GLP-1 receptor agonists in dementia

Abstract

The present invention relates to improved medical therapies for all forms and stages of dementia, including the administration of (i) a GLP-1 receptor agonist to subjects with metabolic syndrome, or (ii) semaglutide.

Description

[Technical field]

[0001] The present invention relates to GLP-1 receptor agonists for use in the treatment of all forms and stages of dementia. [Background technology]

[0002] Currently, there are no therapeutic options to actively prevent or slow the progression of dementia, and no new pharmacological therapies have been approved for the treatment of dementia within the past 20 years. According to the WHO, approximately 50 million people worldwide have dementia, and this number is expected to triple by 2050, with Alzheimer's disease being the most common form of dementia and contributing to 60-70% of cases. Thus far, focused efforts have failed to identify any medical treatment that prevents, slows, or modifies the disease course of dementia, including recent unsuccessful trials focused on reducing the production or enhancing the clearance of amyloid-β. Therefore, improved pharmacological therapies for patients with dementia are desirable. Determining whether GLP-1 receptor agonists have an effect on dementia in humans remains an important unanswered question. Summary of the Invention

[0003] The present invention relates to an improved medical therapy for dementia involving the administration of a GLP-1 receptor agonist.

[0004] In some embodiments, the present invention relates to a method for the treatment of dementia, the method comprising administering a GLP-1 receptor agonist to a subject in need thereof, the subject having metabolic syndrome, and the GLP-1 receptor agonist comprises GLP-1(7-37) (SEQ ID NO:1), optionally comprising one or more substitutions, deletions, additions, and / or modifications.

[0005] In some embodiments, the present invention relates to a method for the treatment of dementia, the method comprising administering semaglutide to a subject in need thereof. [Brief description of the drawings]

[0006] [Figure 1] Figure 1 shows time to dementia with GLP-1 receptor agonists versus placebo in the pooled RCTs, in which 15 patients randomized to GLP-1 receptor agonists (0.66 per 1000 patient-years) and 32 patients randomized to placebo (1.41 per 1000 patient-years) developed dementia. GLP-1RA = GLP-1 receptor agonist. [Diagram 2] Figure 2 shows the hazard ratios for dementia with each 1-year increase in duration of exposure to GLP-1 receptor agonists and other secondary diabetes treatments in a nationwide cohort. Cox proportional hazards regression models were performed for exposure to each treatment. Estimates show hazard ratios for 1-year increase in duration of exposure. Models were adjusted for history of stroke, myocardial infarction, hypertension, educational attainment, and diabetes duration. Sex, age, and calendar days were included via matching. [Diagram 3] Figure 3 shows the hazard ratios for dementia with each year of increase in duration of exposure to GLP-1 receptor agonists by subgroups of the Nationwide Cohort. Cox proportional hazards regression models were performed for exposure to GLP-1 in the various subgroups. Estimates show hazard ratios for each year of increase in duration of exposure. Models were adjusted for history of stroke, myocardial infarction, hypertension, educational attainment, and diabetes duration. Gender, age, and calendar date were included via matching. [Figure 4] Figure 4 shows the study design used in the nationwide cohort. *First secondary diabetes treatment = first treatment with a diabetes treatment not including metformin, eligibility = eligible for the cohort of diabetic patients, case date = date of dementia diagnosis with matching of each case with 10 controls without dementia, exposure period 5 years prior to the case date (when cumulative diabetes treatment duration is assessed). [Figure 5A]Figure 5A shows the hazard ratios for dementia with each yearly increase in duration of exposure to GLP-1 receptor agonists and other secondary diabetes treatments in the national cohort, excluding the past 2 years prior to the case date. Cox proportional hazards regression models conducted for exposure to each treatment. Estimates show hazard ratios for a 1-year increase in duration of exposure. Models were adjusted for history of stroke, myocardial infarction, hypertension, educational attainment, and diabetes duration. Sex, age, and calendar date were included via matching. [Figure 5B] Figure 5B shows the hazard ratios for dementia with each year of increase in duration of exposure to GLP-1 receptor agonists and other secondary diabetes treatments in the nationwide cohort, when diabetes duration was defined as "time from first treatment with metformin or secondary diabetes treatment." Cox proportional hazards regression models were performed for exposure to each treatment. Estimates show hazard ratios for a one-year increase in exposure duration. Models were adjusted for history of stroke, myocardial infarction, hypertension, educational attainment, and diabetes duration. Sex, age, and calendar days were included via matching. [Figure 6A] Figure 6A shows the hazard ratios for dementia with each yearly increase in duration of exposure to GLP-1 receptor agonists assessed 3, 5, and 10 years before dementia diagnosis in a national cohort. *Primary analysis. Cox proportional hazards regression models were conducted for GLP-1 receptor agonist exposure, assessed during the 3-, 5-, and 10-year exposure window before dementia. Estimates show hazard ratios for a 1-year increase in duration of exposure. Models were adjusted for history of stroke, myocardial infarction, hypertension, educational attainment, and diabetes duration. Sex, age, and calendar date were included via matching. [Figure 6B] Figure 6B shows the hazard ratios for dementia with each year of increase in duration of exposure to GLP-1 receptor agonists in the national cohort, adjusted for age, sex, and calendar days via matching. Cox proportional hazards regression models performed for exposure to GLP-1 receptor agonists. Estimates show hazard ratios for one-year increase in duration of exposure. Models were adjusted for sex, age, and calendar days via matching. [Figure 6C] Figure 6C shows hazard ratios for competing risks of death with each year increase in duration of exposure to GLP-1 receptor agonists in a nationwide cohort. Cox proportional hazards regression models performed for exposure to GLP-1 receptor agonists. Estimates show hazard ratios for each year increase in duration of exposure. Models were adjusted for history of stroke, myocardial infarction, hypertension, educational attainment, and diabetes duration. Gender, age, and calendar date were included via matching. [Figure 7] Figure 7 shows the effect of semaglutide administration compared to vehicle on Y-maze alternation behavior in SAMP8 mice. [Figure 8] Figure 8 shows improvement in long-term memory in SAMP8 mice as measured in the step-through passive avoidance test after administration of semaglutide, showing step-through latency (Figure 8) and escape latency (Figure 9) compared to vehicle. [Figure 9] Figure 9 shows improvement in long-term memory in SAMP8 mice as measured in the step-through passive avoidance test after administration of semaglutide, showing step-through latency (Figure 8) and escape latency (Figure 9) compared to vehicle. [Figure 10] Figure 10 shows the effect of semaglutide in lipopolysaccharide (LPS)-induced neuroinflammation, a non-genetic model of Alzheimer's disease in rodents, on the microglial inflammatory marker Iba1 in the hippocampus. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0007] The inventors have surprisingly found that administration of a glucagon-like peptide 1 (GLP-1) receptor agonist reduced the risk of dementia in subjects with metabolic syndrome.Furthermore, the inventors have surprisingly found that semaglutide improved dementia in animal models.

[0008] In some embodiments, the present invention relates to a method for the treatment of dementia, the method comprising administering a GLP-1 receptor agonist to a subject in need thereof, the subject having metabolic syndrome. In some embodiments, the present invention relates to a method for the treatment of dementia, the method comprising administering a GLP-1 receptor agonist to a human subject in need thereof, the subject having one or more indications selected from the group consisting of prediabetes, diabetes, cardiovascular disease, obesity, and hypertension. In some embodiments, the present invention relates to a method for the treatment of dementia, the method comprising administering semaglutide to a subject in need thereof.

[0009] In some embodiments, the present invention relates to a method for reducing the risk of developing dementia, the method comprising administering a GLP-1 receptor agonist to a subject in need thereof, the subject having metabolic syndrome. In some embodiments, the present invention relates to a method for reducing the risk of developing dementia, the method comprising administering a GLP-1 receptor agonist to a subject in need thereof, the subject having one or more indications selected from the group consisting of prediabetes, diabetes, cardiovascular disease, obesity, and hypertension. In some embodiments, the present invention relates to a method for reducing the risk of developing dementia, the method comprising administering semaglutide to a subject in need thereof.

