Therapeutic uses of dulaglutide

Abstract

To provide methods for treating, preventing or delaying disorders relating to cognition, such as cognitive decline, cognitive impairment or dementia in a patient.SOLUTION: Specifically, this method comprises administering dulaglutide in a therapeutically effective amount to a patient once weekly. Further disclosed are methods for improving glycemic control in a patient with type 2 diabetes mellitus, comprising administering dulaglutide in a therapeutically effective amount for reducing the risk of the patient experiencing cognitive decline.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to the field of medicine. More specifically, the present invention relates to a method for treating, preventing, or delaying cognitive decline, cognitive impairment, or disorders related to cognition, such as dementia.

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

[0004] In another aspect, the invention provides a method for preventing or slowing cognitive decline in a patient, comprising administering a therapeutically effective amount of dulaglutide to the patient once a week.

[0005] In another aspect, the 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 dulaglutide to the patient once a week.

[0006] In another aspect, the present invention provides a method for improving glycemic control in a patient having type 2 diabetes, comprising administering a therapeutically effective amount of dulaglutide to the patient once a week, wherein the method results in a reduction in the risk of the patient experiencing cognitive decline.

[0007] In another aspect, the invention provides dulaglutide for use in treating, preventing, or delaying the onset of cognitive impairment in a patient, comprising administering a therapeutically effective amount of dulaglutide to the patient once a week.

[0008] In another aspect, the present invention provides a use of dulaglutide for preparing a medicament for treating, preventing, or delaying the onset of cognitive impairment in a patient, comprising administering a therapeutically effective amount of dulaglutide to the patient once a week.

[0009] Dulaglutide is a human GLP-1 receptor agonist, comprising a dimer of a GLP-1 analog fused at its C-terminus via a peptide linker to the N-terminus of an analog of the Fc portion of an immunoglobulin, identified as CAS Registry Number 923950-08-7, and provided with the following chemical name: 7-37-Glucagon-like peptide I [8-glycine, 22-glutamic acid, 36-glycine] (synthetic human) fusion protein, dimer, comprising peptide (synthetic 16-amino acid linker) fusion protein, comprising immunoglobulin G4 (synthetic human Fc fragment). Each monomer of dulaglutide has the amino acid sequence set forth in SEQ ID NO:1: HGEGTFTSDVSSYLEEQAAKEFIAWLVKGGGGGGGSGGGGGSGGGGSAESKYGPPCPPCPA PEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKP REEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTL PPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLT VDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLG (Sequence number 1).

[0010] Two monomers are linked to form a dimer by a disulfide bond between the cysteine ​​residues at positions 55 and 58 of SEQ ID NO: 1. The structure, function, production, and use of dulaglutide in the treatment of T2DM are described in more detail in US 7,452,966 and US Patent Application Publication No. 2010 / 0196405. As used herein, the term "dulaglutide" refers to any GLP-1 receptor agonist protein dimer of two monomers having the amino acid sequence of SEQ ID NO: 1, and includes any protein that is the subject of a regulatory submission seeking approval of a GLP-1 receptor agonist product that relies in whole or in part on data regarding dulaglutide submitted to a regulatory agency by Eli Lilly and Company, regardless of whether the party seeking approval of the protein actually identifies the protein as dulaglutide or uses some other term. Dulaglutide acts on the GLP-1 receptor, resulting in stimulation of insulin synthesis and secretion, and has been shown to provide improved glycemic control in T2DM patients.

[0011] This application is directed to the recent discovery that dulaglutide can slow or prevent cognitive decline.

[0012] 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).

[0013] 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 1 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.

[0014] 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.

[0015] 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.

[0016] 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.

[0017] 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.

[0018] 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.

[0019] 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.

[0020] 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.

[0021] In certain embodiments, such patients suffer from cardiovascular disease and / or have one or more risk factors for a major adverse cardiovascular event.

[0022] 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.

[0023] 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.

[0024] 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.

[0025] The term "combined" when used herein in reference to multiple outcomes refers to the occurrence of the first of any of the outcomes.

[0026] 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.

[0027] "Therapeutically effective amount" refers to an amount of dulaglutide in the methods and uses of the present invention or pharmaceutical compositions comprising dulaglutide that will induce a biological or medical response in a patient or a desired therapeutic effect in a patient as sought by a researcher, physician, or other clinician. The effective amount of dulaglutide may vary depending on factors such as the disease state, age, sex, and weight of an individual, and the ability of dulaglutide 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 dulaglutide for use in the methods described herein is selected from the group consisting of 1.5, 3.0, and 4.5 mg. In certain embodiments, the therapeutically effective amount of dulaglutide is 3.0 mg. In certain embodiments, the therapeutically effective amount of dulaglutide is 4.5 mg. In a preferred embodiment, the therapeutically effective amount of dulaglutide is 1.5 mg.

