Therapeutic use of dulaglycopeptides

Abstract

The present invention relates to the therapeutic use of dulaglycopeptides, to a method for reducing the risk of a major adverse cardiovascular event in a type 2 diabetes mellitus (T2DM) patient having a variety of cardiovascular risk factors without or with an established cardiovascular disease, and to a method for reducing the risk of a major adverse cardiovascular event in a type 2 diabetes mellitus (T2DM) patient having a variety of cardiovascular risk factors without or with an established cardiovascular disease, the methods comprise administering a glucagon-like peptide-1 (GLP-1) receptor agonist dulaglycopeptide.

Description

[0001] This application is a divisional application of the invention patent application with application date of November 4, 2019, application number 201980095007.7, and name “Therapeutic Uses of Dulaglutide”.

[0002] The present invention relates to the field of medicine. More specifically, the present invention relates to a method for reducing the risk of major adverse cardiovascular events in patients with type 2 diabetes (T2DM) with multiple cardiovascular risk factors or established cardiovascular disease, comprising administering the glucagon-like peptide-1 (GLP-1) receptor agonist dulaglutide.

[0003] Patients with T2DM often suffer from various comorbidities, one of which is cardiovascular disease (CVD). The incidence of CVD in T2DM patients is approximately twice that in non-diabetic individuals, and modification of CVD risk factors (including diet and exercise) is a standard component of T2DM treatment plans, but CVD-related death remains the most common cause of death in T2DM patients.

[0004] The effects of both glucose-lowering and non-glucose-lowering therapies on the incidence of cardiovascular events have been studied. Studies have shown that non-glucose-lowering therapies (including statins, such as atorvastatin; renin angiotensin system modulators, such as ramipril and telmisartan; and a combination of perindopril (angiotensin-converting enzyme (ACE) inhibitor) and indapamide (thiazide diuretics (TZDs)) can reduce the incidence of cardiovascular events in patients with T2DM.

[0005] Studies of the effects of glucose-lowering therapy on the incidence of cardiovascular events have yielded mixed results. For example, pioglitazone has mixed effects on cardiovascular outcomes, basal insulin and dipeptidyl peptidase-4 (DPP-4) inhibitors have neutral effects on cardiovascular outcomes, and empagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, reduces cardiovascular mortality and hospitalization for heart failure.

[0006] Similarly, studies on the effects of different agents on the incidence of cardiovascular events in the GLP-1 receptor agonist class have also produced different results. In one aspect, it was found that lixisenatide (Lixisenatide) did not significantly change the ratio of major adverse cardiovascular events or other serious adverse events in patients with established CVD (Pfeffer MA et al., Lixisenatide in patients with type 2diabetes and acute coronary syndrome, 373 N. Engl. J Med. 2247–2257 (2015) (“ELIXA”)), and it was found that compared with placebo, once-weekly exenatide did not cause a significant difference in the incidence of major adverse cardiovascular events in a patient population (including patients with and without established CVD) (Holman RR et al., Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2Diabetes, 377 N. Engl. J. Med. 1228-1239 (2017) (“EXCSEL”)). In another aspect, albiglutide, liraglutide, and semaglutide were found to reduce the risk of major adverse cardiovascular events in a patient population consisting entirely (albiglutide) or primarily (liraglutide and semaglutide) of patients with established CVD.(Hernandez AF, et al., Albiglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Cardiovascular Disease (Harmony Outcomes): a Double-blind, Randomized Placebo-controlled Trial, 392 Lancet 1519-1529 (2018) (“Harmony Outcomes”); Marso SP, et al., Liraglutide and Cardiovascular Outcomes in Patients with Type 2Diabetes, 375N.Engl.J.Med.311-322(2016)(“LEADER”)); Marso SP, et al., Semaglutide and Cardiovascular Outcomes in Patients with Type 2Diabetes 375N.Engl.J.Med.1834–1844(2016)(“SUSTAIN-6”)).

[0007] Despite the existence of the above-described therapies, there is still a need for new treatment options that can reduce the risk of major adverse cardiovascular events in T2DM patients. In particular, there is still a need for treatment options that can reduce the risk of major adverse cardiovascular events in T2DM patients who do not yet have established cardiovascular disease.

[0008] The methods of the present invention seek to meet those needs. Indeed, it was recently discovered that dulaglutide was able to statistically significantly reduce the risk of major adverse cardiovascular events in a population that included both patients with established cardiovascular disease and patients without established cardiovascular disease. Furthermore, the overall reduction in risk seen was driven by both patients with established cardiovascular disease and patients without established cardiovascular disease and was similar in both.