[0010] Dementia exists in various degrees of severity. In some embodiments, the term "dementia" as used herein refers to all forms and stages in the dementia disease continuum. In some embodiments, the dementia is selected from the group of indications defined in ICD-11: Alzheimer's disease dementia; Early-onset Alzheimer's disease dementia; Autosomal dominant Alzheimer's dementia, presenilin 1 mutation; Autosomal dominant Alzheimer's dementia, presenilin 2 mutation; Autosomal dominant Alzheimer's dementia, amyloid precursor protein mutation; Late-onset Alzheimer's disease dementia; Alzheimer's dementia with cerebrovascular disease, mixed type; Alzheimer's dementia with other non-vascular etiologies. Amnesic Alzheimer's disease, mixed type;Non-amnesic Alzheimer's disease subtype;Non-amnesic Alzheimer's disease, logopenic variant;Non-amnesic Alzheimer's disease with primary progressive aphasia, logopenic variant;Non-amnesic Alzheimer's disease, visuospatial variant;Non-amnesic Alzheimer's disease with posterior cortical atrophy, visuospatial variant;Non-amnesic Alzheimer's dementia, frontal lobe variant;Alzheimer's disease with psychosis;Alzheimer's disease with depression;Dementia due to cerebrovascular disease;Hematologic Vascular dementia hemorrhagic subtype;Vascular dementia ischemic subtype;Multi-infarct dementia;Single-infarct dementia of strategic locations;Dementia due to subcortical vascular encephalopathy;Dementia due to hypoxic encephalopathy;Dementia of genetic causes;Dementia due to central nervous system vasculitis;Dementia due to hypertensive encephalopathy;Dementia due to hypertensive intracerebral hemorrhage;Dementia due to cerebral amyloid angiopathy;Dementia due to Lewy body disease;Frontotemporal dementia;Frontotemporal dementia, behavioral variant;Frontotemporal dementia, language variant;Frontotemporal dementia, non-fluent or agrammatic modal variant;frontotemporal dementia, semantic variant;frontotemporal dementia, logopenic variant;frontotemporal dementia with motor neuron disease;frontotemporal dementia with familial inclusion body myopathy with Paget's disease of bone;frontotemporal dementia due to genetic mutations;frontotemporal dementia due to C9orf72 mutations;frontotemporal dementia due to MAPT mutations;frontotemporal dementia due to VCP mutations;frontotemporal dementia due to GRN mutations;frontotemporal dementia due to CHMP2B mutations;frontotemporal dementia due to FUS mutations;Frontotemporal dementia due to TARDBP mutations;Frontotemporal dementia due to other or new mutations;Dementia due to psychoactive substances including medicines;Dementia due to alcohol use;Dementia due to use of sedatives, hypnotics, or anxiolytics;Post-hallucinogen sensory disorder;Dementia due to use of volatile inhalants;Post-radiation dementia;Dementia due to carbon monoxide poisoning;Dementia due to drug poisoning;Dementia or Parkinsonism due to manganese toxicity;Dementia due to diseases classified elsewhere;Dementia due to certain specified central nervous system degenerative diseases;Dementia due to Parkinson's disease;Dementia due to Huntington's disease ;dementia due to corticobasal degeneration;dementia due to progressive supranuclear palsy;dementia due to neurofilament inclusion disease;dementia due to progressive subcortical gliosis;dementia due to multiple system atrophy;dementia due to spinocerebellar ataxia;dementia due to neurodegeneration with iron deposition in the brain;dementia due to leukodystrophy;dementia due to Guam parkinsonism-dementia complex;dementia due to certain specified infectious diseases;dementia due to human immunodeficiency virus;dementia due to neurosyphilis;dementia due to herpes encephalitis;dementia due to trypanosomiasis;dementia due to neurocysticercosis; Dementia due to Immunodeficiency;Dementia due to Whipple's disease;Dementia due to progressive multifocal leukoencephalopathy;Primary degenerative dementias of certain specified origin;Neurofibrillary tangle dementia;Familial multisystem tauopathy;Argyrophilic grain disease;Dementia due to certain specified central nervous system disorders;Dementia due to multiple sclerosis;Dementia due to prion disease;Dementia due to sporadic Creutzfeldt-Jakob disease;Dementia due to variant Creutzfeldt-Jakob disease;Dementia due to familial Creutzfeldt-Jakob disease;Dementia due to iatrogenic Creutzfeldt-Jakob disease;Dementia due to sporadic fatal insomnia;Fatal familial insomnia dementia due to;dementia due to Gerstmann-Straussler-Scheinker syndrome;dementia due to kuru;dementia due to acute demyelinating encephalomyelitis;dementia due to subacute sclerosing panencephalitis;dementia due to Hashimoto's encephalopathy;dementia due to paraneoplastic encephalitis;dementia due to autoimmune encephalitis;dementia due to primary central nervous system neoplasms;dementia due to metastatic brain tumors;dementia due to epilepsy;dementia due to normal pressure hydrocephalus;dementia due to metabolic disorders involving the brain;dementia due to head injury;dementia due to chronic subdural hematoma;dementia due to obstructive hydrocephalus;dementia due to exposure to heavy metals and other toxins;Dementia due to nutritional deficiencies;Dementia due to thiamine deficiency;Dementia due to vitamin B12 deficiency;Dementia due to folate deficiency;Dementia due to vitamin E deficiency;Dementia due to iron deficiency;Dementia due to other nutritional deficiencies;Dementia due to pellagra;Dementia due to metabolic disorders;Dementia due to hypercalcemia;Dementia due to acquired hypothyroidism;Dementia due to Wilson's disease;Dementia due to dialysis;Dementia due to liver failure;Dementia due to renal failure;Dementia due to chromosomal abnormalities;Dementia due to Down's syndrome;Dementia due to fragile X syndrome;Dementia due to rheumatic diseases Dementia due to polyarteritis nodosa; Dementia due to systemic lupus erythematosus; Dementia due to Behcet's disease; Dementia due to a specific specified cause; Behavioral or psychological disorders in dementia; Psychotic symptoms in dementia; Mood symptoms in dementia; Anxiety symptoms in dementia; Apathy in dementia; Agitation or aggression in dementia; Disinhibition in dementia; Wandering in dementia; Terminal dementia; Degenerative dementia; Presenile psychotic mental disorder; Delusional dementia; Presenile dementia not otherwise specified; Senile dementia; and Geriatric dementia. In some embodiments, the dementia is selected from the group consisting of mild cognitive impairment, Alzheimer's disease, mixed dementia, vascular dementia, dementia with Lewy bodies, frontotemporal dementia, presenile dementia, and senile dementia. In some embodiments, the dementia is mild cognitive impairment or Alzheimer's disease continuum with mild dementia. In some embodiments, the dementia is mild cognitive impairment, such as mild cognitive impairment of the Alzheimer's type. In some embodiments, the dementia is Alzheimer's disease, such as preclinical Alzheimer's disease, mild cognitive impairment of Alzheimer's type, early-onset familial Alzheimer's disease, or prodromal Alzheimer's disease. In some embodiments, the dementia is mild cognitive impairment of Alzheimer's type. In some embodiments, the dementia is mixed dementia. In some embodiments, the dementia is vascular dementia. In some embodiments, the dementia is dementia with Lewy bodies. In some embodiments, the dementia is frontotemporal dementia. In some embodiments, the dementia is presenile dementia. In some embodiments, the dementia is senile dementia.;

[0011] In some embodiments, the term "treatment" as used herein encompasses preventing, delaying, reducing the risk of developing, ameliorating, or curatively treating the referenced medical indication. Treatment may be symptomatic or disease-modifying treatment. In some embodiments, the term treatment as used herein refers to preventing the referenced medical indication. In some embodiments, the term treatment as used herein refers to delaying (e.g., delaying the onset of) the referenced medical indication. In some embodiments, the term treatment as used herein refers to reducing the risk of developing the referenced medical indication. In some embodiments, the term treatment as used herein refers to improving the referenced medical indication. In some embodiments, the term treatment as used herein refers to curatively treating the referenced medical indication.

