Tirzepatide treatment method

Abstract

An embodiment of the present invention relates to a method for increasing HDL-C in a patient in need thereof. One embodiment of the present invention relates to a method for reducing hypertension. One embodiment relates to a treatment method for providing normal HbA1C blood glucose for a patient suffering from refractory type 2 diabetes.

Description

[Technical field]

[0001] The present invention relates to the field of medicine. Methods for treating refractory type 2 diabetes (T2D) in patients not reaching recommended glycemic targets with metformin and SGLT-2 therapy are provided. Methods related to increasing HDL-C levels in patients in need thereof are provided. Methods for lowering blood pressure in patients in need thereof are provided. [Brief description of the drawings]

[0002] [Figure 1] 1 graphically depicts HDL-C increases using efficacy estimands observed at 52 weeks in a clinical trial conducted substantially as described in Example 1. [Diagram 2] 1 is a graph showing the efficacy of Estimand in increasing HDL-C levels observed at 40 weeks in a clinical trial conducted substantially as described in Example 2. [Diagram 3] 1 is a graphical depiction of the reduction in systolic blood pressure in a clinical trial substantially as described in Example 1. [Figure 4] 1 is a graphical depiction of the reduction in diastolic blood pressure in a clinical trial substantially as described in Example 1. Detailed Description of the Invention

[0003] Glycated hemoglobin (HbA 1c ) is considered an important marker of glycemic control in diabetes. The American Diabetes Association (ADA) guidelines recommend an HbA of 5.7% or less. 1c This indicates that patients with HbA 1c Treatment goals for patients with HbA 1cContinued poor control of diabetes contributes disproportionately to the development of diabetes-related complications. Patients suffering from type 2 diabetes often fail to achieve normoglycemia despite treatment with the ADA treatment paradigm. Despite not being within the normal range, the ADA guidelines recommend a reasonable HbA of 7% or less following the current treatment options of diet, exercise, metformin, oral antidiabetic therapy, followed by basal insulin. 1c However, many patients continue to experience high HbA 1c If they are unable to reach their goal, they are considered to have refractory type 2 diabetes.

[0004] Refractory type 2 diabetes is generally explained by an insulin secretion disorder, or a beta cell disorder, which becomes more and more severe over time against a background of (relatively stable) insulin resistance. Patients who have been living with type 2 diabetes for at least 8 years are more likely to suffer from refractory type 2 diabetes. Therefore, a method of treatment that provides normal or near-normal blood glucose in patients suffering from refractory type 2 diabetes is desired. A method of treatment that provides normal or near-normal blood glucose in patients suffering from refractory type 2 diabetes is desired, where the patient has been treating type 2 diabetes for at least 8 years.

[0005] Nearly half of American adults have high blood pressure. High blood pressure is a risk factor for stroke, coronary heart disease (CHD), and other serious health threats. Many patients who have type 2 diabetes and are obese experience high blood pressure. However, approved treatments for diabetes typically have little or no effect on controlling high blood pressure. Treatment options for managing high blood pressure are desirable. Methods for treating high blood pressure in diabetic patients are desirable.

[0006] Low serum levels of high-density lipoprotein cholesterol (HDL-C) are another known risk factor for coronary heart disease (CHD). Patients with type 2 diabetes often experience low serum levels of HDL-C. However, approved diabetes treatments generally fail to raise HDL-C. Long-term longitudinal population studies have confirmed that HDL-C is inversely and independently associated with the risk of developing CHD. Pharmacological therapies that increase HDL-C levels are desirable. Treatment methods that increase HDL-C in patients suffering from type 2 diabetes are desirable.

[0007] The present invention provides a method for treating, preventing, or delaying hypertension, comprising administering tirzepatide or a pharma- ceutically acceptable salt thereof.The present invention further provides a method for treating, preventing, or delaying hypertension in a patient diagnosed with type 2 diabetes, comprising administering tirzepatide or a pharma- ceutically acceptable salt thereof.

[0008] The present invention provides a method for treating, preventing or delaying low HDL-C, comprising administering tirzepatide or a pharma- ceutically acceptable salt thereof.The present invention further provides a method for treating, preventing or delaying HDL-C in a patient diagnosed with type 2 diabetes, comprising administering tirzepatide or a pharma- ceutically acceptable salt thereof.

[0009] The present invention provides a method for treating, preventing or delaying refractory type 2 diabetes in a patient who has suffered from type 2 diabetes for at least 8 years, comprising administering tirzepatide or a pharma- ceutically acceptable salt thereof.

[0010] The present invention provides a method for treating refractory type 2 diabetes in a patient who has suffered from type 2 diabetes for at least 8 years, comprising administering tirzepatide or a pharma- ceutically acceptable salt thereof.

[0011] In one embodiment, a patient in need of treatment for refractory type 2 diabetes has an HbA 1c has.

[0012] In one embodiment, a patient in need of treatment for refractory type 2 diabetes has an HbA 1c has.

[0013] In one embodiment, a patient in need of treatment for refractory type 2 diabetes has an HbA 1c In one embodiment, a patient in need of treatment for refractory type 2 diabetes has a HbA 1c Have a therapeutic goal.

[0014] In one embodiment, a patient in need of treatment for refractory type 2 diabetes has an HbA 1c Have a therapeutic goal.

[0015] In one embodiment, a patient in need of treatment for refractory type 2 diabetes has an HbA 1c Have a therapeutic goal.

[0016] The present invention provides a method for treating refractory type 2 diabetes in a patient who is non-responsive to metformin, SGLT-2, or metformin plus an SGLT-2 inhibitor, comprising administering tirzepatide or a pharma- ceutical acceptable salt thereof.

[0017] Thus, one embodiment provides a method of treating, preventing or delaying hypertension in a patient in need thereof, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week.A further embodiment provides a method of treating hypertension in a patient diagnosed with type 2 diabetes, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week.

