354] d) administering a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0355] e) administering a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0356] f) administering a maintenance dose of the GIP:GLP-1 peptide;

[0357] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0358] In embodiment 24(a), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in improving glycemic control in a patient in need thereof, wherein the use comprises:

[0359] a) administering titrated doses of a GIP:GLP-1 peptide for a minimum of about two weeks, the 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; and subsequently

[0360] b) administering a maintenance dose of the GIP:GLP-1 peptide;

[0361] The titration dose is approximately 50% of the maintenance dose.

[0362] In embodiment 24(b), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in improving glycemic control in a patient in need thereof, wherein the use comprises:

[0363] a) administering a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1 for a minimum of about two weeks; and subsequently

[0364] b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0365] c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0366] d) administering a maintenance dose of the GIP:GLP-1 peptide;

[0367] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0368] In embodiment 24(c), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in improving glycemic control in a patient in need thereof, wherein the use comprises:

[0369] a) administering a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1 for a minimum of about two weeks; and subsequently

[0370] b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0371] c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0372] d) administering a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0373] e) administering a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0374] f) administering a maintenance dose of the GIP:GLP-1 peptide;

[0375] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0376] In embodiment 25(a), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in improving weight management in a patient in need thereof, wherein the use comprises:

[0377] a) administering titrated doses of a GIP:GLP-1 peptide for a minimum of about two weeks, the 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; and subsequently

[0378] b) administering a maintenance dose of the GIP:GLP-1 peptide;

[0379] The titration dose is approximately 50% of the maintenance dose.

[0380] In embodiment 25(b), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in improving weight management in a patient in need thereof, wherein the use comprises:

[0381] a) administering a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1 for a minimum of about two weeks; and subsequently

[0382] b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0383] c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0384] d) administering a maintenance dose of the GIP:GLP-1 peptide;

[0385] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0386] In embodiment 25(c), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in improving weight management in a patient in need thereof, wherein the use comprises:

[0387] a) administering a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1 for a minimum of about two weeks; and subsequently

[0388] b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0389] c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0390] d) administering a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0391] e) administering a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0392] f) administering a maintenance dose of the GIP:GLP-1 peptide;

[0393] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0394] In embodiment 26(a), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in treating chronic kidney disease in a patient in need thereof, wherein the use comprises:

[0395] a) administering titrated doses of a GIP:GLP-1 peptide for a minimum of about two weeks, the 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; and subsequently

[0396] b) administering a maintenance dose of the GIP:GLP-1 peptide;

[0397] The titration dose is approximately 50% of the maintenance dose.

[0398] In embodiment 26(b), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in treating chronic kidney disease in a patient in need thereof, wherein the use comprises:

[0399] a) administering a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1 for a minimum of about two weeks; and subsequently

[0400] b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0401] c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0402] d) administering a maintenance dose of the GIP:GLP-1 peptide;

[0403] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0404] In embodiment 26(c), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in treating chronic kidney disease in a patient in need thereof, wherein the use comprises:

[0405] a) administering a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1 for a minimum of about two weeks; and subsequently

[0406] b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0407] c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0408] d) administering a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0409] e) administering a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0410] f) administering a maintenance dose of the GIP:GLP-1 peptide;

[0411] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0412] In embodiment 27(a), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in treating NAFLD in a patient in need thereof, wherein the use comprises:

[0413] a) administering titrated doses of a GIP:GLP-1 peptide for a minimum of about two weeks, the 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; and subsequently

[0414] b) administering a maintenance dose of the GIP:GLP-1 peptide;

[0415] The titration dose is approximately 50% of the maintenance dose.

[0416] In embodiment 27(b), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in treating NAFLD in a patient in need thereof, wherein the use comprises:

[0417] a) administering a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1 for a minimum of about two weeks; and subsequently

[0418] b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0419] c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0420] d) administering a maintenance dose of the GIP:GLP-1 peptide;

[0421] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0422] In embodiment 27(c), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in treating NAFLD in a patient in need thereof, wherein the use comprises:

[0423] a) administering a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1 for a minimum of about two weeks; and subsequently

[0424] b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0425] c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0426] d) administering a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0427] e) administering a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0428] f) administering a maintenance dose of the GIP:GLP-1 peptide;

[0429] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0430] In embodiment 28(a), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in treating NASH in a patient in need thereof, wherein the use comprises:

[0431] a) administering titrated doses of a GIP:GLP-1 peptide for a minimum of about two weeks, the 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; and subsequently

[0432] b) administering a maintenance dose of the GIP:GLP-1 peptide;

[0433] The titration dose is approximately 50% of the maintenance dose.

[0434] In embodiment 28(b), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in treating NASH in a patient in need thereof, wherein the use comprises:

[0435] a) administering a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1 for a minimum of about two weeks; and subsequently

[0436] b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0437] c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0438] d) administering a maintenance dose of the GIP:GLP-1 peptide;

[0439] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0440] In embodiment 28(c), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in treating NASH in a patient in need thereof, wherein the use comprises:

[0441] a) administering a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1 for a minimum of about two weeks; and subsequently

[0442] b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0443] c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0444] d) administering a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0445] e) administering a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0446] f) administering a maintenance dose of the GIP:GLP-1 peptide;

[0447] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0448] In embodiment 29(a), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in causing diabetes remission or regression or preventing diabetes in a patient in need thereof, wherein the use comprises:

[0449] a) administering titrated doses of a GIP:GLP-1 peptide for a minimum of about two weeks, the 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; and subsequently

[0450] b) administering a maintenance dose of the GIP:GLP-1 peptide;

[0451] The titration dose is approximately 50% of the maintenance dose.

[0452] In embodiment 29(b), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in causing diabetes remission or regression or preventing diabetes in a patient in need thereof, wherein the use comprises:

[0453] a) administering a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1 for a minimum of about two weeks; and subsequently

[0454] b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0455] c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0456] d) administering a maintenance dose of the GIP:GLP-1 peptide;

[0457] wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

[0458] In embodiment 29(c), the present invention provides a GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in causing diabetes remission or regression or preventing diabetes in a patient in need thereof, wherein the use comprises:

[0459] a) administering a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1 for a minimum of about two weeks; and subsequently

[0460] b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0461] c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0462] d) administering a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently

[0463] e) administering a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter

[0464] f) administering a maintenance dose of the GIP:GLP-1 peptide;

[0465] wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

[0466] In embodiment 30, titrated doses of any of embodiments 23(a)-(c), 24(a)-(c), 25(a)-(c), 26(a)-(c), 27(a)-(c), 28(a)-(c), or 29(a)-(c) are each administered for about four weeks before administration of the next higher dose is initiated.

[0467] In embodiment 31, the GIP:GLP-1 peptide of any one of embodiments 23(a)-(c), 24(a)-(c), 25(a)-(c), 26(a)-(c), 27(a)-(c), 28(a)-(c), 29(a)-(c) or 30 is a peptide of SEQ ID NO:3 or a pharmaceutically acceptable salt thereof.

[0468] In embodiment 32, the GIP:GLP-1 peptide of any one of embodiments 23(a)-(c), 24(a)-(c), 25(a)-(c), 26(a)-(c), 27(a)-(c), 28(a)-(c), 29(a)-(c), 30 or 31 has a receptor agonist potency ratio of GIP to GLP-1 of 2.5:1 to about 5:1.

[0469] In embodiment 33, the GIP:GLP-1 peptide of any one of embodiments 23(a)-(c), 24(a)-(c), 25(a)-(c), 26(a)-(c), 27(a)-(c), 28(a)-(c), 29(a)-(c), 30 or 31 has a receptor agonist potency ratio of GIP to GLP-1 of 2.5:1 to about 3.5:1.