[0012] Subpopulation The subject to which a GLP-1 receptor agonist is administered in accordance with the present invention may be a human, such as an adult human (also referred to as an adult). In some embodiments, the subject has metabolic syndrome. As used herein, the term "metabolic syndrome" refers to one or more indications selected from the group consisting of prediabetes, diabetes, cardiovascular disease, obesity, and hypertension. In some embodiments, "metabolic syndrome" refers to at least two indications selected from the group consisting of prediabetes, diabetes, cardiovascular disease, obesity, and hypertension. In some embodiments, "metabolic syndrome" refers to at least three indications selected from the group consisting of prediabetes, diabetes, cardiovascular disease, obesity, and hypertension. In some embodiments, the subject has prediabetes. In some embodiments, the subject has diabetes. In some embodiments, the diabetes is type 2 diabetes. In some embodiments, the subject has obesity. In some embodiments, the subject has cardiovascular disease. In some embodiments, the subject has obesity. In some embodiments, the obesity is at least 27 kg / m 2 or at least 30 kg / m 2 etc., at least 25 kg / m2 In some embodiments, the subject has hypertension. In some embodiments, the cardiovascular disease comprises one or more of coronary artery disease (such as stenosis and myocardial infarction), stroke, heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, heart rhythm abnormalities, congenital heart disease, valvular heart disease, carditis, aortic aneurysm, peripheral arterial disease, thromboembolic disease, and venous thrombosis. In some embodiments, the subject has previously been administered insulin.

[0013] GLP-1 receptor agonists The term "GLP-1 receptor agonist" as used herein refers to a compound that fully or partially activates the human GLP-1 receptor. In some embodiments, the GLP-1 receptor agonist for use in the present invention is an acylated GLP-1 receptor agonist. When used in relation to a GLP-1 receptor agonist, the term "acylated" refers to a GLP-1 receptor agonist that is covalently attached with at least one substituent that includes a lipophilic moiety, such as a fatty acid or a fatty diacid. In some embodiments, the substituent includes a fatty acid or a fatty diacid. In some embodiments, the term GLP-1 receptor agonist, as well as the specific GLP-1 receptor agonists described herein, also encompass their salt forms.

[0014] It follows that a GLP-1 receptor agonist should exhibit "GLP-1 activity", which refers to the ability of a compound, i.e., a GLP-1 receptor agonist, to bind to a GLP-1 receptor and initiate a signal transduction pathway resulting in an insulinotropic effect or other physiological effect as known in the art. In some embodiments, a "GLP-1 receptor agonist" has an affinity constant (K) of, e.g., less than 1 μM, e.g., less than 100 nM, as measured by methods known in the art (see, e.g., WO 98 / 08871). D ) and binds to the GLP-1 receptor or has a potency (EC 50) and exhibits insulinotropic activity, where insulinotropic activity can be measured by in vivo or in vitro assays known to those skilled in the art. For example, GLP-1 receptor agonists can be administered to animals with increased blood glucose (e.g., obtained using an intravenous glucose tolerance test (IVGTT)). Those skilled in the art will be able to determine the appropriate glucose dose and the appropriate blood sampling method (e.g., depending on the animal species for IVGTT) and measure plasma insulin concentration over time. Suitable assays are described, for example, in WO2015 / 155151.

[0015] 50% effective concentration (EC 50 The term EC is commonly used to refer to the concentration that elicits a response halfway between the baseline and maximum, with reference to a dose-response curve. 50 is used as a measure of a compound's potency and represents the concentration at which 50% of its maximal effect is observed. Due to the albumin binding effect of GLP-1 receptor agonists, including the substituents described herein, it is important to note whether the assay includes human serum albumin.

[0016] The in vitro potency of GLP-1 receptor agonists may be determined without human serum albumin (HSA) as described in WO2015 / 155151, Example 29, and may be determined using EC 50 can be determined. 50 The lower the value, the better the potency. In some embodiments, the determined potency (EC50) (without HSA) is between 5 and 1000 pM, such as between 10 and 750 pM, between 10 and 500 pM, or between 10 and 200 pM. In some embodiments, the EC50 (without HSA) is up to 500 pM, such as up to 300 pM, such as up to 200 pM. In some embodiments, the EC50 (without HSA) is equivalent to human GLP-1 (7-37). In some embodiments, the EC50 (without HSA) is up to 50 pM. In further such embodiments, the EC50 is up to 40 pM, such as up to 30 pM, such as up to 20 pM, such as up to 10 pM. In some embodiments, the EC50 is about 10 pM.

[0017] Similarly, or alternatively, binding of GLP-1 receptor agonists to albumin may be measured using the in vitro potency assay of Example 29 of WO2015 / 155151, which includes HSA. In vitro potency in the presence of serum albumin, EC 50 An increase in value reflects affinity with serum albumin. In some embodiments, the determined potency (EC50) (with 1% HSA) is 5-1000 pM, such as 100-750 pM, 200-500 pM, or 100-400 pM. In some embodiments, the EC50 (with 1% HSA) is up to 750 pM, such as up to 500 pM, such as up to 400 pM, such as up to 300, or such as up to 250 pM.

[0018] If necessary, the fold change with respect to a known GLP-1 receptor agonist may be calculated as EC50(test compound) / EC50(known compound), and the potency is considered equivalent if the ratio is 0.5-1.5 or 0.8-1.2, etc. In some embodiments, the potency, EC50 (without HSA) is equivalent to that of liraglutide. In some embodiments, the potency, EC50 (without HSA) is equivalent to that of semaglutide. In some embodiments, the potency, EC50 (with 1% HSA) is equivalent to that of liraglutide. In some embodiments, the potency, EC50 (with 1% HSA) is equivalent to that of semaglutide.