[0018] In another aspect, the invention provides a method for preventing or delaying hypertension in a patient, comprising administering to the patient a therapeutically effective amount of tirzepatide once a week.

[0019] In another aspect, the present invention provides a method for preventing or delaying hypertension in a patient diagnosed with type 2 diabetes, comprising administering to the patient a therapeutically effective amount of tirzepatide once a week.

[0020] In another aspect, the present invention provides the use of tirzepatide for the preparation of a medicament for treating, preventing or delaying the onset of hypertension in a patient, wherein the medicament is administered once weekly.

[0021] The present invention provides a method for treating, preventing or delaying hypertension, comprising administering an effective amount of tirzepatide, or a pharma- ceutically acceptable salt thereof, to a patient in need of such treatment.

[0022] In one embodiment, the patient in need of treatment for hypertension has type 2 diabetes and is non-obese.

[0023] In one embodiment, the patient in need of treatment for hypertension suffers from type 2 diabetes and is obese.

[0024] In one embodiment, the patient in need of treatment for hypertension suffers from refractory type 2 diabetes.

[0025] In one embodiment, the patient in need of treatment for hypertension has had type 2 diabetes for at least 8 years.

[0026] Thus, one embodiment provides a method for treating, preventing or delaying the onset of hypertensive crisis in a patient with refractory type 2 diabetes, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once weekly.

[0027] In one embodiment, the patient in need of treatment for hypertensive crisis has type 2 diabetes and is non-obese.

[0028] In one embodiment, the patient in need of treatment for hypertensive crisis suffers from type 2 diabetes and is obese.

[0029] In one embodiment, the patient in need of treatment for hypertensive crisis suffers from refractory type 2 diabetes.

[0030] In one embodiment, the patient in need of treatment for hypertensive crisis has had type 2 diabetes for at least 8 years.

[0031] Accordingly, one embodiment provides a method for treating, preventing or delaying the onset of low HDL-C in a patient, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week.

[0032] In another aspect, the invention provides a method for preventing or delaying a hypertensive crisis in a patient, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once weekly.

[0033] In another aspect, the present invention provides a method for preventing or delaying low HDL-C in a patient, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week.

[0034] In another aspect, the present invention provides a method for treating hypertension in a patient undergoing clinical treatment for type 2 diabetes with an oral antidiabetic agent for at least 1 year, 2 years, 3 years, 4 years, or 5 years, wherein the patient has an HbA1c greater than 7%, comprising administering to the patient an effective amount of tirzepatide, or a pharma- ceutically acceptable salt thereof, once a week.

[0035] In another aspect, the present invention provides a method for improving glycemic control in a patient suffering from type 2 diabetes mellitus and at risk of hypertension, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once weekly, providing a reduced risk of the patient experiencing a hypertensive crisis.

[0036] In another aspect, the present invention provides a method of improving glycemic control in a patient suffering from type 2 diabetes mellitus and at risk of hypertension, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once weekly for at least 30 weeks, providing a reduced risk of the patient experiencing a hypertensive crisis.

[0037] In another aspect, the present invention provides a method for improving weight control in a patient who is obese and at risk of hypertension, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week, providing a reduced risk of the patient experiencing a hypertensive crisis.

[0038] In another aspect, the present invention provides a method for treating hypertension in a patient, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week, wherein the patient's weight is within the patient's normal weight range.

[0039] In another aspect, the present invention provides a method for improving weight control in a patient who is obese and at risk for hypertension, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week, wherein the method provides a reduction in the risk that the patient will experience hypertension.

[0040] In another aspect, the present invention provides tirzepatide or a pharma- ceutically acceptable salt thereof for use in treating, preventing or delaying the onset of a hypertensive crisis, wherein the tirzepatide or a pharma- ceutically acceptable salt thereof is administered once weekly.

[0041] In another aspect, there is provided tirzepatide or a pharma- ceutically acceptable salt thereof for use in the treatment, prevention or delay of the onset of hypertension, wherein the tirzepatide or the pharma- ceutically acceptable salt thereof is administered once a week.

[0042] In another aspect, an embodiment is the use of tirzepatide or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for treating, preventing or delaying the onset of hypertension, wherein the medicament is administered once weekly.

[0043] In another aspect, there is provided a use of tirzepatide for the preparation of a medicament for treating, preventing or delaying the onset of hypertension, wherein the medicament is administered once weekly.

[0044] In another aspect, an embodiment is the use of tirzepatide or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for treating, preventing or delaying the onset of a hypertensive crisis, wherein the medicament is administered once weekly.

[0045] In another aspect, there is provided a use of tirzepatide for the preparation of a medicament for treating, preventing or delaying the onset of a hypertensive crisis, wherein the medicament is administered once weekly.

[0046] US Patent No. 9,474,780 describes and claims tirzepatide. As used herein, the term "tirzepatide" refers to any GIP / GLP-1 receptor agonist having the amino acid sequence of SEQ ID NO:1, including any protein that is the subject of a regulatory submission seeking approval of a GIP / GLP-1 receptor agonist product that relies in whole or in part on data regarding tirzepatide submitted to regulatory authorities by Eli Lilly and Company, regardless of whether the party seeking approval of the protein actually identifies the protein as tirzepatide or uses some other term. Tirzepatide has been shown to act on the GIP / GLP-1 receptor, resulting in stimulation of insulin synthesis and secretion, providing improved glycemic control in T2DM patients.

[0047] As used herein, "hypertensive crisis" means blood pressure is dangerously high and may threaten the patient's organs or life. A hypertensive crisis is typically a blood pressure that is at least 180 / 120. Hypertension is generally a systolic / diastolic pressure of 130 / 80.

[0048] As used herein, "refractory type 2 diabetes" refers to a condition in which the HbA 1c Refers to patients who are unable to achieve their goals.

