Therapeutic uses of tirzepatide

Abstract

To provide methods for treating, preventing or delaying disorders relating to cognition, such as cognitive decline, cognitive impairment or dementia.SOLUTION: The present invention provides a method of treating, preventing or delaying development of a cognitive disorder in a patient, comprising administering an effective amount of tirzepatide, or a pharmaceutically acceptable salt thereof, to the patient once weekly.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to the field of medicine. Provided is a method for treating, preventing, or delaying cognitive disorders, such as cognitive decline, cognitive impairment, or dementia. Provided is a method for treating, preventing, or delaying heart failure. [Background technology]

[0002] Patients with type 2 diabetes mellitus (T2DM) frequently suffer from a variety of comorbidities, including cognitive problems such as cognitive decline, cognitive impairment, or dementia. People with diabetes are 1.5 to 2 times more likely to experience cognitive decline, minimal cognitive impairment, or dementia than people not affected by diabetes. This relationship is independent of other risk factors for cognitive dysfunction, which accounts for a prevalence of 13% in people with diabetes aged 65 to 74 years and 24% in those aged 75 years or older. No single cause has been identified for the higher risk of cognitive dysfunction in people with diabetes. The possibility that certain diabetes treatments, including glucagon-like peptide-1 (GLP-1) receptor agonists, may have benefits on cognitive function has been proposed and is being investigated. See, for example, GD Femminella, et al., Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: study protocol for a randomized controlled trial (ELAD study), 20TRIALS191 (2019). However, there remains a need for therapies that treat, prevent, or delay cognitive decline, cognitive impairment, or dementia, including in patients with T2DM.

[0003] Patients with type 2 diabetes mellitus (T2DM) are at risk for diastolic dysfunction (HFpEF) as well as systolic dysfunction (HFrEF). See, e.g., J.Ho, et al., Predictors of New-Onset Heart Failure; Circulation: Heart Failure 6:279-286 (2013). Current treatments for HFpEF can include lifestyle modifications to induce weight loss and administration of medications to alleviate symptoms of comorbid conditions. Surgery to treat obesity (bariatric surgery) has shown some benefit in patients with HFpEF. See, e.g., Mikhalkova, et al., Obesity (2018). Despite the increasing incidence of HFpEF, effective treatment options have had little success. See, e.g., Zheng et.al., Drug treatment effects on outcomes in heart failure with preserved ejection fraction: a systematic review and meta-analysis, Heart. 104(5):407-415 (March 2018). Currently, there is no approved pharmaceutical treatment for HFpEF. There is a need for therapies that treat, prevent, or delay HFpEF. There is a need for therapies that treat, prevent, or delay HFrEF. Summary of the Invention

[0004] The present invention provides methods for treating, preventing, or delaying cognitive decline, impairment, or dementia.

[0005] Thus, the present invention provides a method for treating, preventing, or delaying the onset of cognitive impairment in a patient, comprising administering to the patient a therapeutically effective amount of tirzepatide once weekly.

[0006] In another aspect, the invention provides a method for preventing or slowing cognitive decline in a patient, comprising administering a therapeutically effective amount of tirzepatide to the patient once a week.

[0007] In another aspect, the present invention provides a method of improving glycemic control and treating, preventing, or delaying cognitive decline in a patient with type 2 diabetes, comprising administering a therapeutically effective amount of tirzepatide to the patient once a week.

[0008] In another aspect, the present invention provides a method of improving glycemic control in a patient having type 2 diabetes and at risk of cognitive decline, comprising administering a therapeutically effective amount of tirzepatide to the patient once a week, wherein the method provides a reduction in the risk that the patient will experience cognitive decline.

[0009] In another aspect, the present invention provides tirzepatide for use in treating, preventing, or delaying the onset of cognitive impairment in a patient comprising administering a therapeutically effective amount of tirzepatide to the patient once a week.

[0010] In another aspect, the present invention provides a use of tirzepatide for the preparation of a medicament for treating, preventing, or delaying the onset of cognitive impairment in a patient, comprising administering a therapeutically effective amount of tirzepatide to the patient once a week.

[0011] The present invention provides a method for treating, preventing, or delaying heart failure, comprising administering an effective amount of tirzepatide, or a pharma- ceutically acceptable salt thereof, to a patient in need of such treatment.

[0012] Thus, the present invention provides a method for treating, preventing, or delaying the onset of HFpEF in a patient, comprising administering to the patient an effective amount of tirzepatide, or a pharma- ceutically acceptable salt thereof, once weekly.

[0013] Thus, the present invention provides a method for treating, preventing, or delaying the onset of HFrEF in a patient, comprising administering to the patient an effective amount of tirzepatide, or a pharma- ceutically acceptable salt thereof, once weekly.