[0009] Accordingly, the present invention provides a method of reducing the risk of major adverse cardiovascular events in a patient with type 2 diabetes, comprising administering to the patient a therapeutically effective amount of dulaglutide once a week, wherein the patient has type 2 diabetes and any of: multiple cardiovascular risk factors without established cardiovascular disease; or established cardiovascular disease.

[0010] In another aspect, the present invention provides a method for reducing the risk of major adverse cardiovascular events in a patient with type 2 diabetes, comprising: identifying a patient with type 2 diabetes and or multiple cardiovascular risk factors without established cardiovascular disease or with established cardiovascular disease; and administering a therapeutically effective amount of dulaglutide to the patient once a week.

[0011] In another aspect, the present invention provides a method of delaying the occurrence of a major adverse cardiovascular event in a patient with type 2 diabetes, comprising administering to the patient a therapeutically effective amount of dulaglutide once a week, wherein the patient has type 2 diabetes and any of: multiple cardiovascular risk factors without established cardiovascular disease; or established cardiovascular disease.

[0012] In another aspect, the present invention provides a method for improving glycemic control and reducing the risk of a first major adverse cardiovascular event in a patient with type 2 diabetes, comprising administering a therapeutically effective amount of dulaglutide to the patient once a week, wherein the patient has type 2 diabetes and any of: multiple cardiovascular risk factors without established cardiovascular disease; or established cardiovascular disease.

[0013] In another aspect, the invention provides dulaglutide for use in reducing the risk of major adverse cardiovascular events in a patient with type 2 diabetes and either: multiple cardiovascular risk factors without established cardiovascular disease; or established cardiovascular disease.

[0014] In another aspect, the invention provides the use of dulaglutide for the preparation of a medicament for reducing the risk of major adverse cardiovascular events in patients with type 2 diabetes and any of: multiple cardiovascular risk factors without established cardiovascular disease; or established cardiovascular disease.

[0015] 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, and is identified by CAS Registry Number 923950-08-7, which provides the following chemical name: 7-37-Glucagon-like Peptide I [8-Glycine, 22-Glutamic Acid, 36-Glycine] (Synthetic Human) Fusion Protein and Peptide (Synthetic 16-Amino Acid Linker) Fusion Protein and Immunoglobulin G4 (Synthetic Human Fc Fragment), Dimer. Each monomer of Dulaglutide has the amino acid sequence shown in SEQ ID NO: 1: (SEQ ID NO: 1).

[0016] The two monomers are connected by a disulfide bond between the cysteine ​​residues at positions 55 and 58 of SEQ ID NO:1 to form a dimer. The structure, function, production and use of dulaglutide in treating T2DM are described in more detail in US 7,452,966 and US Patent Application Publication No. US20100196405. When 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, including any protein that is the subject of regulatory submission for seeking approval of GLP-1 receptor agonist products (which relies in whole or in part on data related to dulaglutide submitted by Eli Lilly and Company to regulatory agencies), regardless of whether the party seeking approval of the protein actually identifies the protein as dulaglutide or uses some other terminology. Dulaglutide agonizes the GLP-1 receptor that stimulates insulin synthesis and secretion, and has been shown to provide improved glycemic control in patients with T2DM.

[0017] It has now been found that dulaglutide is able to reduce the risk of major adverse cardiovascular events in patients with T2DM and either established cardiovascular disease or without established cardiovascular disease but with multiple cardiovascular risk factors.

[0018] As noted above, several other GLP-1 receptor agonists have been previously studied for their effects on cardiovascular outcomes (referred to as cardiovascular outcomes trials or "CVOTs"), and the results of those studies were mixed, with some demonstrating benefits in patients with T2DM and some not demonstrating such benefits. A summary of the enrollment numbers and composite MACE 3 outcomes from those studies is provided in Table 1 below.

[0019] Table 1. GLP-1 receptor agonist CVOT enrollment and MACE3 outcomes. a 83.0% had established cardiovascular disease (including CKD 3+), and 58.8% had established cardiovascular disease but no CKD; b Cardiovascular disease, cerebrovascular disease, PVD, CRF, CHF; c acute coronary heart disease events within 180 days before screening; d 73% had at least one prior cardiovascular event (70% CAD, 24% PAD, 22% cerebrovascular disease); e Coronary artery disease, cerebrovascular disease, or peripheral arterial disease.