[0049] As used herein, "HbA 1c "Goal" refers to the desired mean HbA to be achieved by the patient, as determined by the patient's clinical treatment plan and measured using a clinically accepted method. 1c Current ADA guidelines state that a reasonable HbA level of 7% or less should be achieved following the current treatment options of diet, exercise, metformin, oral antidiabetic medication, followed by basal insulin. 1c However, many patients continue to experience high HbA 1c In one embodiment, the patient is unable to reach the target and is considered to have refractory type 2 diabetes. 1cThe goal is 7% or less. 1c The target is below 5.7%.

[0050] Among men and women aged 49 to 82 years who were free of CHD at baseline in the Framingham Study (over a 12-year follow-up period), participants with high HDL-C levels (80th percentile) had a 50 percent lower risk of cardiovascular events compared with participants with low HDL-C levels (20th percentile) 2In the Prospective Cardiovascular Munster (PROCAM) study (approximately 4,500 volunteers, ages 16-65, followed for 6 years), individuals with HDL-C < 35 mg / dl were found to have a 4-fold higher coronary risk than those with HDL-C > 35 mg / dl. See Assmann G et al.,High-density lipoprotein cholesterol as a predictor of coronary heart disease risk.The PROCAM experience and pathophysiological implications for reverse cholesterol transport.Atherosclerosis.1996;124(Suppl):S11-S20. Gordon et al. suggested that for every 1 mg / dl increase in HDL-C, there is a 2-3 percent reduction in the combined cardiovascular risk for an individual. Gordon DJ et al.High-density lipoprotein cholesterol and cardiovascular disease:four prospective American studies.Circulation.1989;79:8-15. Results from the Veterans Administration HDL Intervention Trial (VA-HIT) showed that in patients with initially low HDL-C, a modest increase in HDL-C of just 6 percent significantly reduced both coronary morbidity and mortality by 24 percent. Rubins HB,et al.,Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol.Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.N Engl J Med.1999;341:410-8.

[0051] Current treatments for increasing HDL-C may include lifestyle modifications such as increased exercise and reduced dietary fat. In many cases, lifestyle modifications are insufficient to achieve the desired increase in HDL-C. Treatment options are needed for patients in need of elevated HDL-C. There is a need for therapies that treat, prevent or delay low HDL-C.

[0052] As used herein, the terms "treatment," "treat," "treating," and the like are meant to include slowing or attenuating the progression of a disease, condition, or disorder. These terms also include alleviating, ameliorating, attenuating, eliminating, or relieving one or more symptoms of a disorder or condition, even if the disorder or condition is not actually eliminated, and even if the progression of the disorder or condition itself is not slowed or reversed.

[0053] As used herein, the terms "prevent," "preventing," "prevention," and the like are meant to include the avoidance of the onset of a disease, condition, disorder, or symptom.

[0054] As used herein, the terms "delay", "delaying" and the like are meant to include increasing the time period from onset of a disease, condition, disorder or symptom to occurrence.

[0055] The term "combined" when used herein in reference to multiple outcomes refers to the occurrence of the first of any of the outcomes.

[0056] The term "increase in HDL-C" means an increase in measured HDL-C levels from baseline. In one embodiment, the change in increase in HDL-C is a statistically significant increase. In one embodiment, the increase in HDL-C is more than a 2% increase from baseline. In one embodiment, the increase in HDL-C is more than a 5% increase from baseline. In one embodiment, the increase in HDL-C is more than a 7% increase from baseline. In one embodiment, the increase in HDL-C is more than a 10% increase from baseline.

[0057] "Therapeutically effective amount" refers to an amount of tirzepatide or a pharma- ceutically acceptable salt thereof for the method or use of the present invention, or a pharmaceutical composition comprising tirzepatide or a pharma- ceutically acceptable salt thereof for the method or use of the present invention, that will induce a biological or medical response in a patient or a desired therapeutic effect in a patient as sought by a researcher, a physician, or other clinician. The effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof may vary depending on factors such as the disease state, age, sex, and weight of an individual, and the ability of tirzepatide to induce a desired response in an individual. An effective amount is also an amount in which the therapeutically beneficial effects outweigh any toxic or harmful effects. In certain embodiments, the therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof for use in the methods described herein is selected from the group consisting of 5, 10, and 15 mg. In certain embodiments, the therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof is 5.0 mg. In certain embodiments, the therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof is 10.0 mg. In a particular embodiment, the therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof is 15.0 mg.

[0058] Additional embodiments are described below.

[0059] In one embodiment, a method for improving glycemic control and increasing HDL-C in a patient suffering from type 2 diabetes mellitus, comprising administering a therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof to the patient once a week for at least 30 weeks.

[0060] In one embodiment, tirzepatide or a pharma- ceutically acceptable salt thereof is administered for at least 40 weeks.In one embodiment, tirzepatide or a pharma- ceutically acceptable salt thereof is administered for at least 52 weeks.

[0061] Hypertension and normal HbA 1c blood sugar A method for treating, preventing or delaying the onset of hypertension in a patient, comprising administering to the patient a therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week. In one embodiment, the hypertension is selected from the group consisting of hypertension and hypertensive crisis.

[0062] 1. A method for preventing or delaying hypertension in a patient, comprising administering to the patient a therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week.

[0063] A method for improving glycemic control in a patient diagnosed with type 2 diabetes mellitus and treating, preventing or delaying hypertension in the patient, comprising administering to the patient a therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week.

[0064] In one embodiment, the method reduces the risk of the patient experiencing hypertension. In one embodiment, the method reduces the risk of the patient experiencing a hypertensive crisis. In one embodiment, the method reduces the risk of the patient experiencing clinically low HDL-C.

[0065] 1. A method for improving glycemic control in a patient suffering from type 2 diabetes mellitus, comprising administering to the patient a therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week, wherein the method reduces the risk of the patient experiencing hypertension.