[0470] In embodiment 34, a composition is provided comprising a GIP:GLP-1 peptide and a pharmaceutically acceptable excipient, wherein the peptide has a GIP:GLP-1 receptor agonist potency ratio of about 2.5:1 to about 10:1 measured after 60 minutes incubation using a casein cAMP assay normalized to GIP and GLP-1.

[0471] In embodiment 34(a), the composition is administered in ascending doses for at least two weeks.

[0472] In embodiment 34(a1), the composition is administered in ascending doses for at least two weeks.

[0473] In embodiment 34(b), the composition is administered at a maintenance dose for at least two weeks.

[0474] In embodiment 35, a GIP-GLP-1 peptide for use in treating diabetes in a patient in need thereof is provided, wherein the GIP-GLP-1 peptide has a GIP:GLP-1 receptor potency ratio of about 2.5:1 to about 10:1 after 60 minutes of incubation as measured using a casein cAMP assay normalized to GIP and GLP-1.

[0475] In embodiment 35(a) is the GIP-GLP-1 peptide of embodiment 35, wherein the peptide is administered for a minimum of about 2 weeks.

[0476] In embodiment 35(b) is the GIP-GLP-1 peptide of embodiment 35 or 35(a) wherein the peptide is administered in at least one ascending dose for a minimum of about 2 weeks.

[0477] Also provided herein are methods of treating a condition selected from type 2 diabetes, chronic kidney disease, atherosclerosis, NAFLD, and NASH using GIP:GLP-1 peptides in simultaneous, separate, and sequential combination with one or more agents selected from metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium glucose co-transporters, SGLT-2 inhibitors, growth differentiation factor 15 regulator ("GDF15"), peptide tyrosine tyrosine regulator ("PYY"), modified insulin, amylin, dual amylin calcitonin receptor agonists, and oxyntomodulin agonists ("OXM"). Also provided herein are methods for improving glycemic control and / or weight management using GIP:GLP-1 peptides in combination with one or more agents simultaneously, independently and sequentially, the agents being selected from: metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium glucose co-transporters, SGLT-2 inhibitors, GDF15, PYY, modified insulin, amylin, dual amylin calcitonin receptor agonists, and OXM. Also provided herein are methods for curing diabetes, causing diabetes remission or regression, or preventing diabetes using GIP:GLP-1 peptides in combination with one or more agents simultaneously, independently and sequentially, the agents being selected from: metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium glucose co-transporters, SGLT-2 inhibitors, GDF15, PYY, modified insulin, amylin, dual amylin calcitonin receptor agonists, and OXM. In one embodiment, the compounds of the invention are provided in a fixed dose combination with one or more agents selected from the group consisting of metformin, thiazolidinediones, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium glucose co-transporters, SGLT-2 inhibitors, GDF15, PYY, modified insulins, amylin, dual amylin calcitonin receptor agonists, and OXM.

[0478] The present invention provides novel dosing regimens, the dosing regimens comprising administering a titration dose approximately once a week for a minimum of approximately two weeks, and subsequently administering a maintenance dose, wherein the titration dose is approximately 50% of the maintenance dose. In certain embodiments, the titration dose may be administered for approximately four weeks. In certain embodiments, the titration dose may be administered for more than approximately four weeks, determined by a nurse, patient, and / or health care provider.

[0479] As used herein, the term "treating," ...

[0480] As used herein, "normalized to GIP and GLP-1" means that the native peptides provided herein as SEQ ID NO: 1 and SEQ ID NO: 2 were tested as controls for the test compounds in the casein cAMP assay, and the raw CPM data for the concentration curves of the peptide, GLP-1 or GIP were converted to percent inhibition by subtracting nonspecific binding (binding in the presence of excess unlabeled GLP-1 or GIP, respectively) from each CPM value and dividing by the total binding signal also corrected by subtracting nonspecific binding. Four parameters (curve maximum, curve minimum, IC 50 Data were analyzed using the nonlinear regression routine (Genedata Screener, version 12.0.4, Genedata AG, Basel, Switzerland).

[0481] GIP is a 42 amino acid peptide (SEQ ID NO: 1) that is similar to GLP-1, also known as incretin, and plays a physiological role in glucose homeostasis by stimulating insulin secretion from pancreatic β cells in the presence of glucose. GLP-1 is a 36 amino acid peptide, the major biologically active fragment of which (GLP-1 7-36 ) was produced as a 30 amino acid C-terminally amidated peptide (SEQ ID NO: 2).

[0482] The compound of SEQ ID NO:3 provides the desired potency at each of the GIP receptor and the GLP-1 receptor. In one embodiment, the compound of SEQ ID NO:3 has desirable GIP and GLP receptor activity, wherein the GIP agonist potency is about 2.5:1 to about 10 times the potency of the GLP1 receptor as measured by the casein cAMP assay, wherein the potency is normalized to native GIP and GLP on the day the assay is performed. In one embodiment, the compound of SEQ ID NO:3 has desirable GIP and GLP receptor activity, wherein as described below, the GIP agonist potency is about 2.5:1 to about 5 times the potency of the GLP1 receptor as measured by the casein cAMP assay, wherein the potency is normalized to native GIP and GLP on the day the assay is performed.

[0483] As used herein, "maintenance dose" refers to an effective dose for treating a patient when the side effect profile supports long-term administration. The term "effective dose" refers to the amount or dose of a GIP:GLP-1 peptide that provides the desired effect in a patient undergoing diagnosis or treatment when administered to the patient in a single or multiple doses. The effective dose can be determined by a person skilled in the art using the clinical trials described herein and known techniques and by observing the results obtained under similar conditions. When determining the effective dose for a subject, many factors are considered, including, but not limited to: the species of the mammal, its size, age, and overall health; the specific disease or condition involved; the extent or involvement or severity of the disease or condition; the response of the individual patient; the specific compound administered; the mode of administration; the bioavailability characteristics of the administered formulation; the selected dosing regimen; the use of concomitant medications; and other relevant conditions.

[0484] As used herein, the term "titration" or "titrated dose" also means and is interchangeable with increasing or ascending dose.

[0485] As used herein, the term GIP to GLP-1 also means and can be interchanged with GIP:GLP-1. Thus, when "about 2.5 to about 10:1 GIP to GLP-1" or "about 2.5:1 to about 10:1 GIP to GLP-1" is used, it also means about 2.5 to about 10 GIP activity to 1 GLP-1 activity, or about 2.5 to about 10 GIP activity:1 GLP-1 activity.

[0486] When used herein with reference to one or more GIP or GLP-1 receptors, the terms "activity", "activation", etc. refer to the ability of a compound to bind to a receptor and induce a response at the receptor, as measured using assays known in the art (such as the in vitro assays described below). This activity can be measured in vivo using serum. As described below, the receptor agonist potency ratio of GIP:GLP-1 peptides is measured using the casein cAMP assay.

[0487] The affinity of a particular GIP:GLP-1 co-agonist compound for each of the GIP receptor and the GLP-1 receptor can be measured using techniques known in the art for measuring receptor binding levels, including, for example, those described in the Examples below, and is often expressed as a Ki value; however, the GIP potency ratio determined using the casein cAMP assay below is about 2.5 to about 10 times the receptor potency at the GLP-1 receptor.

[0488] In one embodiment, the pharmaceutical composition of the GIP:GLP-1 peptide is suitable for administration by a parenteral (e.g., subcutaneous, intravenous, intraperitoneal, intramuscular or transdermal) route. In one embodiment, the pharmaceutical composition of the GIP:GLP-1 peptide is suitable for oral administration (e.g., tablets, capsules). Such pharmaceutical compositions and methods for their preparation are generally known in the art. (See, e.g., Remington: The Science and Practice of Pharmacy (ed. DB Troy, 21st ed., Lippincott, Williams & Wilkins, 2006). In one embodiment of the invention, the route of administration is subcutaneous. In one embodiment of the invention, the route of administration is oral.