[0019] In some embodiments, the GLP-1 receptor agonist comprises one or more substitutions, deletions, additions, and / or modifications. In some embodiments, the modifications are covalently bonded substituents. In some embodiments, the GLP-1 receptor agonist comprises a peptide that is human GLP-1 (GLP-1(7-37)) or a variant thereof. Human GLP-1, also referred to herein as "GLP-1(7-37)", has the sequence HAEGTFTSDV SSYLEGQAAKEFIAWLVKGRG (SEQ ID NO: 1). In some embodiments, the term "variant" refers to a compound that comprises one or more amino acid substitutions, deletions, additions, and / or modifications. Such additions or deletions of amino acid residues may occur at the N-terminus of the peptide and / or the C-terminus of the peptide. In some embodiments, a simple nomenclature is used to describe the GLP-1 receptor agonist, for example, [Aib8]GLP-1(7-37) denotes a GLP-1(7-37) receptor agonist, where the naturally occurring Ala at position 8 is replaced with Aib. In some embodiments, the GLP-1 receptor agonist comprises up to 12 amino acids modified by substitution, deletion, insertion, and / or modification, for example, compared to GLP-1(7-37) (SEQ ID NO: 1). In some embodiments, the GLP-1 receptor agonist comprises up to 10 amino acids modified by substitution, deletion, insertion, and / or modification, for example, compared to GLP-1(7-37) (SEQ ID NO: 1). In some embodiments, the GLP-1 receptor agonist comprises up to 9 amino acids modified by substitution, deletion, insertion, and / or modification, for example, compared to GLP-1(7-37) (SEQ ID NO: 1). In some embodiments, the GLP-1 receptor agonist comprises up to 8 amino acids modified by substitution, deletion, insertion, and / or modification, for example, compared to GLP-1(7-37) (SEQ ID NO: 1). In some embodiments, the GLP-1 receptor agonist contains up to 7 amino acids that have been altered by substitution, deletion, insertion, and / or modification, for example, compared to GLP-1(7-37) (SEQ ID NO:1).In some embodiments, the GLP-1 receptor agonist comprises up to 6 amino acids modified by substitution, deletion, insertion, and / or modification, for example, compared to GLP-1(7-37) (SEQ ID NO: 1). In some embodiments, the GLP-1 receptor agonist comprises up to 5 amino acids modified by substitution, deletion, insertion, and / or modification, for example, compared to GLP-1(7-37) (SEQ ID NO: 1). In some embodiments, the GLP-1 receptor agonist comprises up to 4 amino acids modified by substitution, deletion, insertion, and / or modification, for example, compared to GLP-1(7-37) (SEQ ID NO: 1). In some embodiments, the GLP-1 receptor agonist comprises up to 3 amino acids modified by substitution, deletion, insertion, and / or modification, for example, compared to GLP-1(7-37) (SEQ ID NO: 1). In some embodiments, the GLP-1 receptor agonist contains up to two amino acids that are altered by substitution, deletion, insertion, and / or modification, for example, compared to GLP-1(7-37) (SEQ ID NO: 1).Unless otherwise specified, GLP-1 contains only L-amino acids.

[0020] In some embodiments, the GLP-1 receptor agonist shows at least 60%, 65%, 70%, 80%, or 90% sequence identity to GLP-1(7-37) over the entire length of GLP-1(7-37). As an example of a method for determining the sequence identity between two compounds, two peptides [Aib8]GLP-1(7-37) and GLP-1(7-37) are aligned. The sequence identity of [Aib8]GLP-1(7-37) to GLP-1(7-37) is obtained by subtracting the number of aligned identical residues from the number of different residues and dividing by the total number of residues in GLP-1(7-37). Thus, in this example, the sequence identity is (31-1) / 31.

[0021] In some embodiments, the C-terminus of the GLP-1 receptor agonist is an amide. In some embodiments, the GLP-1 receptor agonist is GLP-1(7-37) or GLP-1(7-36)amide.

[0022] In order to extend the effect of GLP-1 receptor agonist, it is preferred that GLP-1 receptor agonist has extended half-life.Half-life can be determined by methods known in the art in suitable models such as male Sprague Dawley rats or minipigs, as described in WO2012 / 140117.Rat half-life can be determined as in Example 39 therein, and minipigs half-life can be determined as in Example 37.

[0023] In some embodiments, the GLP-1 receptor agonist according to the invention has a half-life in rats of more than 2 hours. In some embodiments, the GLP-1 receptor agonist according to the invention has a half-life in rats of more than 4 hours, such as more than 6 hours, such as more than 8 hours, such as more than 10 hours, such as more than 12 hours, or such as more than 15 hours.

[0024] In some embodiments, the GLP-1 receptor agonist according to the invention has a half-life in minipigs of more than 24 hours. In some embodiments, the GLP-1 receptor agonist according to the invention has a half-life in minipigs of more than 30 hours, such as more than 36 hours, such as more than 42 hours, such as more than 48 hours, such as more than 54 hours, or such as more than 60 hours.

[0025] In some embodiments, the GLP-1 receptor agonist has a molecular weight of up to 12000 Da, such as up to 7500 Da, for example up to 5000 Da. In some embodiments, the GLP-1 receptor agonist has a molar mass of up to 10000 g / mol, such as up to 8000 g / mol, for example up to 6000 g / mol.

[0026] In some embodiments, the GLP-1 receptor agonist comprises one or two substituents covalently attached to the peptide, the substituents comprising a lipophilic moiety. In some embodiments, the substituent comprises a fatty acid or a fatty diacid. In some embodiments, the substituent comprises a C16, C18, or C20 fatty acid. In some embodiments, the substituent comprises a C16, C18, or C20 fatty diacid.

[0027] In some embodiments, the substituent is a group represented by formula (X): [ka] wherein n is at least 13, e.g., n is 13, 14, 15, 16, 17, 18, or 19. In some embodiments, the substituent comprises formula (X), wherein n is in the range of 13 to 19, e.g., in the range of 13 to 17. In some embodiments, the substituent comprises formula (X), wherein n is 13, 15, or 17. In some embodiments, the substituent comprises formula (X), wherein n is 13. In some embodiments, the substituent comprises formula (X), wherein n is 15. In some embodiments, the substituent comprises formula (X), wherein n is 17. In some embodiments, the substituent comprises formula (XIa), HOOC-(C 6 H 4 )-O-(CH 2 ) m -CO-*(XIa), where m is an integer ranging from 6 to 14. In some embodiments, the substituent is of formula (XIb): [ka] wherein the carboxy group is (C 6 H 4 ) group at position 2, 3, or 4, where m is an integer ranging from 8 to 11. In some embodiments, the substituent comprises Formula (XIa) or Formula (XIb), where m is in the range of 6 to 14, such as in the range of 8 to 11. In some embodiments, the substituent comprises Formula (XIa) or Formula (XIb), where m is 8, 10, or 12. In some embodiments, the substituent comprises Formula (XIa) or Formula (XIb), where m is 9. In some embodiments, the substituent comprises Formula (XIa) or Formula (XIb), where m is 11.

[0028] In some embodiments, the substituent comprises a linker (also called a spacer) located in the substituent proximal to the attachment point between the substituent and the peptide in the GLP-1 receptor agonist. In some embodiments, the substituent comprises a linker located in the substituent proximal to the attachment point between the substituent and the peptide in the GLP-1 receptor agonist. In some embodiments, the substituent comprises one or more 8-amino-3,6-dioxaoctanoic acid (OEG), such as two OEGs. One or more OEGs can be a linker.

[0029] In some embodiments, the substituent is [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl]. In some embodiments, the substituent is [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl]. In some embodiments, the substituent is [2-(2-{2-[2-(2-{2-[(S)-4-carboxy-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl]. In some embodiments, the substituent is {2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]-acetyl}. In some embodiments, the substituent is {2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]-acetyl}. In some embodiments, the substituent is [2-[2-[2-[[2-[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl].

[0030] In some embodiments, the substituent comprises a serum albumin, such as human serum albumin, In some embodiments, the substituent comprises an immunoglobulin domain or fragment, such as an Fc domain or a modified IgG4 Fc domain.

[0031] In some embodiments, the GLP-1 receptor agonist is selected from the group consisting of liraglutide, semaglutide, compound A, and compound B. In some embodiments, the GLP-1 receptor agonist is liraglutide. Liraglutide is the GLP-1 receptor agonist Arg34,Lys26-(N-epsilon-(gamma-L-glutamyl(N-alpha-hexadecanoyl)))-GLP-1(7-37). Liraglutide can be prepared as described in Example 37 of WO98 / 08871. In some embodiments, the GLP-1 receptor agonist is semaglutide. Semaglutide is the GLP-1 receptor agonist N-epsilon 26-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37). Semaglutide may be prepared as described in Example 4 of WO2006 / 097537. In some embodiments, the GLP-1 receptor agonist is compound A, which is shown in Example 2 of WO2011 / 080103 and is N ε26 {2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}-ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]acetyl},N ε37 -{2-[2-(2-{2-[2-(2-{(S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butyrylamino}ethoxy)ethoxy]acetylamino}ethoxy)ethoxy]-acetyl}-[Aib 8 ,Arg 34 ,Lys 37 In some embodiments, the GLP-1 receptor agonist is Compound B, which is shown in Example 31 of WO2012 / 140117 and is a diacylated [Aib8,Arg34,Lys37]GLP-1(7-37) peptide. ε27-[2-[2-[2-[[2-[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]-acetyl], N ε36 The diacylated [Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly is named -[2-[2-[[2-[2-[2-[2-[[(4S)-4-carboxy-4-[10-(4-carboxyphenoxy)decanoylamino]-butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-[Aib8,Glu22,Arg26,Lys27,Glu30,Arg34,Lys36]-GLP-1-(7-37)-peptidyl-Glu-Gly. In some embodiments, the GLP-1 receptor agonist is dulaglutide or albiglutide.