[0066] The method according to any of the above embodiments, wherein the patient suffers from type 2 diabetes mellitus.The method according to any of the above embodiments, wherein the patient suffers from refractory type 2 diabetes.The method according to any of the above embodiments, wherein the patient has suffered from type 2 diabetes for at least 8 years.The method according to any of the above embodiments, wherein the patient has suffered from type 2 diabetes for at least 10 years.The method according to any of the above embodiments, wherein the administration of tirzepatide once a week continues for at least 40 weeks.The method according to any of the above embodiments, wherein the patient is non-obese.

[0067] The method of any of the above embodiments, wherein the patient has one or more of T2DM, hypertension, reduced HDL-C and obesity.

[0068] In one embodiment, the patient has either multiple cardiovascular risk factors without hypertension or clinically significant hypertension.

[0069] In one embodiment, the patient has either multiple cardiovascular risk factors or an HbA1c level greater than 11%.

[0070] As used herein, a "cardiovascular risk factor" includes current tobacco use (tobacco in any form); use of at least one approved lipid modifying therapy to treat hypercholesterolemia or reported untreated low-density lipoprotein cholesterol (LDL-C) ≥ 3.4 mmol / L (100 mg / dL) within the past six months; reported treated or untreated high-density lipoprotein cholesterol (HDL-C) < 1.0 mmol / L (40 mg / dL) for men and < 1.3 mmol / L (50 mg / dL) for women or triglycerides ≥ 2.3 mmol / L (150 mg / dL) within the past six months; use of at least one blood pressure medication to treat hypertension or untreated systolic blood pressure (SBP) ≥ 130 mmHg or diastolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 130 mmHg within the past six months. and a measured waist circumference of 102 cm for men; and a measured waist circumference of 88 cm for women.

[0071] As used herein, "non-obese" means a patient who is not obese by applicable standards. In one embodiment, a non-obese patient has a body mass index of less than 30 BMI.

[0072] As used herein, "co-occurring" means that a patient is diagnosed with two or more medical conditions.

[0073] In one embodiment, the patient's risk of hypertensive crisis is reduced by at least about 14%.

[0074] In one embodiment, the patient's risk of hypertensive crisis is reduced by at least about 10%.

[0075] In one embodiment, HDL-C levels are increased. In one embodiment, HDL-C levels are increased to a clinically desirable level. In one embodiment, a method of improving glycemic control and increasing HDL-C in a patient suffering from type 2 diabetes mellitus, comprising administering a therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof to the patient once a week for at least 30 weeks.

[0076] In one embodiment, the risk of complication of hospitalization or death due to hypertension is reduced.

[0077] In one embodiment, the risk of death or hospitalization due to hypertension is reduced in patients treated with an effective amount of tirzepatide, or a pharma- ceutically acceptable salt thereof.

[0078] In one embodiment, the risk of the combination of high blood pressure and HbA1c above 5.7% is reduced. In one embodiment, the risk of the combination of low HDL-C, high blood pressure and HbA1c above 7% is reduced.

[0079] In one embodiment, the risk of the co-occurring low HDL-C, high blood pressure and HbA1c above 5.7% is reduced.

[0080] In one embodiment, the risk of the co-occurring low HDL-C, high blood pressure and HbA1c above 6% is reduced.

[0081] A method for normalizing HbA1c blood glucose levels in a patient suffering from refractory type 2 diabetes, comprising administering a therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof to the patient once a week.

[0082] In one embodiment, the amount of tirzepatide is selected from the group consisting of about 5.0 mg, about 10.0 mg, and about 15.0 mg. In one embodiment, the amount of tirzepatide is selected from the group consisting of about 7.5 mg and about 12.5 mg.

[0083] In one embodiment, the amount of tirzepatide is about 5.0 mg.

[0084] In one embodiment, the amount of tirzepatide is about 10.0 mg.

[0085] In one embodiment, the amount of tirzepatide is about 15.0 mg.

[0086] In one embodiment, the dose of tirzepatide is about 5.0 mg.

[0087] In one embodiment, the dose of tirzepatide is about 10.0 mg.

[0088] In one embodiment, the dose of tirzepatide is about 15.0 mg.

[0089] In one embodiment, tirzepatide or a pharma- ceutically acceptable salt thereof is administered using a dose escalation protocol.

[0090] In one embodiment, the patient has not achieved an HbA1C<7% ​​with the use of one or two oral antidiabetic agents for at least one year prior to treatment with tirzepatide or a pharma- ceutically acceptable salt thereof.

[0091] In one embodiment, the patient has not achieved an HbA1C<8% with one or two oral medications for at least one year prior to treatment with tirzepatide or a pharma- ceutically acceptable salt thereof.

[0092] In one embodiment, the patient has not achieved an HbA1C<10% with one or two oral medications for at least one year prior to treatment with tirzepatide or a pharma- ceutically acceptable salt thereof.

[0093] In one embodiment, the weekly administration of tirzepatide or a pharma- ceutically acceptable salt thereof is continued for at least 30 weeks. In one embodiment, the weekly administration of tirzepatide or a pharma- ceutically acceptable salt thereof is continued for at least 40 weeks. In one embodiment, the weekly administration of tirzepatide or a pharma- ceutically acceptable salt thereof is continued for at least 50 weeks. In one embodiment, the weekly administration of tirzepatide or a pharma- ceutically acceptable salt thereof is continued for at least 2 years. In one embodiment, the weekly administration of tirzepatide or a pharma- ceutically acceptable salt thereof is continued for at least 3 years. In one embodiment, the weekly administration of tirzepatide or a pharma- ceutically acceptable salt thereof is continued for at least 5 years.

[0094] In one embodiment, the dose of tirzepatide is 15 mg / week. In one embodiment, the dose of tirzepatide is 10 mg / week. In one embodiment, the dose of tirzepatide is 5 mg / week.