[0489] As used herein, "glycemic control" refers to maintaining or reducing a patient's HbA1c level; and "improving" glycemic control means a reduction in HbA1c.

[0490] As used herein, "weight management" refers to managing obesity in an individual; "improving" weight management refers to weight loss.

[0491] As used herein, "HbA1c" refers to the level of glycated hemoglobin, which is formed when hemoglobin binds to glucose in the blood. HbA1c levels are a common indicator of glycemic control in diabetic patients, and reduced HbA1c levels generally indicate improved glycemic control. In the case of the methods of the present invention, the methods of the present invention result in a decrease in HbA1c. In certain embodiments, the decrease in HbA1c is a decrease in HbA1c levels relative to that caused by treatment with a lower dose of GIP:GLP-1 peptide.

[0492] As used herein, the term "administering" refers to administration by a nurse, health care provider, patient or any other individual, including self-administration as directed by a physician. This includes not only delivery into the body, but also prescribing, dispensing or assisting delivery in any way.

[0493] As used herein, the terms "treat," "treating," and the like are meant to include slowing or reducing the progression of a disease or condition. These terms refer to alleviating, relieving, or reducing one or more symptoms of a disorder or condition, even if the disorder or condition is not eliminated. The terms include preventing such manifestations.

[0494] As used herein, "diabetes remission" refers to a patient who is using a GIP:GLP-1 peptide to treat diabetes achieving their glycemic control treatment goal.

[0495] As used herein, the term GIP:GLP-1 peptide is a compound or a pharmaceutically acceptable salt thereof having a GIP:GLP agonist potency ratio of about 2.5:1 to about 10:1. GIP:GLP-1 peptide treatment that cures diabetes can prevent diabetes, reduce its severity, or cause remission in such patients. In one embodiment, patients using GIP:GLP-1 peptides to treat diabetes achieve their glycemic control treatment goals and do not require concomitant diabetes medications to maintain glycemic control goals. In one embodiment, patients using GIP:GLP-1 peptides in the treatment of diabetes at least achieve their glycemic control treatment goals, and when the use of GIP:GLP-1 peptides and all other diabetes medications is discontinued, the treatment goals are still maintained. In one embodiment, patients using GIP:GLP-1 peptides in the treatment of diabetes at least achieve their glycemic control treatment goals, and when the use of GIP:GLP-1 peptides and all other diabetes medications is discontinued, the treatment goals are maintained for at least about one month. In one embodiment, a patient using a GIP:GLP-1 peptide in the treatment of diabetes achieves at least their glycemic control treatment goal, and the treatment goal is maintained for at least about six months when the GIP:GLP-1 peptide and all other diabetes medications are discontinued. In one embodiment, the patient was unable to achieve their glycemic goal prior to GIP:GLP-1 peptide treatment. In one embodiment, the patient did not achieve their glycemic goal using oral diabetes medications. In one embodiment, the patient did not achieve their glycemic goal using metformin treatment. In one embodiment, the patient's glycemic goal is less than about 5.7%.

[0496] As used herein, "patient" refers to a mammal in need of treatment for a condition or disorder. In one embodiment, the patient is a human suffering from a disease or condition that would benefit from treatment with a GIP:GLP-1 peptide, wherein the peptide has a GIP:GLP-1 receptor agonist potency ratio of about 2.5:1 to about 10:1.

[0497] As used herein, "EDTA" refers to ethylenediaminetetraacetic acid. As used herein, "DMSO" refers to dimethyl sulfoxide. As used herein, "CPM" refers to counts per minute. As used herein, "IBMX" refers to 3-isobutyl-1-methylxanthine. As used herein, "LC / MS" refers to liquid chromatography / mass spectrometry. As used herein, "HTRF" refers to homogeneous time-resolved fluorescence. As used herein, "BSA" refers to bovine serum albumin.

[0498] Cures diabetes, causes remission or regression of diabetes, or prevents diabetes

[0499] Despite advances in diabetes treatment, many patients receiving such treatments are unable to achieve their glycemic control goals or HbA1c goals. The present invention provides a cure for diabetes, wherein patients receiving treatment for diabetes using GIP:GLP1 peptides are able to achieve their HbA1c goals, and wherein such patients maintain their HbA1c goals after cessation of GIP:GLP1 peptide treatment. In one embodiment, patients receiving GIP:GLP1 peptide treatment for diabetes maintain their HbA1c goals after discontinuation of all drugs approved for the treatment of glycemic control or diabetes. As used herein, the terms "diabetes drug", "diabetes drug", etc. refer to drugs approved by relevant regulatory agencies for the treatment of type 2 diabetes or glycemic control. In one embodiment, the HbA1c value in patients receiving diabetes treatment is less than or equal to about 5.9%. In one embodiment, the patient maintains his or her HbA1c target level for at least one month without further administration of GIP:GLP1 peptide. In one embodiment, a patient previously treated for diabetes with a GIP:GLP1 peptide maintains their target HbA1 level for at least one month without further administration of the GIP:GLP1 peptide or any other diabetes medication. In one embodiment, a patient maintains their target HbA1c level for at least 6 months without further administration of the GIP:GLP1 peptide or any other diabetes medication.

[0500] As used herein, the term "amino acid" refers to both naturally occurring amino acids and non-natural amino acids. Amino acids are generally described using standard single-letter codes (e.g., L = leucine) as well as α-methyl substituted residues of natural amino acids (e.g., α-methylleucine, or αMeL and α-methyllysine, or αMeK) and certain other non-natural amino acids such as α-aminoisobutyric acid or "Aib", "4Pal", "Orn", etc. The structures of these amino acids are shown below:

[0501]

[0502]

[0503] As used herein, "Orn" refers to ornithine. As used herein, "4Pal" refers to 3-(4-pyridyl)-L-alanine. As used herein, "αMeF(2F)" refers to α-methyl 2-Fl-phenylalanine. As used herein, "αMeY", "αMeK" and "αMeL" refer to α-methyltyrosine, α-methyllysine and α-methylleucine, respectively. As used herein, "e" and "D-Glu" refer to D-glutamic acid.

[0504] As used in this article, the term "with C 16 -C 22"Fatty acid conjugated amino acid" refers to any natural or unnatural amino acid having a functional group, wherein the functional group has been chemically modified for conjugation to a fatty acid by direct bonding to the fatty acid or, preferably, through a linker. Examples of such functional groups include amino, carboxyl, chloro, bromo, iodo, azido, alkynyl, alkenyl, and thiol groups. Examples of natural amino acids containing such functional groups include K (amino), C (thiol), E (carboxyl), and D (carboxyl). In one embodiment, the conjugated amino acid is K.

[0505] As used herein, the term "C 16 -C 22 "Fatty acid" refers to a carboxylic acid having between 16 and 22 carbon atoms. In one embodiment, the C 16 -C 22 The fatty acid may be a saturated diacid. In one embodiment, the fatty acid is C 20 -C 22 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 18 and 20. In one embodiment, q is 18. In one embodiment, q is 20.

[0506] In one embodiment, specific saturated C 16 -C 22 Fatty acids include, but are not limited to, hexadecanoic acid (C 16 Diacid), heptadecanedioic acid (C 17 diacid), octadecyldioic acid (C 18 diacid), nonadecyldioic acid (C 19 diacid), eicosanedioic acid (C 20 Diacid), heneicosane dioic acid (C 21 Docosanoic acid (C 22 diacids), including branched and substituted derivatives thereof.

[0507] In one embodiment, C 16 -C 22 Fatty acids are selected from saturated C 18 Diacid, saturated C 19 Diacid, saturated C 20 Diacids and their branched and substituted derivatives. In one embodiment, C 16 -C 22 The fatty acid is selected from stearic acid, arachidic acid and eicosandioic acid. 16 -C 22 The fatty acid is arachidic acid.