[0032] In some embodiments, the GLP-1 receptor agonist is in the form of a pharma- ceutically acceptable salt, amide, or ester thereof. In some embodiments, the GLP-1 receptor agonist includes one or more pharma- ceutically acceptable counterions.

[0033] Pharmaceutical Compositions The GLP-1 receptor agonist may be administered in the form of a pharmaceutical composition. The pharmaceutical composition may be in liquid or solid form.

[0034] Parenteral Administration The pharmaceutical composition may contain a concentration of the GLP-1 receptor agonist from 0.1 mg / ml to 100 mg / ml. In some embodiments, the pharmaceutical composition contains 0.01 to 50 mg / ml, or 0.01 to 20 mg / ml, or 0.01 to 10 mg / ml of the GLP-1 receptor agonist. In some embodiments, the pharmaceutical composition contains 0.1 to 20 mg / ml of the GLP-1 receptor agonist.

[0035] The pharmaceutical compositions described herein may further comprise one or more pharma- ceutically acceptable excipients, for example, selected from the group consisting of a buffer system, a preservative, a tonicity agent, a chelating agent, a stabilizer, and a surfactant. In some embodiments, the pharmaceutical composition comprises one or more pharma- ceutically acceptable excipients, such as one or more selected from the group consisting of a buffer, an isotonicity agent, and a preservative. Formulations of pharma- ceutically active ingredients with various excipients are known in the art, see, for example, Remington: The Science and Practice of Pharmacy (e.g., 19th Edition (1995), and any subsequent editions). The term "excipient" broadly refers to any ingredient other than the active therapeutic ingredient, for example, a GLP-1 receptor agonist. An excipient may be an inactive, non-active, and / or non-pharma-ceutically active substance.

[0036] In some embodiments, the pharmaceutical composition has a pH in the range of 7.0 to 10.0, such as 7.0 to 9.5 or 7.2 to 9.5. In some embodiments, the pharmaceutical composition has a pH in the range of 7.0 to 8.5, such as 7.0 to 7.8 or 7.8 to 8.2. In some embodiments, the pharmaceutical composition has a pH of 7.4. In some embodiments, the pharmaceutical composition has a pH of 8.15. In some embodiments, the pharmaceutical composition includes a phosphate buffer, such as a sodium phosphate buffer, e.g., disodium phosphate. In some embodiments, the pharmaceutical composition includes an isotonicity agent, such as propylene glycol. In some embodiments, the pharmaceutical composition includes a preservative, such as phenol.

[0037] The pharmaceutical composition may be in the form of a solution or suspension. In some embodiments, the pharmaceutical composition is an aqueous composition, such as an aqueous solution or an aqueous suspension. The term "aqueous composition" is defined as a composition that contains at least 50% w / w water. Similarly, the term "aqueous solution" is defined as a solution that contains at least 50% w / w water, and the term "aqueous suspension" is defined as a suspension that contains at least 50% w / w water. An aqueous composition may contain at least 50% w / w water, or at least 60%, 70%, 80%, or even at least 90% w / w water.

[0038] In some embodiments, the GLP-1 receptor agonist is administered in the form of a pharmaceutical composition comprising about 0.1-20 mg / ml of GLP-1 receptor agonist, about 2-15 mM phosphate buffer, about 2-25 mg / ml of propylene glycol, and has a pH in the range of 7.0-9.0. In some embodiments, the GLP-1 receptor agonist is administered in the form of a pharmaceutical composition comprising about 0.1-20 mg / ml of GLP-1 receptor agonist, about 2-15 mM phosphate buffer, about 2-25 mg / ml of propylene glycol, about 1-18 mg / ml of phenol, and has a pH in the range of 7.0-9.0. In some embodiments, the GLP-1 receptor agonist is administered in the form of a pharmaceutical composition comprising about 1.34 mg / ml of GLP-1 receptor agonist (e.g., semaglutide), about 1.42 mg / ml of disodium phosphate dihydrate, about 14.0 mg / ml of propylene glycol, about 5.5 mg / ml of phenol, and has a pH of about 7.4. In some embodiments, the GLP-1 receptor agonist (e.g., semaglutide) is administered in the form of a pharmaceutical composition comprising about 1.34 mg / ml of GLP-1 receptor agonist, 1.42 mg / ml of disodium phosphate dihydrate, 14.0 mg / ml of propylene glycol, 5.5 mg / ml of phenol, and has a pH of 7.4. In some embodiments, the GLP-1 receptor agonist (e.g., liraglutide) is administered in the form of a pharmaceutical composition comprising a GLP-1 receptor agonist (e.g., 3-8 mg / ml), disodium phosphate dihydrate, propylene glycol, phenol, and has a pH of about 8.0-8.3. In some embodiments, the GLP-1 receptor agonist (e.g., liraglutide) is administered in the form of a pharmaceutical composition comprising a GLP-1 receptor agonist (e.g., about 6.0 mg / ml), disodium phosphate dihydrate, propylene glycol, phenol, and has a pH of about 8.15.

[0039] Oral route The solid composition may be a solid composition suitable for administration by oral route as further described herein. In some embodiments, the solid composition comprises at least one pharma- ceutically acceptable excipient. The term "excipient" as used herein refers broadly to any ingredient other than the active therapeutic or active pharmaceutical ingredient (API). An excipient may be an inert, non-active, and / or therapeutically or pharma- ceutically inactive substance. Excipients may serve a variety of purposes, for example, as carriers, vehicles, fillers, binders, lubricants, glidants, disintegrants, flow control agents, crystallization inhibitors, solubilizers, stabilizers, colorants, flavoring agents, surfactants, emulsifiers, or combinations thereof, and / or to improve administration and / or absorption of the therapeutic or active pharmaceutical ingredient. The amount of each excipient used may vary within ranges that are conventional in the art. Techniques and excipients that can be used to formulate oral dosage forms are described in Handbook of Pharmaceutical Excipients, 8th edition, Sheskey et al., Eds., American Pharmaceuticals Association and the Pharmaceutical Press, publications department of the Royal Pharmaceutical Society of Great Britain (2017), and Remington: the Science and Practice of Pharmacy, 22nd edition, Remington and Allen, Eds., Pharmaceutical Press (2013).In some embodiments, the excipients include binders, such as polyvinylpyrrolidone (povidone); fillers, such as cellulose powder, microcrystalline cellulose, cellulose derivatives, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxy-propylmethylcellulose, dibasic calcium phosphate, corn starch, pregelatinized starch, and the like; lubricants and / or glidants, such as stearic acid, magnesium stearate, sodium stearyl fumarate, glycerol tribehenate, and the like; flow control agents, such as colloidal silica, tallow, and the like; and the like; crystallization inhibitors, such as povidone; solubilizers, such as pluronic, povidone, and the like; colorants, dyes and pigments, including, for example, red or yellow iron oxide, titanium dioxide, talc, and the like; pH adjusters, such as citric acid, tartaric acid, fumaric acid, sodium citrate, dibasic calcium phosphate, dibasic sodium phosphate, and the like; surfactants and emulsifiers, such as pluronic, polyethylene glycol, sodium carboxymethylcellulose, polyethoxylated and hydrogenated castor oil, and the like; and mixtures of two or more of these excipients and / or adjuvants.