[0014] In another aspect, the present invention provides a method of preventing or delaying HFpEF in a patient, comprising administering to the patient an effective amount of tirzepatide, or a pharma- ceutically acceptable salt thereof, once weekly.

[0015] In another aspect, the present invention provides a method for preventing or delaying HFrEF in a patient, comprising administering to the patient an effective amount of tirzepatide, or a pharma- ceutically acceptable salt thereof, once weekly.

[0016] In another aspect, the present invention provides a method of improving glycemic control and treating, preventing, or delaying HFpEF in a patient with type 2 diabetes, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once weekly.

[0017] In another aspect, the present invention provides a method of improving glycemic control and treating, preventing, or delaying HFrEF in a patient with type 2 diabetes, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once weekly.

[0018] In another aspect, the present invention provides a method of improving glycemic control in a patient having type 2 diabetes and at risk for HFpEF, 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 HFpEF.

[0019] In another aspect, the present invention provides a method of improving glycemic control in a patient having type 2 diabetes and at risk for HFrEF, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once weekly, wherein the method provides a reduction in the risk that the patient will experience HFrEF.

[0020] In another aspect, the present invention provides a method of improving weight control in a patient who has obesity and is at risk for HFpEF, 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 HFpEF.

[0021] In another aspect, the present invention provides a method for treating HFpEF in a patient at risk for HFpEF, 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.

[0022] In another aspect, the present invention provides a method for improving weight control in a patient who has obesity and is at risk for HFrEF, 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 HFrEF.

[0023] In another aspect, the present invention provides tirzepatide or a pharma- ceutical acceptable salt thereof for use in treating, preventing, or delaying the onset of HFpEF in a patient, comprising administering to the patient an effective amount of tirzepatide once a week.

[0024] 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 HFrEF in a patient comprising administering to the patient an effective amount of tirzepatide once a week.

[0025] In another aspect, the present invention provides a use of tirzepatide or a pharma- ceutically acceptable salt thereof for the preparation of a medicament for treating, preventing, or delaying the onset of HFpEF in a patient, comprising administering a therapeutically effective amount of tirzepatide to the patient once a week.

[0026] In another aspect, the present invention provides a use of tirzepatide for the preparation of a medicament for treating, preventing, or delaying the onset of HFrEF in a patient, comprising administering to the patient a therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once weekly. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] US9474780 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.

[0028] cognitive decline The onset or progression of cognitive decline may be reflected in scores generated through the administration of measures of cognitive status such as the Montreal Cognitive Assessment (MoCA) and the Digit Symbol Substitution Test (DSST).

[0029] The MOCA is a cognitive function screening test that has been validated in the setting of mild cognitive impairment and has since been adopted in many clinical settings. The test consists of a one-page, 30-item questionnaire designed to be administered in approximately 10 minutes in the participant's first language with a validated interpretation. It assesses seven cognitive domains, including short-term memory, visuospatial ability, executive function, attention, concentration, working memory, and language. See, for example, Nasreddine ZS,et al.The Montreal Cognitive Assessment,MoCA:a brief screening tool for mild cognitive impairment.J.AM.GERIATR.SOC.2005;53(4):695-9; Pendlebury ST,et al.,Underestimation of cognitive impairment by Mini-Mental State Examination versus the Montreal Cognitive Assessment in patients with transient ischemic attack and stroke:a population-based study.STROKE2010;41(6):1290-3. The MOCA score is equal to the number of items out of 30 answered correctly plus one point if the individual reports ≤12 years of education. Controlled validation studies in cognitively normal individuals have reported a mean MOCA score of 27.4 with a standard deviation of 2.2. However, studies based on populations of presumably cognitively intact people have reported much lower mean scores. See, e.g., Rossetti HC,et al.,Normative data for the Montreal Cognitive Assessment(MoCA)in a population-based sample.NEUROLOGY2011;77(13):1272-5.

[0030] The DSST is a subtest of the Wechsler Adult Intelligence Scale (3rd ed.) and assesses a wide range of cognitive domains, including visual-motor speed and coordination, learning ability, attention, concentration, and short-term memory. See Wechsler D, Manual for the Wechsler Adult Intelligence scale. NY, NY. (1955); D W. The Wechsler Adult Intelligence Scale-Revised. NY, NY: The Psychological Corporation (1981). It consists of a row of nine randomly ordered symbols with a blank box below and a clue at the top of the page linking each symbol with a number. Respondents have a two-minute period to fill in the blank below each symbol with the corresponding number as quickly as possible. The score is the number of consecutive number-symbol pairs correctly completed within two minutes; the maximum possible score is 135. It is widely used to measure cognitive function in cognitively intact individuals with or without diabetes, and validation studies have demonstrated that it predicts future cognitive insufficiency and deficits, is relatively easy to administer, is not language specific, and its scores correlate with measures of physical function and future cognitive decline.See, for example, Rosano C, et al., Association Between Lower Digit Symbol Substitution Test Score and Slower Gait and Greater Risk of Mortality and of Developing Incident Disability in Well-Functioning Older Adults, J.AM.GERIATR.SOC.(2008); Knopman D, et al., Cardiovascular risk factors and cognitive decline in middle-aged adults.NEUROLOGY.56(1):42-8(2001).When the DSST was used in randomized controlled trials involving cognitively intact individuals with dysglycemia, the mean baseline scores ranged from 36 to 52. See Cukierman-Yaffe T,et al.,Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia:a substudy of the ORIGIN trial.THE LANCET DIABETES & ENDOCRINOLOGY2014;2(7):562-72; Launer LJ,et al.Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes(ACCORD MIND):a randomised open-label substudy.LANCET NEUROL.(2011);10(11):969-77.