[0508] As used herein, "time extension technology" refers to peptide time extension technology, such as recombinant human serum albumin ("rHSA"), peptides conjugated to pharmaceutically acceptable polymers, such as polymer sequences of amino acids ("XTEN"), non-sulfated heparin-like glycopolymers ("HEP"), hydroxyethyl starch ("HES"), alpaca heavy chain antibody fragments ("VHH"), PEGylation, Fc conjugation, bovine serum albumin ("BSA") (Sleep, D. Epert Opin Drug Del (2015) 12, 793-812; Podust VN et al. J Control. Release, 2015; ePUB; Hey, T. et al., cited in: R. Kontermann (ed.), Therapeutic Proteins: Strategies to Modulate their Plasma Half-Lives, Wiley-VCH VerlagGmbh&Co.KGaA, Weinheim, Germany, 2012, pp. 117-140; DeAngelis, PL, Drug Dev Delivery (2013) January, 12 / 31 / 2012. In one embodiment, the time extension technique is applied using a linker group. In one embodiment, 0, 1, 2 or 3 amino acids are used as linkers and the time extension technique is applied.

[0509] Compounds having a GIP potency ratio of about 2.5 to about 10 times the receptor potency at the GLP-1 receptor can be further modified using peptide time extension technology, such as recombinant human serum albumin ("rHSA"), peptides conjugated to pharmaceutically acceptable polymers such as polymer sequences of amino acids ("XTEN"), non-sulfated heparin-like glycopolymers ("HEP"), and hydroxyethyl starch ("HES").

[0510] In one embodiment is a GIP:GLP-1 peptide of the formula:

[0511] R 1 X 1 X 2 X 3 GTX 6 TSDX 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 25X 26 X 27 X 28 X 29 X 30 X 31 (SEQ ID NO:3)

[0512] in:

[0513] R 1 is an N-terminal amino modification, wherein the modification is selected from Ac and absent;

[0514] X 1 is selected from the group consisting of Y, H, D-Tyr, F, desH and desY,

[0515] X 2 Selected from Aib, αMeP, A, P and D-Ala;

[0516] or X 1 and X 2 Combine to form desH-ψ[NHCO]-Aib;

[0517] X 3 Selected from E, N, Aad and cTA;

[0518] X 6 Selected from F, αMeF and αMeF(2F);

[0519] X 10 Selected from 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-(CH 2 )qCO 2 H;

[0520] X 11 Selected from S, αMeS and D-Ser;

[0521] X 12 Selected from I, S, D-Ile and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H;

[0522] X 13 Selected from Nle, ib, L, αMeL and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH2 )qCO 2 H;

[0523] X 14 Selected from L and K, where K and C 16 -C 22 Fatty acid conjugation, wherein the fatty acid is optionally conjugated to the K via a linker;

[0524] X 16 Selected from K, E, Orn, Dab, Dap, S, T, H, ib, αMeK, R and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H;

[0525] X 17 Select from K, Q, I and C 16 -C 22 Fatty acid-conjugated amino acids, wherein the fatty acid is optionally conjugated to the amino acid via a linker;

[0526] X 19 Selected from Q, A and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H;

[0527] X 20 Selected from Aib, Q, H, R, K, αMeK and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H;

[0528] X 21 Selected from H, Aad, D, Aib, T, A, E, I and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H;

[0529] X 22 Selected from F and αMeF;

[0530] X 23 Selected from I, L, A, G, F, H, E, V and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH2 )qCO 2 H;

[0531] X 24 Selected from 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-(CH 2 )qCO 2 H;

[0532] X 25 is selected from Y and αMeY;

[0533] X 26 Selected from L, αMeL and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H;

[0534] X 27 Selected from L, I and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H;

[0535] X 28 Selected from E, A, S, D-Glu and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H;

[0536] X 29 Selected from Aib, G, A and K (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )qCO 2 H;

[0537] X 30 Selected from C, G, GR 2 and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H;

[0538] X 31 Not present or selected from PX 32 X33 X 34 -R 2 (SEQ ID NO:4), PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2 (SEQ ID NO:5) 、 PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R 2 (SEQ ID NO: 6), K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 -R 2 (SEQ ID NO: 7), K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 --(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2 (SEQ ID NO: 8), and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R 2 (SEQ ID NO:9);

[0539] in:

[0540] X 32 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H];

[0541] X 33 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H];

[0542] X 34 Selected from G, C and K [(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H];

[0543] X 35 is A or K [(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H];

[0544] X 36 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H];

[0545] X 37 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H];

[0546] X 38 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H];

[0547] X 39Selected from C, S and K [(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H];

[0548] X 40 Selected from C and K [(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γ-Glu)-CO-(CH 2 )q-CO 2 H];

[0549] q is selected from the group consisting of 14, 15, 16, 17, 18, 19 and 20; and

[0550] R 2 is a modification of the C-terminal group, where the modification is NH 2 or does not exist;

[0551] or a pharmaceutically acceptable salt thereof;

[0552] If X 30 It is GR 2 , then X 31 does not exist;

[0553] Where 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 No more than one of the substituents may be a fatty acid-containing substituent; and

[0554] Where X 30 , X 34 , X 39 and X 40No more than one of them can be C; and

[0555] If X 30 , X 34 , X 39 and X 40 One of them is C, then 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 None of them contain fatty acid substituents;

[0556] wherein the GIP:GLP-1 peptides have a receptor agonist potency ratio of about 2.5:1 to about 10:1.

[0557] Another embodiment provides a novel GIP:GLP-1 peptide of SEQ ID NO:3, wherein the GIP:GLP-1 peptide has a GIP:GLP-1 receptor agonist potency ratio of about 2.5:1 to about 5:1. Another embodiment of the present invention is a novel GIP:GLP-1 peptide of SEQ ID NO:3, wherein the GIP:GLP-1 peptide has a GIP:GLP-1 receptor agonist potency ratio of about 2.5:1 to about 3.5:1.

[0558] The invention is further illustrated by the following compounds demonstrating desirable GIP potency ratios of about 2.5:1 to about 10-fold greater than receptor potency at the GLP-1 receptor using the cAMP casein assay, however, the peptides of these examples are not to be construed as limiting.

[0559] Peptide Synthesis-Peptide 1

[0560] Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LDEK((2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -(γGlu)-CO-(CH 2 ) 18 -CO 2 H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH 2 (SEQ ID NO: 10).

[0561] The structure of SEQ ID NO: 10 is described below using the standard single letter amino acid code, with the exception of residues Aib2, αMeF(2F)6, αMeL13, K17, ib20, D-Glu24, and Ser39, where the structures of these amino acid residues have been enlarged:

[0562]

[0563] The peptide backbone of Peptide 1 was synthesized on a Symphony X peptide synthesizer (Gyros Protein Technologies. Tucson, AZ) using fluorenylmethoxycarbonyl (Fmoc) / tert-butyl (t-Bu) chemistry.

[0564] The resin is composed of 1% DVB cross-linked polystyrene (Fmoc-Rink-MBHA low-load resin, 100-200 mesh, EMDMillipore) at a substitution rate of 0.3-0.4 meq / g. Standard side chain protecting groups are used. Fmoc-Lys(Mtt)-OH is used for lysine at position 17 and Boc-Tyr(tBu)-OH is used for tyrosine at position 1). The Fmoc group is removed using 20% ​​piperidine in DMF before each coupling step (2x 7 minutes). Using an equimolar ratio of Fmoc amino acids (0.3mM), diisopropylcarbodiimide (0.9mM) and Oxyma (0.9mM), all standard amino acid couplings are performed for 1 hour for primary amines and 3 hours for secondary amines with a 9-fold molar excess over the theoretical peptide loading. The exception is the coupling with Cα-methylated amino acids, which is coupled for 3 hours. After completion of the peptide backbone synthesis, the resin was washed thoroughly 6 times with DCM to remove residual DMF. The Mtt protecting group on the lysine at position 17 was selectively removed from the peptide resin by treatment with 30% hexafluoroisopropanol (Oakwood Chemicals) in DCM twice (2 x 40 min treatments).