[0028] Additional embodiments of the present invention are described below. A method of treating, preventing, or delaying the onset of cognitive impairment in a patient, comprising administering a therapeutically effective amount of dulaglutide to the patient once a week. In one embodiment, the cognitive impairment is selected from the group consisting of MCI and dementia.

[0029] A method for preventing or delaying cognitive decline in a patient, comprising administering a therapeutically effective amount of dulaglutide to the patient once a week.

[0030] A method for improving glycemic control and treating, preventing, or delaying cognitive decline in a patient with type 2 diabetes, comprising administering a therapeutically effective amount of dulaglutide to the patient once a week.

[0031] In one embodiment, the method results in a reduction in the risk that the patient will experience cognitive decline.

[0032] A method for improving glycemic control in a patient having type 2 diabetes, comprising administering a therapeutically effective amount of dulaglutide to the patient once a week, wherein the method results in a reduction in the risk of the patient experiencing cognitive decline.

[0033] The method of any one of the above embodiments, wherein the patient has type 2 diabetes.

[0034] 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.

[0035] In one embodiment, the patient is either cardiovascular disease-free and has multiple cardiovascular risk factors, or is cardiovascular disease-affected.

[0036] 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.

[0037] In one embodiment, the cognitive disorder is selected from the group consisting of MCI and dementia.

[0038] In one embodiment, the patient's risk of cognitive decline is reduced by at least about 14%.

[0039] In one embodiment, the risk of a major adverse cardiovascular event is reduced by at least about 10%.

[0040] In one embodiment, the risk of major adverse cardiovascular events is reduced by at least about 11%.

[0041] In one embodiment, the risk of major adverse cardiovascular events is reduced by about 12%.

[0042] In one embodiment, the risk of occurrence of the composite of the following outcomes: cognitive decline or death is reduced.

[0043] In one embodiment, the risk of occurrence of the composite of the following outcomes: cognitive decline or stroke is reduced.

[0044] In one embodiment, the risk of occurrence of the composite of the following outcomes: cognitive decline, stroke, or transient ischemic attack is reduced.

[0045] In one embodiment, the risk of occurrence of the composite of the following outcomes: cognitive decline, stroke, transient ischemic attack, or death is reduced.

[0046] In one embodiment, the risk of cardiovascular death is lower.

[0047] In one embodiment, the risk of non-fatal stroke is lower.

[0048] In one embodiment, the risk of non-fatal myocardial infarction is lower.

[0049] 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.

[0050] In one embodiment, the amount of dulaglutide is selected from the group consisting of about 1.5 mg, about 3.0 mg, and about 4.5 mg.

[0051] In one embodiment, the amount of dulaglutide is about 1.5 mg.

[0052] In one embodiment, the amount of dulaglutide is about 3.0 mg.

[0053] In one embodiment, the amount of dulaglutide is about 4.5 mg.

[0054] In one embodiment, the weekly administration of dulaglutide is continued for at least two years.

[0055] In one embodiment, the weekly administration of dulaglutide is continued for at least three years.

[0056] In one embodiment, the weekly administration of dulaglutide is continued for at least four years.

[0057] In one embodiment, weekly administration of dulaglutide is continued for approximately five years.

[0058] In one embodiment, the weekly administration of dulaglutide is continued for at least 5.4 years.

[0059] In one embodiment, the patient is also administered standard of care to reduce the risk of major adverse cardiovascular events.

[0060] In one embodiment, the patient is also administered the maximum tolerated dose of an ACE inhibitor.

[0061] In one embodiment, the patient also receives the maximum tolerated dose of an ARB.

[0062] In one embodiment, the patient is also administered a beta blocker.

[0063] In one embodiment, the patient is also administered a calcium channel blocker.

[0064] In one embodiment, the patient is also administered a diuretic.

[0065] In one embodiment, the patient is also administered an anti-thrombotic agent.

[0066] In one embodiment, the patient is also administered aspirin.

[0067] In one embodiment, the patient is also administered a statin.

[0068] Dulaglutide for use in any of the above embodiments.

[0069] Use of dulaglutide in the preparation of a medicament for any of the above embodiments.

[0070] Further embodiments are described in the following examples, which should not be construed as limiting. EXAMPLES

[0071] The Phase 3 clinical study, named Researching Cardiovascular Events with a Weekly INcretin in Diabetes (REWIND), is designed to evaluate the effect of once-weekly administration of dulaglutide compared to placebo on major adverse CV events when added to an existing antiglycemic regimen in patients with type 2 diabetes who are at high risk for CV events. The enrollment criteria, listed in Table 1 below, are designed to include participants similar to those seen in typical diabetes care, with a variety of cardiovascular risk factors or existing cardiovascular disease. [Table 1]

[0072] 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 dulaglutide 1.5 mg or placebo and followed at approximately 6-month intervals. Patients will be followed until approximately 1,200 patients have experienced a primary endpoint event and are deemed to have done so.