[0095] In one embodiment, the patient was diagnosed with type 2 diabetes at least 8 years prior to administration of tirzepatide or a pharma- ceutically acceptable salt thereof.

[0096] In one embodiment, the patient receiving tirzepatide or a pharma- ceutically acceptable salt thereof was diagnosed with type 2 diabetes at least 10 years prior to administration of tirzepatide.

[0097] In one embodiment, the patient receiving tirzepatide or a pharma- ceutically acceptable salt thereof was diagnosed with type 2 diabetes at least 13 years prior to administration of tirzepatide.

[0098] In one embodiment, the patient administered tirzepatide or a pharma- ceutically acceptable salt thereof is at least 46 years of age.

[0099] In one embodiment, the patient administered tirzepatide or a pharma- ceutically acceptable salt thereof is at least 55 years of age.

[0100] In one embodiment, the patient administered tirzepatide or a pharma- ceutically acceptable salt thereof is at least 60 years of age.

[0101] In one embodiment, the patient receiving tirzepatide or a pharma- ceutically acceptable salt thereof is also administered metformin and an oral SGLT2 agent.

[0102] In one embodiment, the patient receiving tirzepatide or a pharma- ceutically acceptable salt thereof is also administered an oral SGLT2 agent.

[0103] In one embodiment, the patient administered tirzepatide, or a pharma- ceutically acceptable salt thereof, is also administered metformin.

[0104] In one embodiment, the patient receiving tirzepatide or a pharma- ceutically acceptable salt thereof is also administered a basal insulin.

[0105] In one embodiment, the patient receiving tirzepatide or a pharma- ceutically acceptable salt thereof is also administered metformin and a basal insulin.

[0106] In one embodiment, the patient administered tirzepatide or a pharma- ceutically acceptable salt thereof is also administered SGLT2 and a basal insulin.

[0107] In one embodiment, the patient administered tirzepatide or a pharma- ceutically acceptable salt thereof is also administered metformin, SGLT2 and basal insulin.

[0108] In one embodiment, the basal insulin is insulin glargine.

[0109] In one embodiment, the basal insulin is insulin degludec.

[0110] In one embodiment, the patient receiving tirzepatide or a pharma- ceutically acceptable salt thereof is also administered an SGLT2 oral medicinal product.

[0111] In one embodiment, the patient administered tirzepatide or a pharma- ceutically acceptable salt thereof is also administered metformin, oral SGLT2, and insulin degludec.

[0112] In one embodiment, the patient administered tirzepatide or a pharma- ceutically acceptable salt thereof is also administered metformin, oral SGLT2, and insulin degludec.

[0113] In one embodiment, the patient administered tirzepatide or a pharma- ceutically acceptable salt thereof is also administered metformin, oral SGLT2, and insulin glargine.

[0114] In one embodiment, the patient receiving tirzepatide, or a pharma- ceutically acceptable salt thereof, is also receiving metformin and insulin glargine.

[0115] Tirzepatide or a pharma- ceutically acceptable salt thereof for use in any of the above embodiments.

[0116] Use of tirzepatide or a pharma- ceutically acceptable salt thereof in the preparation of a medicament for any of the above embodiments.

[0117] Further embodiments are described in the following examples, which should not be construed as limiting.

[0118] One embodiment provides tirzepatide or a pharma- ceutically acceptable salt thereof for use in treating, preventing or delaying hypertension in a patient, wherein the tirzepatide or a pharma- ceutically acceptable salt thereof is administered once weekly.A further embodiment provides tirzepatide or a pharma- ceutically acceptable salt thereof for treating hypertension in a patient diagnosed with type 2 diabetes, wherein the tirzepatide or a pharma- ceutically acceptable salt thereof is administered once weekly.

[0119] In another embodiment, the present invention provides tirzepatide or a pharma- ceutically acceptable salt thereof for use in preventing or delaying hypertension in a patient, wherein the tirzepatide or a pharma- ceutically acceptable salt thereof is administered once a week. In one embodiment, the patient has been diagnosed with type 2 diabetes. In a further embodiment, the patient has type 2 diabetes and is non-obese. In another embodiment, the patient has type 2 diabetes and is obese. In a further embodiment, the patient has refractory type 2 diabetes. In another further embodiment, the patient has type 2 diabetes for at least 8 years.

[0120] In another embodiment, the present invention provides tirzepatide or a pharma- ceutically acceptable salt thereof for use in treating, preventing or delaying the onset of a hypertensive crisis in a patient, wherein the tirzepatide or a pharma- ceutically acceptable salt thereof is administered once a week. In one embodiment, the patient has been diagnosed with type 2 diabetes. In a further embodiment, the patient has type 2 diabetes and is non-obese. In another embodiment, the patient has type 2 diabetes and is obese. In a further embodiment, the patient has refractory type 2 diabetes. In another further embodiment, the patient has type 2 diabetes for at least 8 years.

[0121] In another embodiment, the present invention provides tirzepatide or a pharma- ceutically acceptable salt thereof for use in treating, preventing or delaying the onset of low HDL-C in a patient, wherein the tirzepatide or a pharma- ceutically acceptable salt thereof is administered once a week.

[0122] In another embodiment, the present invention provides tirzepatide or a pharma- ceutically acceptable salt thereof for use in preventing or delaying the onset of low HDL-C in a patient, wherein the tirzepatide or a pharma- ceutically acceptable salt thereof is administered once a week.

[0123] In another embodiment, the present invention provides tirzepatide or a pharma- ceutically acceptable salt thereof for use in the treatment of hypertension in a patient undergoing clinical treatment for type 2 diabetes with an oral antidiabetic agent for at least 1 year, 2 years, 3 years, 4 years, or 5 years, wherein the patient's HbA1c is greater than 7%, and wherein the tirzepatide or a pharma- ceutically acceptable salt thereof is administered once a week.