[0565] The subsequent fatty acid linker moiety was connected by coupling 2-[2-(2-Fmoc-amino-ethoxy)-ethoxy]-acetic acid (Fmoc-AEEA-OH, ChemPep, Inc.), Fmoc-glutamic acid α-tert-butyl ester (Fmoc-Glu-OtBu, Ark Pharm, Inc.), eicosandioic acid (WuXiAppTec, Shanghai, China). A 3-fold excess of reagents (AA: PyAOP: DIPEA = 1: 1: 1 mol / mol) was used for each coupling for 1 hour.

[0566] After the synthesis is complete, the peptide resin is washed with DCM, and then thoroughly dried. The dry resin is treated with 10mL cleavage mixture (trifluoroacetic acid: water: triisopropylsilane, 95:2.5:2.5v / v) at room temperature for 2 hours. Filter out the resin, wash twice, each time with 2mL anhydrous T'FA, and the filtrate combined is treated with 5 times of cold ether (-20 ℃) ​​of excess volume, to precipitate the crude peptide. Subsequently, the peptide / ether suspension is centrifuged for 2 minutes at 3500 rpm, to form a solid precipitate, the supernatant is decanted, and the solid precipitate is ground twice and vacuum dried with ether. The crude peptide is dissolved in 20% acetonitrile / 20% acetic acid / 60% water and purified by RP-HPLC on Luna 5μm phenyl-hexyl preparation column (21x 250mm, Phenomenex) with a linear gradient (30-50% acetonitrile in 60 minutes) of 100% acetonitrile and 0.1% TFA / water buffer system. Peptide purity was assessed using analytical RP-HPLC and the pooling criteria was >95%. The main pool of compound 1 was found to be 98.0% pure. The final main product pool was then lyophilized to produce the lyophilized peptide TFA salt. The molecular weight was determined by LC-MS (found: M+3=1657.2; calculated M+3=1657.0).

[0567] Peptide 2 to Peptide 265

[0568] The compounds Peptide 2 (SEQ ID NO: 11) to Peptide 265 (SEQ ID NO: 145) shown in Table 1 below were prepared essentially as described for the Peptide 1 procedure.

[0569] Binding assay

[0570] Glucagon (referred to as Gcg) is a reference substance prepared by Eli Lilly and Company in the United States. GLP-1, 7-36-NH 2(referred to as GLP-1) was obtained from CPC Scientific (Sunnyvale, CA, 97.2% purity, 100 μM aliquots in 100% DMSO). GIP 1-42 (referred to as GIP) (>80% purity, 100 μM aliquots in 100% DMSO) was prepared at Eli Lilly Research Laboratories using peptide synthesis and HPLC chromatography as described above. 125 I]-lactoperoxidase, prepared [ 125 I] Radiolabeled Gcg, GLP-1 or GIP.

[0571] Stably transfected cell lines were prepared by subcloning the receptor cDNA into the pcDNA3 expression plasmid and transfecting into human embryonic kidney (HEK) 293 (hGcgR and hGLP-1R) or Chinese hamster ovary (CHO) (hGIPR) cells, followed by selection with Geneticin (hGLP-1R and hGIPR) or Hygromycin B (hGcgR).

[0572] Two methods were used to prepare crude cell membranes.

[0573] Method 1 The frozen cell pellet was incubated on ice in 50 mM Tris HCl, pH 7.5, and Roche Complete TM Lyse in hypotonic buffer containing protease inhibitors. The cell suspension was broken up by hitting 25 times with a glass Potter-Elvehjem homogenizer with a pestle. The homogenate was centrifuged at 1100 x g for 10 minutes at 4°C. The supernatant was collected and stored on ice, while the pellet was resuspended in homogenization buffer and homogenized again as described above. The homogenate was centrifuged at 1100 x g for 10 minutes. The second supernatant was combined with the first supernatant and centrifuged at 35000 x g for 1 hour at 4°C. The resulting membrane pellet was resuspended in homogenization buffer containing about 1 to 3 mg / mL protease inhibitors, snap frozen in liquid nitrogen and stored as aliquots in a -80°C freezer until use.

[0574] Method 2 The frozen cell pellet was incubated on ice in 50 mM Tris HCl, pH 7.5, 1 mM MgCl 2 、Roche Complete TM Lyse in hypotonic buffer containing EDTA-free protease inhibitors and 25 units / ml DNase I (Invitrogen). The glass Potter-Elvehjem homogenizer of pestle hits 20 to 25 times to break up the cell suspension. The homogenate is centrifuged at 1800x g for 15 minutes at 4°C. The supernatant is collected and stored on ice, and the precipitate is resuspended in homogenization buffer (without DNase I) and homogenized again as described above. The homogenate is centrifuged at 1800x g for 15 minutes. The second supernatant is merged with the first supernatant and centrifuged at 1800x g for an additional 15 minutes. The entire homogenate is then centrifuged at 25000x g for 30 minutes at 4°C. The resulting membrane precipitate is resuspended in a homogenization buffer (without DNase I) containing approximately 1 to 3mg / mL protease inhibitors and stored in a -80°C refrigerator as aliquots until use.

[0575] Binding assay

[0576] because[ 125 I] The parent material was high in propanol, therefore, the equilibrium binding dissociation constants (K) for various receptor / radioligand interactions were determined from homogeneous competition binding assays. d ) rather than from saturation binding. K determined for receptor preparations d Values ​​are as follows: hGcgR (3.9 nM), hGLP-1R (1.2 nM), and hGIPR (0.14 nM).

[0577] [ 125 I]-glucagon binding

[0578] Human Gcg receptor binding assays were performed using wheat germ agglutinin (WGA) beads (Perkin Elmer) in scintillation counting proximity assay (SPA) mode. The binding buffer contained 25 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH 7.4, 2.5 mM CaCl 2 , 1 mM MgCl 2 , 0.1% (w / v) bacitracin (Research Products), 0.003% (w / v) polyoxyethylene sorbitan monolaurate ( -20) and Roche Complete EDTA-free TM Protease inhibitors. Peptides and Gcg were thawed and serially diluted 3-fold in 100% DMSO (10-point concentration response curve). Subsequently, 5 μL of the serially diluted compound or DMSO was transferred into 3632 clear bottom assay plates containing 45 μL of assay binding buffer or unlabeled Gcg control (non-specific binding or NSB, final concentration 1 μM). Subsequently, 50 μL of [ 125I]-Gcg (final concentration 0.15 nM), 50 μL human GcgR membrane (1.5 μg / well) and 50 μL WGA SPA beads (80 to 150 μg / well). The plate was sealed and mixed on a plate shaker (setting 6) for 1 minute and then incubated at room temperature for 12 hours after incubation / sedimentation time using a PerkinElmer Trilux Scintillation counter readings. Final assay concentrations typically ranged from 1150 nM to 0.058 nM for the peptides tested in the response curves and from 1000 nM to 0.05 nM for the control Gcg.