[0031] Previous studies have suggested that normal ranges for cognitive test scores may vary across countries. Rossetti HC,et al.,Normative data for the Montreal Cognitive Assessment(MoCA)in a population-based sample.NEUROLOGY2011;77(13):1272-5; Thomann AE,et al.The Montreal Cognitive Assessment:Normative Data from a German-Speaking Cohort and Comparison with International Normative Samples.J.ALZHEIMER'S DIS.2018;64(2):643-55.Thus, when assessing substantial decline in a population that includes individuals from multiple countries, it may be desirable to standardize each individual's score at each time point to the mean baseline score and standard deviation of values ​​achieved in their country of origin, as opposed to the mean and standard deviation of the entire population.

[0032] Previous studies have also found that cognitive test scores in groups of middle-aged individuals decline very slowly over time, although some individuals experience a faster decline than others. See Cukierman-Yaffe T,et al.Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia:a substudy of the ORIGIN trial.THE LANCET DIABETES & ENDOCRINOLOGY2014;2(7):562-72; Proust-Lima C,et al.,Sensitivity of four psychometric tests to measure cognitive changes in brain aging-population-based studies.AM.J.EPIDEMIOL.2007;165(3):344-50. These and other studies support the use of a definition based on a threshold of a decline of 1.5 or more standard deviations from baseline.Also, Group SR,et al.Effect of Intensive vs Standard Blood Pressure Control on Probable Dementia:A Randomized Clinical Trial.JAMA 2019;321(6):553-61;Group SR.A Randomized Trial of Intensive versus Standard Blood-Pressure Control.N.ENGL.J.MED.2015, Bissels GJ,et al.Rationale and design of the See CAROLINA(R)-cognition substudy: a randomized controlled trial on cognitive outcomes of linagliptin versus glimepiride in patients with type 2 diabetes mellitus.BMC NEUROL.2018;18(1):7.

[0033] As used herein, the term "cognitive impairment" refers to any condition involving impairment in a person's cognitive functions, such as difficulty in memory, learning new things, ability to concentrate, and / or decision making that affects the person's daily life. Such impairments range from mild cognitive impairment (MCI) to mild, moderate, and severe dementia. MCI refers to a stage of cognitive impairment between the expected cognitive changes consistent with aging and mild dementia, and can be characterized by a slight but noticeable decline in measurable cognitive abilities, including memory and thinking, but not including loss of ability to perform daily activities. More severe impairment, or dementia, is associated with loss of ability to perform daily activities, and, depending on severity, loss of ability to read, write, and / or understand the meaning or significance of things.

[0034] The methods provided herein may be most effective for patients who are at higher risk of experiencing cognitive decline.In certain embodiments, such patients are those who have one or more of T2DM; high blood pressure; high cholesterol and / or obesity.

[0035] In certain embodiments, such patients suffer from cardiovascular disease and / or have one or more risk factors for a major adverse cardiovascular event.

[0036] heart failure Diastolic dysfunction (HFpEF) is a form of heart failure in which the ejection fraction - the percentage of blood ejected from the left ventricle with each heart beat divided by the volume of blood in the left ventricle when it is maximally filled - is normal and defined as greater than 50%. Despite the increasing incidence of HFpEF, efforts to effectively treat HFpEF have met with little success.

[0037] Traditionally, heart failure has been treated with a variety of drugs to treat comorbid conditions. Such treatments include alpha-adrenergic agonists, beta-adrenergic agonists, calcium channel antagonists, cardiac glycosides, diuretics, nitrates, phosphodiesterase inhibitors, prazosin, and a variety of vasodilators. These treatments are associated with undesirable side effects. For example, alpha-adrenergic agonists can be associated with peripheral tissue edema. Certain treatments are associated with desensitization to the drug, rendering the treatment ineffective. There is a continuing need for a treatment for HFpEF with an acceptable pharmacological side effect profile. Furthermore, there is a continuing need for a treatment for HFrEF with an acceptable pharmacological side effect profile.