[0124] In another embodiment, the present invention provides tirzepatide or a pharma- ceutically acceptable salt thereof for use in improving glycemic control in a patient suffering from type 2 diabetes mellitus and at risk of hypertension, wherein the tirzepatide or a pharma- ceutically acceptable salt thereof is administered once a week. In one embodiment, the tirzepatide or a pharma- ceutically acceptable salt thereof is administered once a week for at least 30 weeks.

[0125] In another embodiment, the present invention provides tirzepatide or a pharma- ceutically acceptable salt thereof for use in improving weight control in a patient who is obese and at risk of hypertension, wherein the tirzepatide or a pharma- ceutically acceptable salt thereof is administered once a week.

[0126] In another embodiment, the present invention provides tirzepatide or a pharma- ceutically acceptable salt thereof for use in treating hypertension in a patient, wherein the tirzepatide or a pharma- ceutically acceptable salt thereof is administered once a week, and the patient's weight is within the normal weight range for the patient.

[0127] Embodiment 1. Tirzepatide or a pharma- ceutically acceptable salt thereof for use in the treatment of refractory type 2 diabetes in a patient, wherein the tirzepatide or a pharma- ceutically acceptable salt thereof is administered once weekly.

[0128] Embodiment 2. Tirzepatide or a pharma- ceutically acceptable salt thereof for use in the treatment of hypertension in a patient, wherein said tirzepatide or a pharma- ceutically acceptable salt thereof is administered once weekly.

[0129] Embodiment 3. Tirzepatide or a pharma- ceutically acceptable salt thereof for use in raising HDL-C in a patient, wherein said tirzepatide or a pharma- ceutically acceptable salt thereof is administered once a week.

[0130] Embodiment 4. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 3, wherein the patient has been suffering from type 2 diabetes for at least 8 years.

[0131] Embodiment 5. HbA 1c Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 4, wherein the target is less than 7%.

[0132] Embodiment 6. The patient's HbA 1c Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 5, wherein the target is 5.7% or less.

[0133] Embodiment 7. HbA 1c Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 6, wherein the α-tocopherol concentration is greater than 10%.

[0134] Embodiment 8. HbA 1c Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 7, wherein the α-tocopherol concentration is greater than 11%.

[0135] Embodiment 9. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 8, wherein the patient is at least 46 years of age.

[0136] Embodiment 10. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 9, wherein the patient is at least 60 years old.

[0137] Embodiment 11. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 10, wherein the patient is taking an SGLT2 inhibitor.

[0138] Embodiment 12. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 11, wherein the patient is taking metformin.

[0139] Embodiment 13. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 12, wherein the patient is not receiving basal insulin.

[0140] Embodiment 14. The patient is taking metformin and an SGLT2 inhibitor, but has HbA 1c Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 13, which does not achieve the target.

[0141] Embodiment 15. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 14, wherein said tirzepatide or a pharma- ceutically acceptable salt thereof is administered for at least 40 weeks.

[0142] Embodiment 16. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 15, wherein said tirzepatide or a pharma- ceutically acceptable salt thereof is administered for at least 50 weeks.

[0143] Embodiment 17. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 16, wherein said tirzepatide or a pharma- ceutically acceptable salt thereof is administered for at least 2 years.

[0144] Embodiment 18. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 17, wherein the patient is non-obese.

[0145] Embodiment 19. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 18, wherein the weekly dose of said tirzepatide or a pharma- ceutically acceptable salt thereof is 5 mg.

[0146] Embodiment 20. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 18, wherein the weekly dose of said tirzepatide or a pharma- ceutically acceptable salt thereof is 10 mg.

[0147] Embodiment 21. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 18, wherein the weekly dose of said tirzepatide or a pharma- ceutically acceptable salt thereof is 15 mg.

[0148] Embodiment 22. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 21, wherein the patient also suffers from hypertension.

[0149] Embodiment 23. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 22, wherein the patient also has low HDL-C.

[0150] Embodiment 24. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 17 or 19 to 22, wherein the patient is also suffering from obesity.

[0151] Embodiment 25. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 21, wherein the patient has at least two cardiovascular risk factors.

[0152] Embodiment 26. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 21, wherein the patient has no cardiovascular risk factors.

[0153] Embodiment 27. Tirzepatide or a pharma- ceutically acceptable salt thereof for use according to any one of embodiments 1 to 26, wherein the patient has been suffering from type 2 diabetes for at least 10 years.

[0154] As used herein, "estimand" refers to the efficacy and treatment regimen evaluated to determine the efficacy of tirzepatide due to requirements by certain regulatory agencies. Efficacy estimands are used to evaluate outcomes in humans prior to discontinuing study drug or initiating rescue therapy for persistent severe hyperglycemia. Treatment regimen estimands - required by certain regulatory agencies, including the U.S. Food and Drug Administration - evaluate the efficacy of treatment in humans in the study, regardless of adherence to tirzepatide or introduction of rescue therapy for persistent severe hyperglycemia. EXAMPLES

[0155] Example 1. Clinical trial using tirzepatide The enrollment criteria, set forth in Table 1 below, include participants similar to those seen in typical diabetes care and are designed to include some patients with type 2 diabetes that are refractory to oral treatment. Elderly patients are included. The average duration of type 2 diabetes is approximately 8 years. The study will last 52 weeks.

[0156] [Table 1]

[0157] The study is designed to consist of a screening visit followed by a single-blind, 3-week placebo run-in period. Patients are then randomized to tirzepatide 5, 10, or 15 mg (administered using an ascending dose protocol) or insulin degludec (standard titration protocol) and followed at approximately monthly intervals. Patients receiving insulin degludec will follow the standard insulin degludec titration protocol during the study. The study protocol includes blood pressure measurements at each visit using standard clinical methods, as well as serum lipid profiles at study entry and at week 52. Blood pressure measurements using the method of Example 1 are shown in Figures 3 and 4. HDL-C levels using the method of Example 1 are shown in Figure 1.