[0020] As can be seen in Table 1, the results of three of the studies indicated a positive effect of the tested agent, while the results of two of the studies did not show a statistically significant difference from placebo.

[0021] Furthermore, even in those studies that demonstrated a benefit, the positive results were driven by patients with established cardiovascular disease. As can also be seen in Table 1, two of the studies included only patients with prior CVD. For studies that did include patients without established CVD, a comparison of the results for patients with established CVD compared to patients without established CVD (but with multiple risk factors) in the remaining studies is provided in Table 2 below.

[0022] Table 2. "No prior CVD" refers to patients without established CVD (but with multiple risk factors). "Prior CVD" refers to patients with established CVD.

[0023] As seen above in Table 2, none of the patient populations in the studies enrolling patients without established CVD drove improvements in major adverse cardiovascular events. In contrast, as described in more detail below in the Examples, it was found that treatment with dulaglutide was able to statistically significantly reduce the risk of major adverse cardiovascular events in a population that included patients with and without established cardiovascular disease, and that both of those patient groups drove the reduction in risk seen and that the reduction in risk seen in both patient groups was similar.

[0024] The terms "established CVD" or "established cardiovascular disease" when used herein to describe a patient refers to a patient with one or more of the following: prior myocardial infarction (MI); prior ischemic stroke; prior unstable angina; prior revascularization (coronary, carotid, or peripheral arterial); prior hospitalization for an ischemia-related event (unstable angina or myocardial ischemia found on imaging or requiring percutaneous coronary intervention); and prior documented myocardial ischemia.

[0025] When used in this article, the term "major adverse cardiovascular events" refers to cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. These events are sometimes also referred to as MACE or MACE3 events. Any of these events that occur first is a frequently used composite endpoint in CVOT.

[0026] When used in this article in relation 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 major adverse cardiovascular events in a T2DM patient. Such risk factors include, in particular, any of the following: current tobacco use (any form of tobacco); use of at least 1 approved lipid-modulating therapy (e.g., statins, such as atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin, fluvastatin, or pitavastatin; PCSK9 inhibitors, such as evolocumab or alirocumab; and ezetimibe) to treat hypercholesterolemia or Untreated low-density lipoprotein cholesterol (LDL-C) ≥3.4mmol / L (130mg / dL) recorded in the past 6 months; treated or untreated high-density lipoprotein cholesterol (HDL-C) <1.0mmol / L (40mg / dL) (for men) and <1.3mmol / L (50mg / dL) (for women) or triglycerides ≥2.3mmol / L (200mg / dL) recorded in the past 6 months; use of at least 1 antihypertensive drug to treat hypertension (such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), thiazide-like diuretics, and dihydropyridine calcium channel blockers) or untreated systolic blood pressure (SBP) ≥140mmHg or diastolic blood pressure (DBP) ≥95mmHg; measured waist-to-hip ratio >1.0 for men and >0.8 for women.

[0027] As used herein, the term "plurality" means more than one.

[0028] As used herein, the terms "treatment," "treat," "treating," and the like are meant to include slowing or reducing the progression of a disease or condition. These terms also include alleviating, ameliorating, reducing, 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.

[0029] When used herein in conjunction with the risk of major adverse cardiovascular events, the terms "reduce", "reduce", "reduces", "reducing", etc. refer to reducing the probability of a major adverse cardiovascular event occurring. When used herein, the term "delaying the occurrence" of a major adverse cardiovascular event means increasing the time period before a major adverse cardiovascular event occurs.

[0030] When used herein in conjunction with multiple outcomes, the term "composite" refers to whichever occurs first among any of the outcomes.

[0031] As used herein, the term "hazard ratio" refers to a measure of the relative rate of progression to an endpoint compared to a control group. In an outcome-based clinical trial (such as a CVOT described herein), a reduction in the hazard ratio of a test group compared to a control group indicates that the therapy used in the test group reduces the risk of an endpoint (in the case of the studies described herein, a major adverse cardiovascular event).

[0032] The methods and uses described herein can be provided in combination with standard of care for reducing the risk of major adverse cardiovascular events simultaneously or sequentially, wherein the standard of care for reducing the risk of major adverse cardiovascular events includes administration of maximum tolerated doses of ACE inhibitors and ARBs, and appropriate treatment of blood pressure, lipids and HbA1c according to local guidelines. In certain embodiments, the methods described herein further include administering to the patient a maximum tolerated dose of ACE inhibitors. In certain embodiments, the methods described herein further include administering to the patient a maximum tolerated dose of ARBs. Other agents that may be administered include beta blockers, calcium channel blockers, diuretics, antithrombotic agents, aspirin and statins.