[0579] [ 125 I]-GLP-1 binding

[0580] Human GLP-1 receptor binding assay was performed with WGA beads using SPA mode. Binding buffer contained 25 mM HEPES, pH 7.4, 2.5 mM CaCl 2 , 1 mM MgCl 2 , 0.1% (w / v) bacitracin, 0.003% (w / v) -20 and Roche Complete EDTA-free TM Protease inhibitors. Peptides and GLP-1 were thawed and serially diluted 3-fold in 100% DMSO (10 point concentration response curve). Subsequently, 5 μL of serially diluted compound or DMSO was transferred into 3632 clear bottom assay plates containing 45 μL of assay binding buffer or unlabeled GLP-1 control (non-specific binding or NSB, final concentration 0.25 μM). Subsequently, 50 μL of [ 125 I]-GLP-1 (final concentration 0.15 nM), 50 μL human GLP-1R membrane (0.5 μg / well) and 50 μL WGA SPA beads (100 to 150 μg / well). The plate was sealed and mixed on a plate shaker (setting 6) for 1 minute and after 5 to 12 hours incubation / sedimentation time at room temperature with a PerkinElmer Trilux Scintillation counter readings. The final assay concentration range for the peptides tested in the response curves was generally 1150 nM to 0.058 nM and for the control GLP-1 was 250 nM to 0.013 nM.

[0581] [ 125 I]-GIP binding

[0582] Human GIP receptor binding assay was performed with WGA beads using SPA mode. The binding buffer contained 25 mM HEPES, pH 7.4, 2.5 mM CaCl 2 , 1 mM MgCl 2, 0.1% (w / v) bacitracin, 0.003% (w / v) -20 and Roche Complete EDTA-free TM Protease inhibitors. Peptides and GIP were thawed and serially diluted 3-fold in 100% DMSO (10 point concentration response curve). Subsequently, 5 μL of serially diluted compound or DMSO was transferred into 3632 clear bottom assay plates containing 45 μL of assay binding buffer or unlabeled GIP control (non-specific binding or NSB, final concentration 0.25 μM). Subsequently, 50 μL of [ 125 I]-GIP (final concentration 0.075-0.15 nM), 50 μL human GIPR membrane (3 μg / well) and 50 μL WGA SPA beads (100 to 150 μg / well). The plate was sealed and mixed on a plate shaker (setting 6) for 1 minute and after 2.5 to 12 hours incubation / sedimentation time at room temperature with a PerkinElmer Trilux Scintillation counter readings. The final assay concentration range for the peptides tested in the response curves was typically 1150 to 0.058 nM or 115 nM to 0.0058 nM, while the control GIP was 250 nM to 0.013 nM.

[0583] Normalization of binding assay data

[0584] The raw CPM data of the concentration curves of peptide, Gcg, GLP-1 or GIP were converted to percent inhibition by subtracting nonspecific binding (binding in the presence of excess unlabeled Gcg, GLP-1 or GIP, respectively) from each CPM value and dividing by the total binding signal also corrected for subtracting nonspecific binding. Four parameters (curve maximum, curve minimum, IC 50 The data were analyzed using the nonlinear regression routine (Genedata Screener, version 12.0.4, Genedata AG, Basel, Switzerland). i =IC 50 / (1+D / K d ), from IC 50 Absolute value calculation of affinity constant (K i ), where D = the concentration of radioligand used in the experiment, IC 50 is the concentration causing 50% inhibition of binding, K d is the equilibrium binding dissociation constant of the radioligand (described above). K iValues ​​are reported as geometric means, with errors expressed as standard errors of the mean (SEM), and n equal to the number of independent replicates (measured in experiments performed on different days). The geometric mean is calculated as follows:

[0585] Geometric mean = 10^(arithmetic mean of Log Ki values)

[0586] Calculate the Ki ratio (Ki of native control peptide / Ki of test compound) at each receptor and each substance. The Ki ratio is a quick indication of the apparent affinity of the peptide compared to the native control peptide. A Ki ratio <1 indicates that the test peptide has a lower affinity (higher Ki value) for the receptor than the native peptide, while a Ki ratio >1 indicates that the test peptide has a higher affinity (lower Ki value) for the receptor than the native peptide. Example 1

[0587] cAMP pharmacological function assay in the presence of casein

[0588] An additional set of cAMP assays was performed in HEK293 cells expressing human GLP-1 receptor (GLP-1R), gastric inhibitory peptide receptor (GIPR), glucagon receptor (GcgR). The pharmacological activity of hGLP1R / GIPR peptides was determined in HEK293 cells stably expressing human GLP-1 receptor (GLP-1R), gastric inhibitory peptide receptor (GIPR), or GLP-2 receptor (GLP-2R). Each cell line overexpressing the receptor (20 μl) was treated with the test peptide in DMEM (Gibco catalog number 31053) supplemented with 0.1% casein (Sigma catalog number C4765), 250 μM IBMX, 1X GlutaMAXTM (Gibco catalog number 35050), and 20 mM HEPES (HyClone catalog number SH30237.01) in a 20 μl test volume. After 60 minutes of incubation at room temperature, the resulting intracellular cAMP increase was quantitatively determined using the CisBio cAMPDynamic 2HTRF assay kit (62AM4PEJ). Lysis buffer containing cAMP-d2 conjugate (20 μl) and antibody anti-cAMP-Eu3+-cryptate (20 μl) was subsequently added to determine cAMP levels. After 1 hour of incubation at room temperature, the HTRF signal was detected using an Envision2104 plate reader (PerkinElmer). The two incubation steps (60 minutes and 1 hour) can each be implemented at about room temperature or about 37°C, as long as the 60-minute incubation and 1-hour incubation are completed at about the same temperature for each run of the assay. Fluorescence emission at 620 nm and 665 nm was measured and the ratio between 620 nm and 665 nm was calculated, and then converted to nM cAMP per well using the cAMP standard curve. Dose response curves for compounds were plotted as percent stimulation normalized to minimum (buffer only) and maximum (maximum concentration of each control ligand) and analyzed using a four-parameter nonlinear regression fit with variable slope (Genedata Screener 13). The EC50 is the concentration of compound that causes a half-maximal simulated effect in the dose response curve. Relative EC50 was derived by nonlinear regression analysis using the percent maximal response versus the concentration of peptide added for a four-parameter logistic equation fit. 50 value.

[0589] Using homogeneous time-resolved fluorescence, assays were performed to determine the intrinsic potency of the example and control molecules in the presence of casein (instead of serum albumin) as a non-specific blocking agent that does not interact with the fatty acid moieties of the molecules being analyzed.

[0590] Intracellular cAMP levels were determined by extrapolation using the standard curve. Compound dose response curves were plotted as percent stimulation normalized to minimum (buffer only) and maximum (maximum concentration of each control ligand) and analyzed using a four-parameter nonlinear regression fit with variable slope (Genedata Screener 13). EC 50 is the concentration of compound that causes half-maximal simulated effect in the dose response curve. Each relative EC50 value used for geometric mean calculation was determined from the curve fit.

[0591] Compound concentration response curves were plotted as percent stimulation normalized to minimum (buffer only) and maximum (maximum concentration of each control ligand) values ​​and analyzed using a four-parameter nonlinear regression fit with variable slope (GenedataScreener 13). The EC50 is the concentration of compound that causes half the maximal simulated effect in the dose response curve.

[0592] Calculate EC as follows 50 Summary Statistics:

[0593] Geometric mean:

[0594] GM=10^(log 10 Converted EC 50 arithmetic mean of the values).

[0595] The standard error of the mean is reported as follows:

[0596] SEM = geometric mean x (log 10 Converted EC 50 standard deviation of the values / square root of the number of runs)xlog e 10.

[0597] Logarithmic transformation leads to EC 50 Values ​​decrease on a multiple scale rather than an arithmetic scale.

[0598] The assay was run daily with the test peptides as well as the native ligands GIP and GLP-1 and buffer only as baseline (minimum), and the highest concentration of the corresponding GIP and GLP-1 standards of the day was used as maximum for calculations.

[0599] Table 1: Functional activation of hGLP-1R and hGIPR in the presence of 0.1% casein.