[0158] Up to 92.6 percent of participants treated with tirzepatide had an HbA of less than 7 percent, the target recommended by the American Diabetes Association for people with diabetes. 1c Up to 48.5 percent of participants receiving tirzepatide in the study achieved an HbA 1c - levels seen in non-diabetic people.

[0159] [Table 2]

[0160] The mean insulin degludec dose at week 52 was 48.8 units per day.

[0161] Example 2. Clinical trial using tirzepatide The enrollment criteria, shown in Table 3 below, include patients who are considered refractory to oral type 2 diabetes treatment. However, oral diabetes treatment will continue throughout the study. The average duration of type 2 diabetes is approximately 13 years. The study will last for 40 weeks.

[0162] Clinical Trial 2, Table 3

[0163] [Table 3]

[0164] The study is designed to consist of a 3-week run-in period, followed by a screening visit. Patients will then begin a 40-week randomized, double-blind study with tirzepatide 5, 10, or 15 mg or placebo as an add-on to previous treatment with insulin glargine with or without metformin. The dose of insulin glargine was titrated throughout the study using a validated "treat-to-target algorithm." Patients will be followed at approximately weekly and then monthly intervals. The study protocol includes blood pressure measurements at each visit using standard clinical methods, as well as serum lipid profiles at study entry and at week 40.

[0165] Three doses of tirzepatide (5 mg, 10 mg, and 15 mg) demonstrated superior HbA reductions from baseline compared with placebo as add-on to titrated insulin glargine with or without metformin in adults with type 2 diabetes using clinical investigational doses. 1c Across the three tirzepatide doses, up to 97.4 percent of participants achieved an HbA of less than 7 percent. 1c Additionally, 62.4 percent of participants treated with the highest tirzepatide dose achieved an HbA of less than 5.7 percent. 1c was achieved.

[0166] [Table 4]

[0167] [Table 5]

[0168] HDL-C levels using the method of Example 1 are shown in FIG.

[0169] array SEQ ID NO:1 Tirzepatide YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS X1 is Aib, X2 is Aib, and K at the 20th position is (2-[2-(2-amino-ethoxy)-ethoxy]-acetyl)2-(γGlu)1-CO—(CH2) 18 It is chemically modified through conjugation of the K side chain with -CO2H to the epsilon-amino group, and the C-terminal amino acid is amidated as a C-terminal primary amide. The invention as originally claimed in the present application is set forth below. [1] A method for treating refractory type 2 diabetes in a patient in need thereof, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week. [2] The method according to [1], wherein the patient has had type 2 diabetes for at least 8 years. [3] The patient's HbA 1c The method according to [1] or [2], wherein the goal is less than 7%. [4] The patient's HbA 1c The method according to any of [1] to [3], wherein the goal is 5.7% or less. [5] The patient's HbA 1c The method according to any one of [1] to [4], wherein the concentration of the ion exchange resin is more than 10%. [6] The patient's HbA 1c The method according to any one of [1] to [4], wherein the concentration of the ion exchange resin is more than 11%. [7] The method according to any of [1] to [6], wherein the patient is at least 46 years old. [8] The method according to any of [1] to [7], wherein the patient is at least 60 years old. [9] The method according to any of [1] to [8], wherein the patient is taking an SGLT2 inhibitor.

[10] The method according to any one of [1] to [9], wherein the patient is taking metformin.

[11] The method according to any of [1] to

[10] , wherein the patient is not administered basal insulin.

[12] The patient was taking metformin and an SGLT2 inhibitor, but had high HbA 1c A method according to any of [1] to

[11] that does not achieve the target.

[13] The method according to any of [1] to

[12] , wherein the treatment with tirzepatide or a pharma- ceutically acceptable salt thereof is continued for at least 40 weeks.

[14] The method according to any of [1] to

[13] , wherein the patient is administered tirzepatide for at least 50 weeks.

[15] The method according to any of [1] to

[14] , wherein the patient is administered tirzepatide for at least two years.

[16] The method according to any of [1] to

[15] , wherein the patient is non-obese.

[17] The method according to any of [1] to

[16] , wherein the effective amount is 5 mg.

[18] The method according to any of [1] to

[16] , wherein the effective amount is 10 mg.

[19] The method according to any of [1] to

[16] , wherein the effective amount is 15 mg.

[20] The method according to any of [1] to

[19] , wherein the patient also suffers from hypertension.

[21] The method according to any of [1] to

[20] , wherein the patient also has low HDL-C.

[22] The method according to any one of [1] to

[15] or

[17] to

[19] , wherein the patient also suffers from obesity.

[23] The method according to any of [1] to

[22] , wherein the patient has at least two cardiovascular risk factors.

[24] The method according to any of [1] to

[19] , wherein the patient has no cardiovascular risk factors.

[25] The method according to any of [1] to

[24] , wherein the patient has been suffering from type 2 diabetes for at least 10 years.

[26] A method for treating hypertension in a patient in need thereof, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once weekly.

[27] The method according to

[26] , wherein the patient has had type 2 diabetes for at least 8 years.

[28] The method according to

[26] or

[27] , wherein the patient suffers from refractory type 2 diabetes.

[29] The patient's HbA 1c The method according to

[27] or

[28] , wherein the goal is less than 7%.

[30] The patient's HbA 1c The goal is 5.7% or less, as described in any of

[26] to

[29] .

[31] The patient's HbA 1c The method according to any one of

[26] to

[30] , wherein the concentration of the ion exchange resin is greater than 10%.

[32] The patient's HbA 1c The method according to any one of

[26] to

[31] , wherein the concentration of the serotonin-containing compound is greater than 11%.

[33] The method according to any of

[26] to

[32] , wherein the patient is at least 46 years old.

[34] The method according to any of

[26] to

[33] , wherein the patient is at least 60 years old.