[0033] "Therapeutically effective amount" means the amount of dulaglutide used in the methods and uses of the present invention or a pharmaceutical composition comprising dulaglutide used in the methods and uses of the present invention, which will elicit a biological or medical response in a patient or a desired therapeutic effect on a patient sought by a researcher, physician or other clinician. The effective amount of dulaglutide may vary according to factors such as the disease state, the age, sex and weight of the individual, and the ability of dulaglutide to elicit a desired response in the individual. An effective amount is also an amount in which the therapeutically beneficial effects outweigh any toxic or deleterious effects. In certain embodiments, the therapeutically effective amount of dulaglutide used in the methods described herein is selected from 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.

[0034] The following describes additional embodiments of the invention: A method of reducing the risk of major adverse cardiovascular events in a patient with type 2 diabetes comprising administering to the patient a therapeutically effective amount of dulaglutide once weekly, wherein the patient has type 2 diabetes and any of: multiple cardiovascular risk factors without established cardiovascular disease; or established cardiovascular disease.

[0035] A method of reducing the risk of major adverse cardiovascular events in a patient with type 2 diabetes, comprising: identifying a patient with type 2 diabetes and multiple cardiovascular risk factors without established cardiovascular disease or with established cardiovascular disease; and administering to the patient once weekly a therapeutically effective amount of dulaglutide.

[0036] A method of delaying the onset of a major adverse cardiovascular event in a patient with type 2 diabetes comprising administering to the patient a therapeutically effective amount of dulaglutide once weekly, wherein the patient has type 2 diabetes and any of: multiple cardiovascular risk factors without established cardiovascular disease; or established cardiovascular disease.

[0037] A method for improving glycemic control and reducing the risk of a first major adverse cardiovascular event in a patient with type 2 diabetes comprising administering a therapeutically effective amount of dulaglutide to the patient once weekly, wherein the patient has type 2 diabetes and either: multiple cardiovascular risk factors without established cardiovascular disease; or established cardiovascular disease.

[0038] A method of improving glycemic control in a patient with type 2 diabetes comprising administering a therapeutically effective amount of dulaglutide to the patient once weekly, wherein the patient has type 2 diabetes and any of: multiple cardiovascular risk factors without established cardiovascular disease; or established cardiovascular disease; and wherein the risk of major adverse cardiovascular events is reduced in the patient.

[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 a major adverse cardiovascular event 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 cardiovascular death is lower.

[0043] In one embodiment, the risk of non-fatal stroke is lowered.

[0044] In one embodiment, the risk of non-fatal myocardial infarction is lowered.

[0045] In one embodiment, the risk of the composite of the following outcomes is reduced: diabetic retinopathy requiring laser, anti-VEGF therapy, or vitrectomy; clinical proteinuria; a 30% decrease in eGFR; or chronic renal replacement therapy.

[0046] In one embodiment, the patient has multiple cardiovascular risk factors without established cardiovascular disease.

[0047] In one embodiment, the risk factors for cardiovascular disease are selected from: current tobacco use (any form of tobacco); use of at least 1 approved lipid-modulating therapy to treat hypercholesterolemia or untreated low-density lipoprotein cholesterol (LDL-C) ≥ 3.4 mmol / L (130 mg / dL) recorded in the past 6 months; 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 (200 mg / dL) recorded in the past 6 months; use of at least 1 antihypertensive medication to treat hypertension or untreated systolic blood pressure (SBP) ≥ 140 mm Hg or diastolic blood pressure (DBP) ≥ 95 mmHg; a measured waist-to-hip ratio > 1.0 for men and > 0.8 for women.

[0048] In one embodiment, the amount of dulaglutide is selected from about 1.5 mg, about 3.0 mg, and about 4.5 mg.

[0049] In one embodiment, the amount of dulaglutide is about 1.5 mg.

[0050] In one embodiment, the amount of dulaglutide is about 3.0 mg.

[0051] In one embodiment, the amount of dulaglutide is about 4.5 mg.

[0052] In one embodiment, the once weekly administration of dulaglutide continues for approximately 5 years.

[0053] In one embodiment, the patient is also administered standard therapy to reduce the risk of major adverse cardiovascular events.

[0054] In one embodiment, the patient is also administered a maximum tolerated dose of an ACE inhibitor.

[0055] In one embodiment, the patient is also administered a maximum tolerated dose of an ARB.