[0038] As used herein, the term "substantial cognitive decline" or "SCD" refers to a significant decrease in a subject's score on a standardized cognitive assessment, such as the MoCA or DSST, of 1.5 or more standard deviations.

[0039] As used herein, the terms "country-standardized," "country-standardized," and the like refer to normalizing cognitive function scores by calculating the baseline mean and standard deviation of the scores within each country, and using these baseline means and standard deviations to calculate standardized MOCA and DSST scores for each individual at each time point by subtracting the country-specific baseline mean score from each individual's score at that time point and dividing the difference by the country-specific baseline standard deviation.

[0040] As used herein, the term "major adverse cardiovascular events" refers to cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.These events are also sometimes referred to as MACE or MACE3 events.The first occurrence of any of these events is a composite endpoint that is frequently used in CVOT.

[0041] As used herein with respect to major adverse cardiovascular events, the term "risk factor" refers to a characteristic of a T2DM patient that is understood to increase the risk of a major adverse cardiovascular event. Such risk factors include, among others, any of the following: current smoker (any form of tobacco); at least one approved lipid-modifying therapy to treat hypercholesterolemia or documented and untreated low-density lipoprotein cholesterol (LDL-C) ≧3.4 mmol / L (130 mg / dL) within the past six months (e.g., a statin such as atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or pitavastatin; a PCSK9 inhibitor such as evolocumab or alirocumab); use of rituximab (a vasodilator; and ezetimibe); recorded and treated or untreated high-density lipoprotein cholesterol (HDL-C) < 1.0 mmol / L (40 mg / dL) in men and < 1.3 mmol / L (50 mg / dL) in women, or triglycerides ≥ 2.3 mmol / L (200 mg / dL) within the past 6 months; use of at least one blood pressure lowering medication to treat hypertension (e.g., angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), thiazide-like diuretics, and dihydropyridine calcium channel blockers) or untreated systolic blood pressure (SBP) ≥ 140 mm Hg or diastolic blood pressure (DBP) ≥ 95 mm Hg); waist-to-hip ratio measurements of > 1.0 in men and > 0.8 in women.

[0042] As used herein, "improved weight management" means that the patient's weight is within or close to the patient's clinically defined normal weight range. A particular patient's "normal weight" can be determined by a clinician, taking into account applicable considerations that are well known to a skilled clinician. Typically, improved weight management means that the patient loses weight to reach a weight that is within or close to the desired weight range for the patient. As used herein, a "normal weight range" should be the weight that a skilled clinician determines to be the normal weight for a particular patient. The normal weight range may vary based on the patient's height and other factors that are considered by a skilled clinician in weight assessment.

[0043] 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 reducing 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. As used herein, the terms "prevent", "preventing", "prevention" and the like are meant to include avoiding the onset of a disease, condition, disorder, or symptom. As used herein, the terms "delay", "delaying" and the like are meant to include increasing the time period for the onset of a disease, condition, disorder, or symptom to occur.

[0044] The term "combined" when used herein in reference to multiple outcomes refers to the occurrence of the first of any of the outcomes.

[0045] As used herein, the term "hazard ratio" refers to the measure of the relative progression rate to an end point compared to a control group.In outcome-based clinical trials, a reduction in the hazard ratio for the test arm compared to the control indicates that the therapy used in the test arm reduces the risk of the end point, i.e., in the case of the study described herein, major adverse cardiovascular events.

[0046] "Therapeutically effective amount" refers to the amount of tirzepatide in the method and use of the present invention or pharmaceutical composition comprising tirzepatide that will induce the biological or medical response of the patient or the desired therapeutic effect in the patient that is sought by a researcher, a physician, or other clinician. The effective amount of tirzepatide may vary depending on factors such as the disease state, age, sex, and weight of the individual, and the ability of tirzepatide to induce the desired response in the individual. An effective amount is also an amount in which the therapeutically beneficial effects outweigh the toxic or harmful effects. In certain embodiments, the therapeutically effective amount of tirzepatide 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 is 5.0 mg. In certain embodiments, the therapeutically effective amount of tirzepatide is 10.0 mg. In a preferred embodiment, the therapeutically effective amount of tirzepatide is 15.0 mg.

[0047] Additional embodiments of the present invention are described below.

[0048] Cognitive impairment A method for treating, preventing or delaying the onset of cognitive impairment in a patient, comprising administering a therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof to the patient once a week. In one embodiment, the cognitive impairment is selected from the group consisting of MCI and dementia.

[0049] 1. A method for preventing or slowing cognitive decline in a patient, comprising administering to the patient a therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week.

[0050] A method for improving glycemic control and treating, preventing, or delaying cognitive decline in a patient having type 2 diabetes, comprising administering to the patient a therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week.