[0040] The solid composition may include binders such as povidone; starch; cellulose and its derivatives, such as microcrystalline cellulose, such as Avicel PH from FMC (Philadelphia, PA), hydroxypropyl cellulose, hydroxyethyl cellulose, and hydroxypropyl methylcellulose METHOCEL from Dow Chemical Corp. (Midland, MI); sucrose; dextrose; corn syrup; polysaccharides; and gelatin. The binder may be selected from the group consisting of dry binders and / or wet granulation binders. Suitable dry binders are, for example, cellulose powder and microcrystalline cellulose, such as Avicel PH 102 and Avicel PH 200. In some embodiments, the solid composition includes Avicel, such as Avicel PH 102. Suitable binders for wet or dry granulation are corn starch, polyvinylpyrrolidone (povidone), vinylpyrrolidone-vinyl acetate copolymer (copovidone), and cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropylmethylcellulose. In some embodiments, the solid composition comprises povidone.

[0041] In some embodiments, the solid composition comprises a filler that may be selected from lactose, mannitol, erythritol, sucrose, sorbitol, calcium phosphate, e.g., calcium hydrogen phosphate, microcrystalline cellulose, powdered cellulose, powdered sugar, compressible sugar, dextrates, dextrin, and dextrose. In some embodiments, the solid composition comprises microcrystalline cellulose, such as Avicel PH 102 or Avicel PH 200.

[0042] In some embodiments, the solid composition comprises a lubricant and / or glidant. In some embodiments, the composition comprises a lubricant and / or glidant, such as talc, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, glyceryl debehenate, behenoyl polyoxyl-8 glyceride, polyethylene oxide polymer, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, hydrogenated vegetable oil, silicon dioxide, and / or polyethylene glycol. In some embodiments, the solid composition comprises magnesium stearate or glyceryl debehenate (such as the product Compritol® 888ATO).

[0043] In some embodiments, the solid composition comprises a disintegrant, such as sodium starch glycolate, polacrilin potassium, sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethylcellulose, or dry cornstarch. The solid composition may comprise one or more surfactants, such as a surfactant, at least one surfactant, or two different surfactants. The term "surfactant" refers to any molecule or ion that consists of a water-soluble (hydrophilic) portion and a fat-soluble (lipophilic) portion. The surfactant may be selected from the group consisting of, for example, anionic surfactants, cationic surfactants, nonionic surfactants, and / or zwitterionic surfactants.

[0044] The solid composition may further comprise a delivery agent or an absorption enhancer, which in the present invention is an excipient that can increase the oral exposure of GLP-1 receptor agonist.The delivery agent may be a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (also referred to herein as salt of NAC), including an anion N-(8-(2-hydroxybenzoyl)amino)caprylate.The structural formula of N-(8-(2-hydroxybenzoyl)amino)caprylate is shown in formula (I). [ka]

[0045] In some embodiments, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid includes one monovalent cation, two monovalent cations, or one divalent cation. In some embodiments, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is selected from the group consisting of sodium, potassium, and calcium salts of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. In some embodiments, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is selected from the group consisting of sodium, potassium, and / or ammonium salts. In some embodiments, the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is the sodium or potassium salt. Salts of N-(8-(2-hydroxybenzoyl)amino)caprylate can be prepared using methods described, for example, in WO96 / 030036, WO00 / 046182, WO01 / 092206, or WO2008 / 028859. Salts of N-(8-(2-hydroxybenzoyl)amino)caprylic acid can be crystalline and / or amorphous. In some embodiments, the delivery agent comprises an anhydrate, monohydrate, dihydrate, trihydrate, solvate, or one-third hydrate of salts of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, as well as combinations thereof. In some embodiments, the delivery agent is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, as described in WO2007 / 121318. In some embodiments, the delivery agent is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (referred to herein as "SNAC"), also known as sodium 8-(salicyloylamino)octanoate.

[0046] In some embodiments, compositions for use in the present invention are in the form of a solid composition, such as a tablet, for oral administration.

[0047] In some embodiments, the solid composition comprises an amount of GLP-1 receptor agonist in the range of 0.1 to 50 mg, such as 0.5 to 40 mg or 1 to 30 mg. In some embodiments, the solid composition comprises an amount of GLP-1 receptor agonist in the range of 2 to 20 mg, such as 3 to 18 mg or 5 to 15 mg. In some embodiments, the solid composition comprises an amount of GLP-1 receptor agonist in the range of about 3 mg, such as about 7 mg or about 14 mg.

[0048] In some embodiments, at least 30% (w / w) of the solid composition (e.g., tablet) is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. In some embodiments, at least 50% (w / w) of the solid composition (e.g., tablet) is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. In some embodiments, the amount of salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid per dose unit of the composition is in the range of 0.20 to .5 mmol, 0.25 to 1.0 mmol, 0.30 to 0.75 mmol, or 0.45 to 0.65 mmol, etc. In some embodiments, the amount of SNAC in the composition is in the range of 75 to 600 mg. In some embodiments, the amount of SNAC in the composition is in the range of 75 to 400 mg, such as about 100 to about 300 mg, such as 80 to 350 mg, per dose unit.

[0049] In some embodiments, the solid composition includes a lubricant, such as magnesium stearate. In some embodiments, a unit dose of the solid composition includes 0.1-50 mg of a GLP-1 receptor agonist, 25-600 mg of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), such as the sodium salt of NAC (SNAC), and 0-25 mg of a lubricant.

[0050] Dosing regimen The GLP-1 receptor agonist may be administered in a therapeutically effective amount, such as an amount therapeutically effective for treating type 2 diabetes. The therapeutically effective amount of the GLP-1 receptor agonist may be assessed by a physician. The dose of the GLP-1 receptor agonist may be in the range of 0.01 to 50 mg, such as 1 to 30 mg or 3 to 20 mg. In some embodiments, the GLP-1 receptor agonist is administered at any time of day.

[0051] GLP-1 receptor agonists such as semaglutide may be administered once a week, or more frequently, such as once daily.

[0052] In some embodiments, the GLP-1 receptor agonist is administered in an amount in the range of 0.05-30 mg per week, such as 0.5 or 1.0 mg per week, optionally by weekly administration. In some embodiments, the GLP-1 receptor agonist is administered in an amount of at least 0.1 mg per week, such as at least 0.5 mg per week or at least 1 mg per week, optionally by weekly administration. In some embodiments, the GLP-1 receptor agonist is administered in an amount of no more than 25 mg per week, such as no more than 20 mg per week or no more than 15 mg per week, optionally by weekly administration. In some embodiments, the GLP-1 receptor agonist is administered in an amount of no more than 10 mg per week, such as no more than 6 mg per week or no more than 3 mg per week, optionally by weekly administration. In some embodiments, the GLP-1 receptor agonist is administered in an amount of 0.5 or 1.0 mg per week.

[0053] In some embodiments, the methods of the present invention reduce the risk of death.

[0054] In some embodiments, administration of the GLP-1 receptor agonist is a chronic treatment, where semaglutide is administered for at least 12 months, such as at least 16 months or at least 18 months.

[0055] Parenteral Administration The GLP-1 receptor agonist may be administered parenterally, for example, via subcutaneous injection. The GLP-1 receptor agonist may be administered using a pen syringe, such as a 3 ml disposable pen syringe.

[0056] In some embodiments, the dose of the GLP-1 receptor agonist is in the range of 0.1 to 5.0 mg, such as in the range of 0.1 to 3.0 mg. In some embodiments, the daily dose of the GLP-1 receptor agonist is selected from the group consisting of 0.5 and 1.0 mg.