[0056] In one embodiment, the patient is also administered a beta blocker.

[0057] In one embodiment, a calcium channel blocker is also administered to the patient.

[0058] In one embodiment, the patient is also administered a diuretic.

[0059] In one embodiment, an antithrombotic agent is also administered to the patient.

[0060] In one embodiment, aspirin is also administered to the patient.

[0061] In one embodiment, the patient is also administered a statin.

[0062] Dulaglutide for use in any one of the above embodiments.

[0063] Use of dulaglutide in the preparation of a medicament for use in any one of the above embodiments. Example

[0064] A Phase 3 clinical study named Researching Cardiovascular Events with a Weekly INcretin in Diabetes (REWIND) was designed to evaluate the effect of once-weekly administration of dulaglutide on major adverse CV events compared with placebo when added to an existing antihyperglycemic regimen in patients with type 2 diabetes who are at high risk for CV events. The enrollment criteria listed in Table 3 below were designed to include participants similar to those seen in typical diabetes practice, with varying cardiovascular risk factors or established cardiovascular disease: Table 3. Registration criteria.

[0065] The study was designed to include a screening visit followed by a single-blind 3-week placebo run-in period. Afterwards, patients were randomized to dulaglutide 1.5 mg or placebo and followed up at approximately 6-month intervals. Patients were followed up until approximately 1200 patients experienced a primary endpoint event (as adjudicated).

[0066] The primary efficacy measure was the time to the composite endpoint of death, non-fatal myocardial infarction (MI) or non-fatal stroke due to CV causes for the first time (after randomization). Secondary outcomes included each component of the primary composite cardiovascular outcome, composite clinical microvascular outcomes including retina or nephropathy, hospitalization for unstable angina, heart failure requiring hospitalization or urgent heart failure visits, and all-cause mortality. These results are indicated in Table 4. All deaths and cardiovascular, pancreatic and thyroid events (i.e., both efficacy and safety outcomes) were adjudicated by an external adjudicator who was blind to treatment allocation.

[0067] Table 4. Secondary and safety outcomes. Abbreviations: VEGF, vascular endothelial growth factor; eGFR, estimated glomerular filtration rate.

[0068] The sample size calculation was based on a 3-year recruitment period, an expected primary outcome event rate of 2% per year in the control group, an annual withdrawal rate of 0.15%, and a 2-sided type I error of 5%. These assumptions indicated that recruitment of 9600 patients would result in a total of 1200 participants with at least 1 major cardiovascular outcome over a maximum follow-up period of 8 years and would provide 90% power to detect a hazard ratio of 0.82 for cardiovascular events. Follow-up ended after 1200 participants had been confirmed by adjudication to have had a major cardiovascular outcome.

[0069] All efficacy and safety analyses were designed to be performed using an intention-to-treat approach, which included all randomized participants regardless of compliance. Baseline continuous variables were summarized as mean or median values ​​and their standard deviation or interquartile range, and categorical variables were intended to be summarized as numbers and percentages. The effect of the intervention on the time of first appearance of the primary outcome was designed to be analyzed using a Cox proportional hazards regression model, in which the only independent variable was assigned to dulaglutide vs placebo. The proportional hazard assumption will be evaluated in graphical form. Kaplan-Meier curves will be generated together with long-rank P values. The incidence rate per 100 person-years for each treatment group will be calculated for all key results. All secondary results will be analyzed in a predetermined order defined by the graphical method to control overall type I errors. If the null hypothesis of no effect is rejected due to the primary result, the graphical test method will be simplified to assign α to each secondary result. The exploratory subgroups to be examined include patients with previous CVD vs. those without known CVD. For subgroup analysis, it is considered that interaction P values ​​<0.1 suggest interactions. No adjustments will be made to multiplicity.

[0070] 12,137 individuals were screened and 9901 individuals at 370 sites in 24 countries or regions were randomized to dulaglutide or placebo. The main reasons for non-randomization included failure to meet eligibility criteria (68%) or personal decision (25%). The first participant was randomized in August 2011 and recruitment ended in August 2013. As noted in Tables 5 and 6, the mean age of the participants was 66 years and the mean BMI was 32 kg / m 2 , and 31% had a history of CVD (defined as a history of MI, ischemic stroke, revascularization, hospitalization for unstable angina with consistent new ischemic ECG changes, or positive stress test with consistent imaging). In addition, 93% had a history of hypertension, 9% had a history of previous heart failure, and the mean blood pressure was 137 / 78 mmHg. The mean reported duration of diabetes was 10 years, 24% of participants were taking insulin, 81% were taking metformin, 57% were taking sulfonylureas, and the mean baseline HbA1c was 7.3%. 81% of participants used angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), 45% were taking beta-blockers, 66% were taking statins at baseline, 51% were taking acetylsalicylic acid, 8% were taking other antiplatelet agents, and the mean baseline LDL cholesterol was 2.56 nmol / L.