[0600]

[0601]

[0602]

[0603]

[0604]

[0605]

[0606]

[0607]

[0608]

[0609]

[0610]

[0611]

[0612]

[0613] As demonstrated by the data in Table 1, peptides normalized to baseline and native peptide stimulated cAMP from both human GLP-1R and GIPR in the presence of 0.1% casein with GIP potency ratios ranging from about 2.5-fold to about 10-fold that of the GLP-1 receptor.

[0614] In one embodiment is a GIP:GLP-1 co-agonist compound, wherein the peptide is a potent GIPR / GLP-1R dual agonist that is a partial agonist to GLP-1R, such as through cell membrane guanosine 5'-(γ-thio) triphosphate-[ 35 S] (GTPγS) binding assay, and is a partial agonist for GLP-1R as shown by β-arrestin-2 recruitment assay. One embodiment is a GIP:GLP-1 co-agonist compound or a pharmaceutically acceptable salt thereof, wherein the compound has a GLP-1R HEK293 cell membrane guanosine 5'-(γ-thio) triphosphate-[ 35 Gα S](GTPγS) binding assay induced by GLP-1R stimulation s Activation. In one embodiment, the GLP-1R HEK293 cell membrane guanosine 5'-(γ-thio) triphosphate-[ 35 Compounds that show a partial agonism of 75% or less in the [S](GTPγS) binding assay and a partial agonism of 35% or less in the GLP-CHO cell β-arrestin recruitment assay.

[0615] In one embodiment is a method for treating diabetes, the method comprising administering an effective amount of guanosine 5'-(γ-thio) triphosphate-[ 35 S] (GTPγS) binding assay and an effective amount of a compound as a GIP agonist. In one embodiment, guanosine 5'-(γ-thio) triphosphate-[ 35 Compounds that show partial agonism in the [S](GTPγS) binding assay are co-administered with compounds that have GIP agonist activity. In one embodiment, guanosine 5'-(γ-thio) triphosphate-[ 35 A compound that exhibits partial agonism in a [S](GTPγS) binding assay is administered as an active substance within one week before or after a compound having GIP agonist activity. In one embodiment, a method for treating diabetes comprises administering an effective amount of a compound that exhibits 35% or less partial agonism in a GLP-CHO cell β-arrestin recruitment assay and administering an effective amount of a compound that exhibits guanosine 5'-(γ-thio) triphosphate-[S](GTPγS) binding assay in a GLP-1RHEK293 cell membrane. 35 Compounds that show partial agonism of 75% or less in the [S](GTPyS) binding assay.

[0616] GLP-1R HEK293 cell membrane [ 35 S]GTPγS binding assay

[0617] GLP-1 receptors are GTP-bound Gα receptors that increase upon ligand-induced receptor activation. s G-protein coupled receptors. Gα expression induced by peptide stimulation of GLP-1R was determined using purified membrane preparations from HEK293 cells expressing human GLP-1R. s The assay was performed in a manner similar to that described previously (Bueno et al., J. Biol. Chem., (2016) 291, 10700 and Willard et al., Mol. Pharmacol. (2012) 82, 1066). The peptides to be tested were dissolved in DMSO and diluted in 20 mm HEPES pH 7.4, 50 mm NaCl, 5 mm MgCl 2 , 40 μg / ml saponin, 0.1% BSA and 500 pm 35 5 μg of membranes labeled with S-GTPγS were added to the reaction buffer at room temperature for 30 min. sThe reaction was terminated with 0.2% Nonidet P-40 detergent with polyclonal antibody and 0.5 mg anti-rabbit polyvinyltoluene beads. The mixture was developed for 30 min, centrifuged at 80 × g for 10 min, and counted for 1 min / well using a MicroBeta TriLux instrument. The peptide concentration-response curves were fitted to a four-parameter logistic model and the EC 50 The efficacy of the peptide was determined. DMSO and GLP-1 (7-36) were used as the minimum and maximum controls of the receptor, and the stimulation % was normalized (Campbell et al., Assay Guidance Manual 2017). The Gα induced by the sample peptide stimulating the GIPR was determined. s The potency results confirmed that the peptide was a Gα s Partial agonist at activated GLP-1R.

[0618] GLP-1R CHO cell β-arrestin recruitment assay

[0619] Activated G-protein coupled receptors can interact with the β-arrestin family of signaling proteins. The efficacy of peptides on GLP-1R-induced arrestin recruitment was determined using the PathHunter enzyme fragment complementation method essentially as described in (von Degenfeld et al., FASEB J., 2007 (14): 3819-26 and Hamdouchi et al., J. Med Chem., 2016 59 (24): 10891-10916). CHO-K1 cells expressing human GLP-1R with a Pro-Link tag and β-arrestin-2 with an enzyme-acceptor tag can be obtained from DiscoveRx and prepared as frozen cells for the assay. The test peptides were dissolved in DMSO and serially diluted using an Echo acoustic dispenser (LabCyte). The assay medium was PathHunter cell assay buffer (DiscoveRx) containing 0.1% w / v hydrolyzed casein (Sigma). In a 384-well plate, 100 nl of peptide was dispensed into 10 μl of assay medium and then 10 μl of cells in assay medium were added to yield 5000 cells / well. Plates were incubated at 37°C / 5% CO 2 The plates were incubated in an incubator for 90 minutes, 10 μl of PathHunter detection reagent (DiscoveRx) was added and the plates were incubated at room temperature for 60 minutes. The luminescent signal was measured. The peptide concentration-response curves were fitted to a four-parameter logistic model and the EC 50The efficacy of the peptides was determined. The data were normalized for % stimulation using DMSO and GLP-1 (7-36) as minimum and maximum controls (Campbell et al., Assay Guidance Manual 2017). The efficacy of the sample peptides in stimulating β-arrestin recruitment caused by GLP-1R was determined. The efficacy results determined that the peptides were partial agonists on GLP-1R for β-arrestin-2 recruitment.

[0620] Clinical study to determine maintenance dose of GIP:GLP-1 peptide

[0621] A 6-month (26-week) Phase II double-blind clinical study was designed to evaluate the safety, efficacy and PK / PD of four dose levels (1 mg, 5 mg, 10 mg and 15 mg) of GIP:GLP-1 peptide administered once weekly (QW) in patients with T2DM who had inadequate glycemic control with controlled diet and exercise, with or without stable doses of metformin, compared with dulaglutide 1.5 mg and placebo QW. The GIP:GLP peptide dose was titrated upward to the maintenance dose using the following weekly dose increments:

[0622]

[0623] The study also has a 4-week follow-up phase. In addition to safety and efficacy in treating T2DM, efficacy endpoints include the effects of GIP:GLP-1 peptide on HbA1c, FBG, body weight, lipids, and waist circumference compared with placebo and with dulaglutide 1.5 mg. The study also evaluated the effects of GIP:GLP-1 peptide on GI tolerability, hypoglycemia, hypersensitivity reactions, and pancreatic safety, as well as the development of anti-drug antibodies that occurred during treatment. Model-based dose-response analyses were performed to predict the likelihood of significant reductions in HbA1c and weight loss in longer-term studies.

[0624] Statistical analysis

[0625] Effectiveness : The primary efficacy outcome of change in HbA1c from baseline to the 26-week endpoint was analyzed using a Bayesian dose-response model. The analysis was performed on the intention-to-treat population (mITT) analysis set. Supportive analysis of the primary efficacy outcome of the mITT data set was based on body mass index (BMI) (<30 kg / m 2 , ≥30kg / m 2 ), metformin use, treatment, visit, and treatment-by-visit interaction as fixed effects, baseline HbA1c as a covariate, and patient as a random effect.