[0073] The primary efficacy measure is time to first occurrence (after randomization) of the composite endpoint of death from CV causes, nonfatal myocardial infarction (MI), or nonfatal stroke. Secondary outcomes include components of the primary composite cardiovascular outcome, a composite clinical microvascular outcome including retinal or renal disease, hospitalization for unstable angina, heart failure or emergency heart failure presentation requiring hospitalization, and all-cause mortality.

[0074] Exploratory analyses included evaluation of the effect of dulaglutide on cognitive decline, as measured through administration of two different cognitive measures - the MoCA and the DSST - at baseline, and at the 2-, 5-year, and end-of-study visits. The MoCA and DSST methods are described in more detail above.

[0075] The primary cognitive outcome was country-standardized substantial cognitive decline (SCD), defined as a reduction in either MoCA or DSST scores of ≥ 1.5 standard deviations below the baseline mean score in the participant's country. Country-standardization was achieved by first calculating the baseline mean and standard deviation of MoCA and DSST scores within each country. These baseline means and standard deviations were then used to calculate standardized MoCA and DSST scores for each participant at each time point. This was 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 included 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.

[0076] These cognitive analyses are restricted to participants with a baseline MoCA or DSST score and at least one follow-up score of the same type.

[0077] 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 dulaglutide 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 dulaglutide in least squares mean difference on 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.

[0078] All reported p-values ​​are two-sided and use a nominal significance level of 0.05. All statistical analyses are performed using SAS software (version 9.4).

[0079] A total of 12,137 individuals were screened and 9901 individuals at 370 sites located in 24 countries were randomly assigned to receive either dulaglutide or placebo. The first participant was randomized in August 2011, recruitment ended in August 2013, and patients were followed up until August 2018. During a median follow-up of 5.4 years (interquartile range 5.1, 5.9) involving 51,820 person-years of observation, final composite outcome status was available in 9610 patients.

[0080] Results were available for 8828 participants with baseline MoCA or DSST scores and at least one follow-up score of the same type. Characteristics of these participants are provided in Table 2 below. [Table 2]

[0081] The overall incidence of SCD standardized by country, and an analysis of the effect of dulaglutide in subgroups defined according to tertiles of baseline MoCA and DSST scores, are shown below in Table 3. As can be seen in Table 3, the overall incidence of SCD standardized by country in those randomly assigned to dulaglutide and placebo was 4.05 and 4.34 per 100 person-years of observation, respectively (HR 0.93, 95% CI 0.85, 1.02; p=0.11). The effect of dulaglutide in subgroups defined according to tertiles of baseline MoCA and DSST scores was higher in those with the lowest baseline scores, suggesting a statistically significant (P for heterogeneity 0.004 and 0.028, respectively) effect. [Table 3]

[0082] Subsequent analyses adjusted for each individual's baseline MoCA and DSST scores. Results are provided in Table 4 below. [Table 4]

[0083] After this adjustment, individuals in the dulaglutide group had a 14% lower hazard of SCD than those in the placebo group (HR 0.86, 95% CI 0.79, 0.95; p = 0.002), as seen in Table 4. Similar estimated effects were observed after further adjustment for age, education, ethnicity, or competing risks of death, and after including SCD in various composite outcomes.

[0084] Furthermore, similar beneficial effects were seen in those receiving dulaglutide compared with placebo across subgroups defined based on age (<70 years), education (<12 years), previous cardiovascular disease, previous stroke or TIA, standardized baseline MoCA score (<1 unit), HbA1c (<0.081%), natural log of albumin:creatinine ratio (<-0.062; -0.062 to 1.35; and >1.35), and eGFR (<60 mL / min / 1.73 m2) (all P interactions >0.07).

Claims

1. A method for treating, preventing, or delaying the onset of cognitive impairment in a patient, comprising administering a therapeutically effective amount of dulaglutide to the patient once a week.

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

3. A method for preventing or delaying cognitive decline in a patient, comprising administering a therapeutically effective amount of dulaglutide to the patient once a week.

4. 10. The method of any one of the preceding claims, wherein the patient has type 2 diabetes.

5. A method for improving glycemic control and preventing or delaying cognitive decline in a patient with type 2 diabetes, comprising administering a therapeutically effective amount of dulaglutide to the patient 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. A method for improving glycemic control in a patient having type 2 diabetes, comprising administering a therapeutically effective amount of dulaglutide to the patient once a week, wherein the method results in a reduction in the risk of the patient experiencing 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 dulaglutide is selected from the group consisting of about 1.5 mg, about 3.0 mg, and about 4.5 mg.

11. 11. The method of claim 10, wherein the therapeutically effective amount of dulaglutide is about 1.5 mg.

12. The method of any one of claims 1 to 11, wherein the weekly administration of dulaglutide 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.

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