[0051] In one embodiment, the method results in a reduction in the risk that the patient will experience cognitive decline.

[0052] A method for improving glycemic control in a patient having type 2 diabetes, comprising administering to the patient a therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week, wherein the method results in a reduction in the risk of the patient experiencing cognitive decline.

[0053] The method of any one of the above embodiments, wherein the patient has type 2 diabetes.

[0054] The method of any one of the above embodiments, wherein the patient has one or more of: T2DM; high blood pressure; high cholesterol, and obesity.

[0055] In one embodiment, the patient is either cardiovascular disease-free and has multiple cardiovascular risk factors, or is cardiovascular disease-affected.

[0056] In one embodiment, the risk factors for cardiovascular disease are selected from the group consisting of: current smoker (all forms of tobacco); use of at least one approved lipid-altering therapy to treat hypercholesterolemia or documented and untreated low-density lipoprotein cholesterol (LDL-C) > 3.4 mmol / L (130 mg / dL) within the past 6 months; documented and treated or untreated high-density lipoprotein cholesterol (HDL-C) < 1.0 mmol / L (40 mg / dL) for men, < 1.3 mmol / L (50 mg / dL) for women, or triglycerides > 2.3 mmol / L (200 mg / dL) within the past 6 months; use of at least one blood pressure lowering medication to treat hypertension or untreated systolic blood pressure (SBP) > 140 mm Hg or diastolic blood pressure (DBP) > 95 mmHg; and waist-to-hip ratio measurements of > 1.0 for men and > 0.8 for women.

[0057] In one embodiment, the cognitive disorder is selected from the group consisting of MCI and dementia.

[0058] In one embodiment, the patient's risk of cognitive decline is reduced by at least about 14%.

[0059] In one embodiment, the risk of a major adverse cardiovascular event is reduced by at least about 10%.

[0060] In one embodiment, the risk of major adverse cardiovascular events is reduced by at least about 11%.

[0061] In one embodiment, the risk of major adverse cardiovascular events is reduced by about 12%.

[0062] In one embodiment, the risk of occurrence of the composite of the following outcomes: cognitive decline or death is reduced.

[0063] In one embodiment, the risk of occurrence of the composite of the following outcomes: cognitive decline or stroke is reduced.

[0064] In one embodiment, the risk of occurrence of the composite of the following outcomes: cognitive decline, stroke, or transient ischemic attack is reduced.

[0065] In one embodiment, the risk of occurrence of the composite of the following outcomes: cognitive decline, stroke, transient ischemic attack, or death is reduced.

[0066] In one embodiment, the risk of cardiovascular death is lower.

[0067] In one embodiment, the risk of non-fatal stroke is lower.

[0068] In one embodiment, the risk of non-fatal myocardial infarction is lower.

[0069] In one embodiment, the risk of occurrence of a combination of the following outcomes is reduced: diabetic retinopathy requiring laser therapy, anti-VEGF therapy, or vitreoretinal surgery; clinical proteinuria; a 30% decline in eGFR; or chronic renal replacement therapy.

[0070] A method for treating, preventing or delaying the onset of cognitive impairment in a patient, comprising administering a therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof to the patient once a week. In one embodiment, the cognitive impairment is selected from the group consisting of MCI and dementia.

[0071] 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.

[0072] In one embodiment, the amount of tirzepatide is about 5.0 mg.

[0073] In one embodiment, the amount of tirzepatide is about 10.0 mg.

[0074] In one embodiment, the amount of tirzepatide is about 15.0 mg.

[0075] In one embodiment, the once weekly administration of tirzepatide or a pharma- ceutically acceptable salt thereof is continued for at least two years.

[0076] In one embodiment, the once weekly administration of tirzepatide or a pharma- ceutically acceptable salt thereof is continued for at least three years.

[0077] In one embodiment, the once weekly administration of tirzepatide or a pharma- ceutically acceptable salt thereof is continued for at least four years.

[0078] In one embodiment, the once weekly administration of tirzepatide or a pharma- ceutically acceptable salt thereof is continued for approximately five years.

[0079] In one embodiment, the once weekly administration of tirzepatide or a pharma- ceutically acceptable salt thereof is continued for at least 5.4 years.

[0080] In one embodiment, tirzepatide or a pharma- ceutically acceptable salt thereof is administered using a dose escalation protocol.

[0081] In one embodiment, the patient is also administered standard of care to reduce the risk of major adverse cardiovascular events.

[0082] In one embodiment, the patient is also administered the maximum tolerated dose of an ACE inhibitor.

[0083] In one embodiment, the patient also receives the maximum tolerated dose of an ARB.

[0084] In one embodiment, the patient is also administered a beta blocker.