[0057] Oral route The GLP-1 receptor agonist may be orally administered, for example, in the form of a tablet, a coated tablet, a sachet, or a capsule, such as a hard or soft gelatin capsule, all such compositions being considered solid oral dosage forms. Oral administration may be once a day. In some embodiments, the dose of the GLP-1 receptor agonist is in the range of 1 to 30 mg, such as 2 to 20 mg or 3 to 15 mg. In some embodiments, the dose of the GLP-1 receptor agonist is 3, 7, or 14 mg. The composition may be in the form of a dosage unit, such as a tablet. In some embodiments, the weight of the unit dose is in the range of 50 mg to 1000 mg, such as in the range of 50 to 750 mg, or about 100 to 500 mg. In some embodiments, the weight of the unit dose is in the range of 75 to 350 mg, such as in the range of 50 to 300 mg or 100 to 400 mg. Tablets for oral administration may contain 30% (w / w) of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, such as the sodium salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (SNAC). In some embodiments, the composition may be granulated before being compressed into a tablet. The composition may contain a granular portion and / or an extragranular portion, where the granular portion is granulated and the extragranular portion is added after granulation. The GLP-1 receptor agonist may be contained in the granular portion or the extragranular portion. In some embodiments, the extragranular portion contains the GLP-1 receptor agonist. In one embodiment, the extragranular portion may further contain a lubricant and / or glidant. In one embodiment, the granular portion may further contain a lubricant and / or glidant. In one embodiment, the granular portion and the extragranular portion may contain a lubricant and / or glidant.

[0058] In some embodiments, the GLP-1 receptor agonist is the only pharmacologic active ingredient administered according to the present invention. In some embodiments, the GLP-1 receptor agonist is combined with one or more further pharmacologic active ingredients in the present invention. In some embodiments, the GLP-1 receptor agonist is combined with one or more further pharmacologic active ingredients selected from the group consisting of rivastigmine, menantine (such as menantine hydrochloride), donepezil, and galantamine. In some embodiments, the GLP-1 receptor agonist is combined with rivastigmine. In some embodiments, the GLP-1 receptor agonist is combined with menantine, such as menantine hydrochloride. In some embodiments, the GLP-1 receptor agonist is combined with donepezil. In some embodiments, the GLP-1 receptor agonist is combined with galantamine.

[0059] In some embodiments, the term "chronic treatment" as used herein with respect to a GLP-1 receptor agonist refers to administration in an amount and frequency to produce a therapeutic effect. In some embodiments, the term "chronic treatment" as used herein with respect to a GLP-1 receptor agonist refers to weekly administration of 0.1 to 3.0 mg of a GLP-1 receptor agonist (e.g., semaglutide), such as 0.5 or 1.0 mg. In some embodiments, the term "chronic treatment" as used herein with respect to a GLP-1 receptor agonist refers to daily administration of 0.05 to 0.3 mg of a GLP-1 receptor agonist (e.g., semaglutide), such as 0.05, 0.1, 0.2, or 0.3 mg. In some embodiments, the term "chronic treatment" as used herein with respect to a GLP-1 receptor agonist refers to daily administration of 0.1 to 6 mg of a GLP-1 receptor agonist (e.g., liraglutide), such as 0.5 to 4 mg. The term "chronic treatment" as used herein refers to administration of a drug according to a prescribed dosing regimen (e.g., once weekly administration) for an extended period of time (e.g., at least 2 years or at least 5 years), in which up to 10%, such as up to 5%, of the doses may be missed, provided that no more than 10 consecutive doses are missed.

[0060] Unless otherwise stated, a range includes its endpoints. In some embodiments, the term "a" means "one or more." In some embodiments, unless otherwise indicated herein, terms provided in the singular also include plural contexts. As used herein, the term "about" means ±10% of the referenced value, inclusive of that value.

[0061] Non-Limiting Embodiments of the Invention Non-limiting embodiments of the present invention include the following. 1. A method for the treatment of dementia, the method comprising administering a GLP-1 receptor agonist to a subject in need thereof, wherein the subject has metabolic syndrome. 2. A method for the treatment of dementia, the method comprising administering semaglutide to a subject in need thereof. 3. A method for reducing the risk of developing dementia, the method comprising administering a GLP-1 receptor agonist to a human subject in need thereof, the subject having one or more indications selected from the group consisting of prediabetes, diabetes, cardiovascular disease, obesity, and hypertension. 4. A method for reducing the risk of developing dementia, the method comprising administering a GLP-1 receptor agonist to a subject in need thereof, wherein the subject has metabolic syndrome. 5. A method for reducing the risk of developing dementia, the method comprising administering a GLP-1 receptor agonist to a subject in need thereof, the subject having one or more indications selected from the group consisting of prediabetes, diabetes, cardiovascular disease, obesity, and hypertension. 6. A method for reducing the risk of developing dementia, the method comprising administering semaglutide to a subject in need thereof. 7. The method of any one of embodiments 1-6, wherein the treatment reduces the risk of developing dementia. 8. The method of any one of embodiments 1-7, wherein said metabolic syndrome is one or more indications selected from the group consisting of prediabetes, diabetes, cardiovascular disease, obesity, and hypertension. 9. The method of any one of embodiments 1-8, wherein the subject has prediabetes. 10. The method of any one of embodiments 1-9, wherein the subject has diabetes. 11. The method of any one of embodiments 1-10, wherein the subject has cardiovascular disease. 12. The method of any one of embodiments 1-11, wherein the subject has obesity. 13. The method of any one of embodiments 1-12, wherein the subject has hypertension. 14. The method of any one of embodiments 1-13, wherein the GLP-1 receptor agonist comprises GLP-1(7-37) (SEQ ID NO:1), optionally containing one or more substitutions, deletions, additions, and / or modifications. 15. The method of any one of embodiments 1 to 14, wherein the GLP-1 receptor agonist comprises up to 12 amino acids that have been altered, for example by substitution, deletion, insertion, and / or modification, compared to GLP-1(7-37) (SEQ ID NO:1). 16. The method of any one of embodiments 1 to 15, wherein the GLP-1 receptor agonist comprises up to 10 amino acids that have been altered, for example by substitution, deletion, insertion, and / or modification, compared to GLP-1(7-37) (SEQ ID NO:1). 17. The method of any one of embodiments 1 to 16, wherein the GLP-1 receptor agonist comprises up to 8 amino acids that have been altered, for example by substitution, deletion, insertion, and / or modification, compared to GLP-1(7-37) (SEQ ID NO:1). 18. The method of any one of embodiments 1 to 17, wherein the GLP-1 receptor agonist comprises up to 6 amino acids that have been altered, for example by substitution, deletion, insertion, and / or modification, compared to GLP-1(7-37) (SEQ ID NO:1). 19. The method of any one of embodiments 1-18, wherein the GLP-1 receptor agonist comprises one or more substituents. 20. The method of any one of the preceding embodiments, wherein the substituent comprises a linker, such as one or more OEGs. 21. The method of any one of embodiments 1-20, wherein the linker is located in the substituent proximal to the point of attachment between the substituent and the peptide in the GLP-1 receptor agonist. 22. The method of any one of embodiments 1-21, wherein the GLP-1 receptor agonist has an EC50 (without HSA) of up to 500 pM. 23. The method of any one of embodiments 1-22, wherein the GLP-1 receptor agonist is 12 kDa or less. 24. The method of any one of embodiments 1-23, wherein the GLP-1 receptor agonist is selected from the group consisting of liraglutide, semaglutide, and compound A and compound B. 25. The method of any one of embodiments 1-24, wherein the GLP-1 receptor agonist is liraglutide. 26. The method of any one of embodiments 1-25, wherein the GLP-1 receptor agonist is semaglutide. 27. The method of any one of embodiments 1-26, wherein the GLP-1 receptor agonist is compound A. 28. The method of any one of embodiments 1-27, wherein the GLP-1 receptor agonist is compound B. 29. The method of any one of embodiments 1-28, wherein the GLP-1 receptor agonist is dulaglutide. 30. The method of any one of embodiments 1-29, wherein the GLP-1 receptor agonist is albiglutide. 31. The method of any one of embodiments 1-30, wherein the subject is a human. 32. The method of any one of embodiments 1-31, wherein the dementia is all forms and stages in the dementia disease continuum. 33. The method of any one of embodiments 1-32, wherein the dementia is mild cognitive impairment. 34. The method of any one of embodiments 1-33, wherein the dementia is Alzheimer's disease. 35. The method of any one of embodiments 1-34, wherein the dementia is selected from the group consisting of preclinical Alzheimer's disease, mild cognitive impairment of the Alzheimer's type, early-onset familial Alzheimer's disease, and prodromal Alzheimer's disease. 36. The method of any one of embodiments 1-35, wherein the dementia is preclinical Alzheimer's disease. 37. The method of any one of embodiments 1-36, wherein the dementia is mild cognitive impairment of the Alzheimer's type. 38. The method of any one of embodiments 1-37, wherein the dementia is early-onset familial Alzheimer's disease. 39. The method of any one of embodiments 1-38, wherein the dementia is prodromal Alzheimer's disease. 40. The method of any one of embodiments 1-39, wherein the GLP-1 receptor agonist is the only pharma- ceutically active ingredient administered to the subject. 41. The method of any one of embodiments 1-40, wherein the GLP-1 receptor agonist is administered subcutaneously. 42. The method of any one of embodiments 1-41, wherein the GLP-1 receptor agonist is administered in a composition that is in the form of a solution or suspension. 43. The method of any one of the preceding claims, wherein the composition comprises at least 90% water. 44. The method of any one of embodiments 1 to 43, wherein the GLP-1 receptor agonist is semaglutide, is administered subcutaneously, and is in the form of a solution containing at least 90% water and having a pH in the range of 7.0 to 9.0. 45. The method of any one of embodiments 1-44, wherein the GLP-1 receptor agonist is administered orally. 46. ​​The method of any one of embodiments 1-45, wherein the GLP-1 receptor agonist is administered in the form of a tablet. 47. The method of any one of embodiments 1 to 46, wherein at least 30% (w / w) of the tablet is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. 48. The method according to any one of the preceding embodiments, wherein at least 50% (w / w) of the tablet is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. 49. The method according to any one of the preceding embodiments, wherein said salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC. 50. The method of any one of embodiments 1-49, wherein the subject has previously been administered insulin. 51. The method of any one of embodiments 1 to 50, wherein the method reduces the risk of death in the subject. 52. The method of any one of embodiments 1 to 51, wherein said administration of said GLP-1 receptor agonist is a chronic treatment, in which semaglutide is administered for at least 12 months, such as at least 16 months or at least 18 months. EXAMPLES