[0071] Table 5. Baseline clinical characteristics of the 9901 randomized participants.

[0072] Abbreviations: IQR, interquartile range; sd, standard deviation; a Coronary, carotid, or peripheral arteries; b unstable angina or myocardial ischemia found on imaging or the need for percutaneous coronary intervention; c Albumin / creatinine ≥3.39mg / mmol.

[0073] Table 6. Baseline use of medication classes among randomized participants. Values ​​represent counts and percentages for all randomizations.

[0074] Patients were followed until August 2018. During a median follow-up of 5.4 years (interquartile range, 5.1, 5.9), including 51,820 person-years, the final composite outcome status was known in 9610 patients. During follow-up, 1731 participants assigned to dulaglutide and 1761 assigned to placebo had at least 1 study drug discontinuation, whereas 4277 assigned to dulaglutide and 4196 assigned to placebo were taking study drug at the last visit. Participants assigned to dulaglutide or placebo took study drug for 85.8% and 87.1% of the follow-up time, respectively, from randomization until they experienced the primary outcome or last follow-up.

[0075] The results are provided in Tables 7 and 8 below.

[0076] Table 7. Effects of dulaglutide on primary and secondary outcomes.

[0077] As seen in Table 7, weekly injections of dulaglutide significantly and safely reduced the risk of CV outcomes by 12% compared with placebo. Furthermore, the benefits were consistent across all 3 components of the composite primary outcome, with the largest estimated effect size noted for nonfatal stroke. The incidence of the composite microvascular outcome was also lower in participants assigned to dulaglutide compared with placebo.

[0078] Table 8. Subgroup analysis.

[0079] As seen in Table 8, the positive effect of dulaglutide on the primary outcome was similar in participants with or without prior CV events.

Claims

1. Use of dulaglutide in the preparation of a medicament for reducing the risk of non-fatal stroke in a patient with type 2 diabetes, wherein a therapeutically effective amount of dulaglutide is administered to the patient once a week, wherein the patient has type 2 diabetes and (a) multiple cardiovascular risk factors without established cardiovascular disease; or (b) established cardiovascular disease, and wherein the risk of non-fatal stroke is reduced by at least about 10%.

2. The method of claim 1, wherein the cardiovascular risk factor is selected from the group consisting of (a), (b), (c), (d) and (e): (a) tobacco use; (b) At least one of the following: i) use of at least 1 approved lipid-modulating therapy to treat hypercholesterolemia; or ii) untreated low-density lipoprotein cholesterol (LDL-C) ≥ 3.4 mmol / L (130 mg / dL) recorded in the past 6 months; (c) At least one of the following: i) High-density lipoprotein cholesterol (HDL-C) measured within the past 6 months: <1.0 mmol / L (40 mg / dL) for men; and <1.3 mmol / L (50 mg / dL) for women; or ii) triglycerides ≥2.3mmol / L (200mg / dL) in the past 6 months; (d) At least one of the following: i) taking at least 1 antihypertensive drug to treat hypertension; or ii) untreated systolic blood pressure (SBP) ≥140 mm Hg or diastolic blood pressure (DBP) ≥95 mm Hg; and (e) Waist-to-hip ratio measured, >1.0 for males and >0.8 for females.

3. The use of claim 1, wherein the therapeutically effective amount of dulaglutide is selected from the group consisting of 1.5 mg, 3.0 mg and 4.5 mg.

4. The use according to claim 1, wherein the therapeutically effective amount of dulaglutide is 1.5 mg.

5. The use of claim 1, wherein the weekly administration of dulaglutide continues for approximately 5 years.

6. The use of claim 1, further comprising administering to the patient one or more of the following: angiotensin converting enzyme (ACE) inhibitors; angiotensin receptor blockers (ARBs); beta blockers; calcium channel blockers; diuretics; antithrombotic agents; acetylsalicylic acid or statins.

7. The use of claim 1, wherein the patient has multiple cardiovascular risk factors but no established cardiovascular disease.

8. The use of claim 1, wherein the risk of non-fatal stroke is reduced by at least about 20%.

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