[0085] In one embodiment, the patient is also administered a calcium channel blocker.

[0086] In one embodiment, the patient is also administered a diuretic.

[0087] In one embodiment, the patient is also administered an anti-thrombotic agent.

[0088] In one embodiment, the patient is also administered aspirin.

[0089] In one embodiment, the patient is also administered a statin.

[0090] Tirzepatide or a pharma- ceutically acceptable salt thereof for use in any of the above embodiments.

[0091] Use of tirzepatide or a pharma- ceutically acceptable salt thereof in the preparation of a medicament for any of the above embodiments.

[0092] heart failure A method for treating, preventing, or delaying the onset of heart failure 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 heart failure is selected from the group consisting of HFpEF and HFrEF.

[0093] 1. A method for preventing or delaying heart failure in a patient, comprising administering to the patient a therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week.

[0094] A method for improving glycemic control and treating, preventing, or delaying heart failure in a patient with type 2 diabetes, comprising administering to the patient a therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week.

[0095] In one embodiment, the method results in a reduction in the risk that the patient will experience HFpEF.In one embodiment, the method results in a reduction in the risk that the patient will experience HFrEF.

[0096] A method for improving glycemic control in a patient having type 2 diabetes, comprising administering to the patient a therapeutically effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week, wherein the method results in a reduction in the risk of the patient experiencing cognitive decline.

[0097] The method of any one of the above embodiments, wherein the patient has type 2 diabetes.

[0098] The method of any one of the above embodiments, wherein the patient has one or more of: T2DM; high blood pressure; high cholesterol, and obesity.

[0099] In one embodiment, the patient is either cardiovascular disease-free and has multiple cardiovascular risk factors, or is cardiovascular disease-affected.

[0100] In one embodiment, the risk factors for cardiovascular disease are selected from the group consisting of: current smoker (all forms of tobacco); use of at least one approved lipid-altering therapy to treat hypercholesterolemia or documented and untreated low-density lipoprotein cholesterol (LDL-C) > 3.4 mmol / L (130 mg / dL) within the past 6 months; documented and treated or untreated high-density lipoprotein cholesterol (HDL-C) < 1.0 mmol / L (40 mg / dL) for men, < 1.3 mmol / L (50 mg / dL) for women, or triglycerides > 2.3 mmol / L (200 mg / dL) within the past 6 months; use of at least one blood pressure lowering medication to treat hypertension or untreated systolic blood pressure (SBP) > 140 mm Hg or diastolic blood pressure (DBP) > 95 mmHg; and waist-to-hip ratio measurements of > 1.0 for men and > 0.8 for women.

[0101] In one embodiment, the heart failure is selected from the group consisting of HFpEF and HFrEF.

[0102] In one embodiment, the patient's 6-minute walk test is improved. In one embodiment, the patient's 6-minute walk test demonstrates improved exercise capacity.

[0103] In one embodiment, the patient's Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) improves. In one embodiment, improved KCCQ-CSS correlates with net clinical benefit.

[0104] In one embodiment, the patient's risk of heart failure is reduced by at least about 14%.

[0105] In one embodiment, the risk of heart failure is reduced by at least about 10%.

[0106] In one embodiment, the Pro-C3 inflammatory marker is reduced. In one embodiment, the Pro-C3 inflammatory marker is reduced to a clinically desirable level.

[0107] In one embodiment, the CRP level is reduced. In one embodiment, the CRP level is reduced to a clinically desirable level.

[0108] In one embodiment, the risk of occurrence of the composite of the following outcomes: hospitalization or death due to HFpEF is reduced.

[0109] In one embodiment, the risk of death or hospitalization due to HFpEF is reduced in patients treated with an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof.

[0110] In one embodiment, the risk of occurrence of the composite of the following outcomes: HFpEF or cognitive decline is reduced.

[0111] In one embodiment, the risk of occurrence of the composite of the following outcomes: cognitive decline, HFpEF, or HFrEF is reduced.

[0112] In one embodiment, the risk of occurrence of the composite of the following outcomes: cognitive decline, HFpEF, or death is reduced.

[0113] A method for treating, preventing, or delaying the onset of heart failure 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 heart failure is selected from the group consisting of HFpEF and HFrEF.

[0114] 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.

[0115] In one embodiment, the amount of tirzepatide is about 5.0 mg.

[0116] In one embodiment, the amount of tirzepatide is about 10.0 mg.

[0117] In one embodiment, the amount of tirzepatide is about 15.0 mg.

[0118] In one embodiment, the patient is at least 50 years of age. In one embodiment, the patient is at least 65 years of age.

[0119] In one embodiment, the once weekly administration of tirzepatide is continued for at least two years.

[0120] In one embodiment, the weekly administration of tirzepatide is continued for at least three years.