[35] The method described in any of

[26] to

[34] , wherein the patient is taking an SGLT2 inhibitor.

[36] The method according to any one of

[26] to

[35] , wherein the patient is taking metformin.

[37] The method according to any of

[26] to

[36] , wherein the patient is not administered basal insulin.

[38] The patient was taking metformin and an SGLT2 inhibitor, but had high HbA 1c A method according to any of

[26] –

[37] that does not achieve the target.

[39] The method according to any of

[26] to

[38] , wherein the treatment with tirzepatide is continued for at least 40 weeks.

[40] The method according to any of

[26] to

[39] , wherein the patient also suffers from obesity.

[41] The method according to any of

[26] to

[39] , wherein the patient is non-obese.

[42] The method according to any of

[26] to

[41] , wherein the effective amount is 5 mg.

[43] The method according to any of

[26] to

[41] , wherein the effective amount is 10 mg.

[44] The method according to any of

[26] to

[41] , wherein the effective amount is 15 mg.

[45] The method according to any of

[26] to

[44] , wherein the patient also has low HDL-C.

[46] The method according to any of

[26] to

[45] , wherein the patient has at least two cardiovascular risk factors.

[47] The method according to any of

[26] to

[46] , wherein the hypertension is hypertensive crisis.

[48] ​​The method according to any one of

[26] to

[47] , wherein the method prevents hypertensive crisis.

[49] The method according to any one of

[26] to

[48] , wherein the method prevents stroke.

[50] A method of raising HDL-C in a patient in need thereof, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week.

[51] The method according to

[50] , wherein the patient has had type 2 diabetes for at least 8 years.

[52] The method according to

[50] or

[51] , wherein the patient suffers from refractory type 2 diabetes.

[53] The method according to any of

[50] to

[52] , wherein the patient is at least 46 years old.

[54] The method according to any of

[50] to

[53] , wherein the patient is at least 60 years old.

[55] The method described in any of

[50] to

[54] , wherein the patient is taking an SGLT2 inhibitor.

[56] The method according to any one of

[50] to

[55] , wherein the patient is taking metformin.

[57] The method according to any of

[50] to

[56] , wherein the patient is not administered basal insulin.

[58] The method according to any of

[50] to

[57] , wherein the treatment with tirzepatide is continued for at least 40 weeks.

[59] The method according to any of

[50] to

[58] , wherein the patient is non-obese.

[60] The method according to any of

[50] to

[59] , wherein the effective amount is 5 mg.

[61] The method according to any of

[50] to

[59] , wherein the effective amount is 10 mg.

[62] The method according to any of

[50] to

[59] , wherein the effective amount is 15 mg.

[63] The method according to any of

[50] to

[62] , wherein the patient has at least two cardiovascular risk factors.

[64] The method according to any one of

[50] to

[63] , wherein the patient also suffers from hypertension.

[65] The method according to any of

[50] to

[64] , wherein the administration of tirzepatide is continued for at least 50 weeks.

[66] The method described in any of

[50] to

[65] , wherein the administration of tirzepatide once a week is continued for at least two years.

Claims

1. A pharmaceutical composition for treating refractory type 2 diabetes in a patient in need thereof, comprising an effective amount of tirzepatide or a pharma- ceutical acceptable salt thereof, said pharmaceutical composition being administered to said patient once a week; The patient also suffers from hypertension. Pharmaceutical compositions.

2. The pharmaceutical composition of claim 1, wherein the patient has had type 2 diabetes for at least 8 years.

3. The patient's HbA １ｃ The pharmaceutical composition of claim 1 or 2, wherein the target is less than 7%.

4. The patient's HbA １ｃ The pharmaceutical composition according to any one of claims 1 to 3, wherein the target is 5.7% or less.

5. The patient's HbA １ｃ The pharmaceutical composition according to any one of claims 1 to 4, wherein the content of the glycerol in the glycerol is more than 10%.

6. The patient's HbA １ｃ The pharmaceutical composition according to any one of claims 1 to 4, wherein the solubility in water is greater than 11%.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the patient is at least 46 years old.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the patient is at least 60 years old.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the patient is taking an SGLT2 inhibitor.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the patient is taking metformin.

11. The pharmaceutical composition according to any one of claims 1 to 10, wherein the patient is not receiving basal insulin.

12. The patient was taking metformin and an SGLT2 inhibitor, but had low HbA １ｃ The pharmaceutical composition according to any one of claims 1 to 11, which does not achieve its objective.

13. The pharmaceutical composition according to any one of claims 1 to 12, wherein the treatment with tirzepatide or a pharma- ceutically acceptable salt thereof continues for at least 40 weeks.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the patient is administered tirzepatide for at least 50 weeks.

15. The pharmaceutical composition according to any one of claims 1 to 14, wherein the patient is administered tirzepatide for at least 2 years.

16. The pharmaceutical composition according to any one of claims 1 to 15, wherein the patient is non-obese.

17. The pharmaceutical composition according to any one of claims 1 to 16, wherein the effective amount is 5 mg.

18. The pharmaceutical composition according to any one of claims 1 to 16, wherein the effective amount is 10 mg.

19. The pharmaceutical composition according to any one of claims 1 to 16, wherein the effective amount is 15 mg.

20. The pharmaceutical composition according to any one of claims 1 to 19, wherein the patient is also suffering from low HDL-C.

21. The pharmaceutical composition according to any one of claims 1 to 15 or 17 to 19, wherein the patient is also suffering from obesity.

22. The pharmaceutical composition according to any one of claims 1 to 21, wherein the patient has at least two cardiovascular risk factors.

23. The pharmaceutical composition according to any one of claims 1 to 19, wherein the patient has no cardiovascular risk factors.

24. The pharmaceutical composition according to any one of claims 1 to 23, wherein the patient has been suffering from type 2 diabetes for at least 10 years.

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