[0626] Similar dose-effect models were used to analyze mean changes from baseline in body weight at weeks 12 and 26, and mean change from baseline in HbA1c at week 12 as the primary analysis. The percentage of patients with a weight loss of ≥5% or ≥10%, achieving an HbA1c goal of ≤6.5% or ≤7.0% at week 26, or requiring rescue therapy were analyzed using logistic regression with fixed effects of treatment and stratification and baseline as covariates. FBG (fasting blood glucose), SMBG (self-monitored blood glucose) levels, change from baseline in waist circumference, and mean percentage changes from baseline to weeks 12 and 26 in lipids were analyzed using a similar MMRM as used for the primary analysis.

[0627] Clinical study to determine the GIP:GLP-1 peptide titration schedule

[0628] This is a 12-week treatment with 1 week screening (visit 1), followed by 1 week introduction (visit 2), followed by 12 weeks of treatment (visits 3-10, including telephone visits), and then 4 weeks of safety visits. It is a Phase II study designed to investigate the efficacy and tolerability of subcutaneously administered GIP:GLP-1 peptide once weekly compared to placebo in patients with type 2 diabetes who have inadequate glycemic control with diet and exercise alone or with a stable dose of metformin. The study was designed and conducted to refine the titration regimen as described below.

[0629]

[0630]

[0631] Amino acid sequence

[0632] SEQ ID NO:1

[0633] GIP(people)

[0634] YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ

[0635] SEQ ID NO:2

[0636] GLP-1(7-36)(Human)

[0637] HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH 2 SEQ ID NO:3

[0638] R 1 X 1 X 2 X 3 GT X 6 TSD X10 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

[0639] SEQ ID NO:4

[0640] PX 32 X 33 X 34 -R 2

[0641] SEQ ID NO:5

[0642] PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2

[0643] SEQ ID NO:6

[0644] PX 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R 2

[0645] SEQ ID NO:7

[0646] K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -γGlu-CO-(CH 2 )q-CO 2 H]X 32 X 33X 34 -R 2

[0647] SEQ ID NO:8

[0648] K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -γGlu-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 -R 2

[0649] SEQ ID NO:9

[0650] K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl) 2 -γGlu-CO-(CH 2 )q-CO 2 H]X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 X 40 -R 2 .

Claims

1. A method for treating type 2 diabetes in a patient in need thereof, comprising: a) administering to said patient titrated doses 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 subsequently b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; The titration dose is approximately 50% of the maintenance dose.

2. A method for treating type 2 diabetes in a patient in need thereof, comprising: a) administering to said patient a first titrated 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 subsequently b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

3. A method for treating type 2 diabetes in a patient in need thereof, comprising: a) administering to said patient a first titrated 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 subsequently b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

4. Methods to improve glycemic control in patients in need, including: a) administering to said patient titrated doses 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 subsequently b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; The titration dose is approximately 50% of the maintenance dose.

5. Methods to improve glycemic control in patients in need, including: a) administering to said patient a first titrated 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 subsequently b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

6. Methods to improve glycemic control in patients in need, including: a) administering to said patient a first titrated 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 subsequently b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

7. Methods to improve weight management in patients in need, including: a) administering to said patient titrated doses 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 subsequently b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; The titration dose is approximately 50% of the maintenance dose.

8. Methods to improve weight management in patients in need, including: a) administering to said patient a first titrated 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 subsequently b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

9. Methods to improve weight management in patients in need, including: a) administering to said patient a first titrated 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 subsequently b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

10. Methods of treating chronic kidney disease in patients in need thereof, including: a) administering to said patient titrated doses 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 subsequently b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; The titration dose is approximately 50% of the maintenance dose.

11. Methods of treating chronic kidney disease in patients in need thereof, including: a) administering to said patient a first titrated 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 subsequently b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

12. Methods of treating chronic kidney disease in patients in need thereof, including: a) administering to said patient a first titrated 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 subsequently b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

13. Methods for treating NAFLD in patients in need thereof, including: a) administering to said patient titrated doses 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 subsequently b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; The titration dose is approximately 50% of the maintenance dose.

14. Methods for treating NAFLD in patients in need thereof, including: a) administering to said patient a first titrated 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 subsequently b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

15. Methods for treating NAFLD in patients in need thereof, including: a) administering to said patient a first titrated 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 subsequently b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

16. Methods of treating NASH in patients in need thereof, comprising: a) administering to said patient titrated doses 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 subsequently b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; The titration dose is approximately 50% of the maintenance dose.

17. Methods of treating NASH in patients in need thereof, comprising: a) administering to said patient a first titrated 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 subsequently b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

18. Methods of treating NASH in patients in need thereof, comprising: a) administering to said patient a first titrated 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 subsequently b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

19. Methods for curing diabetes, causing remission or regression of diabetes, or preventing diabetes in a patient in need thereof, including: a) administering to said patient titrated doses 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 subsequently b) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; The titration dose is approximately 50% of the maintenance dose.

20. Methods for curing diabetes, causing remission or regression of diabetes, or preventing diabetes in a patient in need thereof, including: a) administering to said patient a first titrated 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 subsequently b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently d) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

21. Methods for curing diabetes, causing remission or regression of diabetes, or preventing diabetes in a patient in need thereof, comprising: a) administering to said patient a first titrated 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 subsequently b) administering to said patient a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently c) administering to said patient a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently d) administering to said patient a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently e) administering to said patient a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter f) administering a maintenance dose of the GIP:GLP-1 peptide to said patient; wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

22. The method of any one of claims 1-21, wherein the titrated doses are each administered for about four weeks before administration of the next higher dose is initiated.

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

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

1.

25. The method of any one of claims 1-23, wherein the GIP:GLP-1 peptide has a receptor agonist potency ratio of GIP to GLP-1 of 2.5:1 to about 3.5:

1.

26. GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in treating type 2 diabetes in a patient in need thereof, wherein the use comprises: a) administering titrated doses of a GIP:GLP-1 peptide for a minimum of about two weeks, the 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; and subsequently b) administering a maintenance dose of the GIP:GLP-1 peptide; The titration dose is approximately 50% of the maintenance dose.

27. GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in treating type 2 diabetes in a patient in need thereof, wherein the use comprises: a) administering a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1 for a minimum of about two weeks; and subsequently b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently d) administering a maintenance dose of the GIP:GLP-1 peptide; wherein the first titrated dose is about 25% of the maintenance dose, the second titrated dose is about 50% of the maintenance dose and the third titrated dose is about 75% of the maintenance dose.

28. GIP:GLP-1 peptide or a pharmaceutically acceptable salt thereof for use in treating type 2 diabetes in a patient in need thereof, wherein the use comprises: a) administering a first titrated 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 after 60 minutes incubation as measured using a casein cAMP assay normalized to GIP and GLP-1 for a minimum of about two weeks; and subsequently b) administering a second titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently c) administering a third titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently d) administering a fourth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and subsequently e) administering a fifth titrated dose of the GIP:GLP-1 peptide for a minimum of about two weeks; and thereafter f) administering a maintenance dose of the GIP:GLP-1 peptide; wherein the first titrated dose is about 17% of the maintenance dose, the second titrated dose is about 33% of the maintenance dose, the third titrated dose is about 50% of the maintenance dose, the fourth titrated dose is about 66% of the maintenance dose and the fifth titrated dose is about 83% of the maintenance dose.

29. A composition comprising a GIP:GLP-1 peptide and a pharmaceutically acceptable excipient, the peptide having a GIP:GLP-1 receptor agonist potency ratio of about 2.5:1 to about 10:1 measured after 60 minutes incubation using a casein cAMP assay normalized to GIP and GLP-1.

30. The composition of claim 29, wherein the composition is administered in ascending doses for at least two weeks.

31. The composition of claim 29 or 30, wherein the composition is administered in ascending doses for at least four weeks.

32. The composition of any one of claims 29 to 31, wherein the composition is administered at a maintenance dose for at least two weeks.

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