[0121] In one embodiment, the weekly administration of tirzepatide is continued for at least four years.

[0122] In one embodiment, the weekly administration of tirzepatide is continued for approximately five years.

[0123] In one embodiment, the once weekly administration of tirzepatide is continued for at least 5.5 years.

[0124] In one embodiment, tirzepatide or a pharma- ceutically acceptable salt thereof is administered using a dose escalation protocol.

[0125] In one embodiment, the patient is also administered standard of care to reduce the risk of major adverse cardiovascular events.

[0126] In one embodiment, the patient is also administered standard of care to treat the symptoms of conditions comorbid with HFrEF.

[0127] In one embodiment, the patient is also administered the maximum tolerated dose of an ACE inhibitor.

[0128] In one embodiment, the patient also receives the maximum tolerated dose of an ARB.

[0129] In one embodiment, the patient is also administered a beta blocker.

[0130] In one embodiment, the patient is also administered a calcium channel blocker.

[0131] In one embodiment, the patient is also administered a diuretic.

[0132] In one embodiment, the patient is also administered an anti-thrombotic agent.

[0133] In one embodiment, the patient is also administered aspirin.

[0134] In one embodiment, the patient is also administered a statin.

[0135] Tirzepatide or a pharma- ceutically acceptable salt thereof for use in any of the above embodiments.

[0136] Use of tirzepatide or a pharma- ceutically acceptable salt thereof in the preparation of a medicament for any of the above embodiments.

[0137] Further embodiments are described in the following examples, which should not be construed as limiting. EXAMPLES

[0138] The enrollment criteria, set forth in Table 1 below, are designed to include participants similar to patients seen in typical diabetes care, with a variety of cardiovascular risk factors or suffering from cardiovascular disease. [Table 1]

[0139] The study is designed to consist of a screening visit followed by a single-blind, 3-week placebo run-in period. Patients will then be randomized to either tirzepatide 5, 10, or 15 mg (administered using an escalating dose protocol) or placebo and will be followed at approximately 6-month intervals. Patients will be followed until approximately 1200 patients have experienced a primary endpoint event and are deemed to have done so.

[0140] Analyses will include evaluation of the effect of tirzepatide on cognitive decline as measured through administration of two different cognitive measures - the MOCA and the DSST - at baseline, and at the 2-year, 5-year, and end-of-study visits. The MOCA and DSST methods are described in more detail above.

[0141] The primary cognitive outcome is country-standardized substantial cognitive decline (SCD), defined as a reduction in either MOCA or DSST score of ≥ 1.5 standard deviations from the individual's baseline score. Country-standardization is achieved by first calculating the baseline mean and standard deviation of the MOCA and DSST scores within each country. These baseline means and standard deviations are used to calculate standardized MOCA and DSST scores for each participant at each time point. This is done by subtracting the country-specific baseline mean score from the individual's score at that time point and dividing the difference by the country-specific baseline standard deviation. Additional cognitive outcomes include SCD due to death, stroke, stroke or TIA, and composite SCD due to stroke, TIA, or death, as well as change in standardized MOCA and DSST scores over time.

[0142] Cognitive analyses will be restricted to participants with a baseline MOCA or DSST score and at least one follow-up score of the same type.

[0143] Continuous variables are summarized using means with standard deviations, and dichotomous variables are summarized using counts with percentages. Cox proportional hazards models are used to estimate the hazards of SCD and composite outcomes based on SCD with tirzepatide versus placebo, both before and after accounting for each individual's baseline standardized MOCA and DSST scores. The sensitivity of the Cox models to the discrete nature of the outcomes due to intermittent administration of cognitive tests is assessed by repeating the main analyses using a discrete time proportional odds logistic model. Where indicated, the Cox models take into account competing risks of death. See Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. Journal of the American Statistical Association 1999;94:496-509. Differences in effects within subgroups are explored by including subgroup and subgroup-treatment interaction terms in the models. Finally, the effect of tirzepatide in the least squares mean difference in standardized MOCA and DSST scores is estimated by a repeated measures linear mixed effects model with standardized baseline scores as covariates, participants as random effects, and fixed effects for treatment, visit, and treatment-visit interaction fixed effects.See Senn S. Change from baseline and analysis of covariance revisited.Stat Med 2006;25(24):4334-44.

[0144] Statistical analysis is completed using SAS software.

[0145] Example 2 A 52-week, three-phase, maximum tolerated dose, up to 15 mg / week, 6-minute walk test ("6MWT") study will be conducted in patients with obesity and HFpEF. A sample size of 500 patients will be randomized 1:1 to placebo or tirzepatide (maximum tolerated dose up to 15 mg / week). The study will measure 6MWT, weight loss, Kansas City Cardiomyopathy Questionnaire ("KCCQ"), Churg-Strauss Syndrome ("CSS"), left ventricular volume index ("LAVI"), ectopic ventricular tachycardia ("EAT"), and magnetic resonance imaging ("MRI") measures of interest including, for example, left ventricular ("LV") strain, LV muscle mass index.

[0146] Example 3 In a Phase 2 study (GPGB), tirzepatide patients receiving 15 mg / week of tirzepatide showed improvements in C-reactive protein ("CRP"), vascular cell adhesion molecule 1 ("VCAM-1"), and intercellular adhesion molecule-1 ("ICAM-1"). Improvements in plasma collagen type III ("Pro-C3") biomarkers have been observed in the 10 mg / week and 15 mg / week patient groups.

[0147] array SEQ ID NO:1 Tirzepatide YX1EGTFTSDYSIX2LDKIAQKAFVQWLIAGGPSSGAPPPS In the formula, 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 attachment to the epsilon-amino group of the K side chain with -CO2H, and the C-terminal amino acid is amidated as a C-terminal primary amide.

Claims

1. 1. A method for treating, preventing, or delaying the onset of cognitive impairment in a patient, comprising administering to said patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once weekly.

2. 2. The method of claim 1, wherein the cognitive disorder is selected from the group consisting of MCI and dementia.

3. 1. A method for preventing or slowing cognitive decline in a patient, comprising administering to said patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week.

4. The method of any one of claims 1 to 3, wherein the patient has type 2 diabetes.

5. 1. A method of improving glycemic control and preventing or delaying cognitive decline in a patient having type 2 diabetes, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week.

6. The method of any one of claims 1 to 5, wherein said method results in a reduced risk of said patient experiencing cognitive decline.

7. 1. A method of improving glycemic control in a patient having type 2 diabetes, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week, wherein the method results in a reduction in the risk that the patient will experience cognitive decline.

8. 8. The method of any one of claims 1 to 7, wherein the patient's risk of cognitive decline is reduced by about 14%.

9. The method of any one of claims 1 to 8, wherein the patient's risk of occurrence of the composite of the following outcomes: cognitive decline, stroke, transient ischemic attack, or death is reduced.

10. The method of any one of claims 1 to 9, wherein the therapeutically effective amount of tirzepatide is selected from the group consisting of about 5.0 mg, about 10.0 mg, and about 15.0 mg.

11. 11. The method of claim 10, wherein the therapeutically effective amount of tirzepatide is about 15.0 mg.

12. The method according to any one of claims 1 to 11, wherein the once weekly administration of tirzepatide is continued for at least two years.

13. The method according to any one of claims 1 to 12, wherein the patient is either free of cardiovascular disease and has multiple cardiovascular risk factors, or is suffering from cardiovascular disease.

14. 1. A method for treating, preventing, or delaying the onset of heart failure in a patient, comprising administering to said patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once weekly.

15. 15. The method of claim 14, wherein the heart failure is selected from the group consisting of HFrEF and HFpEF.

16. 16. The method of claim 15, wherein the heart failure is HFpEF.

17. 1. A method of preventing or delaying HFpEF in a patient, comprising administering to said patient an effective amount of tirzepatide, or a pharma- ceutically acceptable salt thereof, once weekly.

18. The method of any one of claims 14 to 17, wherein the patient has type 2 diabetes.

19. The method according to any one of claims 14 to 18, wherein the patient's weight is obese.

20. The method according to any one of claims 14 to 18, wherein the patient is not obese.

21. 1. A method of improving weight control and preventing or delaying HFpEF in a patient with type 2 diabetes, comprising administering to the patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once weekly.

22. The method of any one of claims 14 to 21, wherein said method provides a reduced risk of hospitalization due to HFpEF.

23. 23. The method of any one of claims 14 to 22, comprising administering to said patient an effective amount of tirzepatide or a pharma- ceutically acceptable salt thereof once a week, said method resulting in a reduction in the risk of death from HFpEF.

24. 24. The method of any one of claims 14 to 23, wherein the patient's 6 minute walk test improves by about 10%.

25. The method of any one of claims 14 to 24, wherein the patient's risk of occurrence of the composite of the following outcomes: cognitive decline, hospitalization due to HFpEF, or death is reduced.

26. The method of any one of claims 14 to 25, wherein the therapeutically effective amount of tirzepatide is selected from the group consisting of about 5.0 mg, about 10.0 mg, and about 15.0 mg.

27. 27. The method of claim 26, wherein the therapeutically effective amount of tirzepatide is about 15.0 mg.

28. The method according to any one of claims 14 to 27, wherein the once weekly administration of tirzepatide is continued for at least two years.

29. The method according to any one of claims 14 to 28, wherein the patient is either free of cardiovascular disease and has multiple cardiovascular risk factors, or is suffering from cardiovascular disease.

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