[0062] Example 1 - Reducing the risk of dementia in subjects with metabolic syndrome method Exposure to GLP-1 receptor agonists and subsequent dementia diagnosis were assessed in data sources with long-term treatment exposure, including three pooled double-blind randomized controlled trials (RCTs) and a national cohort of patients with diabetes mellitus. This was done to investigate whether the use of GLP-1 receptor agonists reduces the incidence of dementia in patients with diabetes mellitus.

[0063] Exams and Registration We adopted a triangulation approach, integrating study designs and data sources across different primary sources of potential bias, to obtain more reliable answers. First, we pooled data from three large RCTs of the GLP-1 receptor agonists, liraglutide (LEADER; 9,340 patients), subcutaneous semaglutide (SUSTAIN-6; 3,297 patients), and oral semaglutide (PINEER 6; 3,183 patients). All three studies were multicenter, double-blind, placebo-controlled cardiovascular outcomes studies. Patients with type 2 diabetes at high risk for or with established cardiovascular disease were randomly assigned in a 1:1 ratio to receive placebo or liraglutide (LEADER), or semaglutide (SUSTAIN-6; PIONEER 6), in addition to standard care. In these studies, treatment for diabetes (excluding GLP-1 receptor agonists, dipeptidyl peptidase-4 inhibitors (DPP4 inhibitors), and pramlintide) was adjusted or added in both arms at the investigator's discretion, as previously described. The formulation tested in LEADER was an aqueous composition containing liraglutide, disodium phosphate dihydrate, propylene glycol, and phenol at pH 8.15. The formulation tested in SUSTAIN-6 was an aqueous composition containing semaglutide, disodium phosphate dihydrate, propylene glycol, and phenol at pH 7.4. The formulation tested in PIONEER was a tablet containing semaglutide and SNAC.

[0064] We then identified a national cohort of patients treated for diabetes using the Danish National Prescription Register (Table S1), which holds information on all prescription drugs reimbursed in Denmark since 1 January 1995. All individuals who received a first prescription for second-line diabetes treatment (Table S2) between 1 January 1995 and 31 December 2017 were identified.

[0065] Follow-up for the onset of dementia began on January 1, 2009 (Figure 4), as this was the time when GLP-1 receptor agonists could be considered a well-known and available treatment for diabetes in Denmark. To correctly identify patients who were first prescribed for secondary diabetes treatment, we excluded patients who were prescribed between January 1, 1995 and June 30, 1995. Furthermore, patients with dementia established before the start of follow-up or who developed dementia before the age of 50 years were excluded.

[0066] The main analysis included all those with at least 5 years of exposure to secondary diabetes treatment.

[0067] Exposure to GLP-1 receptor agonists The given treatment durations for the three RCTs are listed in Supplementary Table S4. In the nationwide cohort, all prescriptions for GLP-1 receptor agonists were identified (Table S2), and years of cumulative GLP-1 receptor agonist exposure were updated throughout the follow-up period. Patients were considered exposed if they had at least one prescription reimbursed for any GLP-1 receptor agonist. Exposure duration was accumulated according to 6-month long intervals in which at least one prescription was reimbursed.

[0068] Exposure to other diabetes treatments In the nationwide cohort, we evaluated "other second-line diabetes treatments" to test whether the potential impact of GLP-1 receptor agonists on dementia prevention was specific to treatment with GLP-1 receptor agonists. We identified other second-line diabetes treatments, namely insulin, sulfonylureas, DPP4 inhibitors, acarbose, and meglitinides, that were available as alternative treatment options to GLP-1 receptor agonists during the follow-up period (Table S2). Exposure time was accumulated according to a 6-month long interval in which at least one prescription was redeemed. Monotherapy with metformin was not evaluated because it is considered a first-line treatment for diabetes and therefore does not represent an equivalent treatment option to GLP-1 receptor agonists.

[0069] Dementia In the RCT, dementia-related adverse events were identified using the narrow search term dementia using the Standardized Medical Terminology for Regulatory Purposes (MedDRA, version 21.1) (Table S3). In the national cohort, dementia was defined as a diagnosis of dementia in the national patient registry or as the first prescription for an approved dementia-specific treatment in the national registry (cholinesterase inhibitors and memantine) (Tables S1 and S2 list ICD10 and ATC codes).

[0070] statistical analysis For pooled RCTs, we performed intention-to-treat analyses using Cox regression with treatment allocation as the only explanatory variable to determine hazard ratios for incident dementia for GLP-1 receptor agonists versus placebo. We reported hazard ratios for dementia for patients randomized to GLP-1 receptor agonists versus placebo. Incidence rates of dementia with death as a competing risk were calculated using the Aalen-Johansen estimator.

[0071] A nested case-control study design was employed in which each patient at the case date (date of dementia diagnosis) was matched for age, sex, and calendar date to 10 controls without dementia in the national cohort. The effect of differences in cumulative exposure to GLP-1 receptor agonists on dementia onset was modeled using Cox regression over a 5-year exposure window prior to the case date (Figure 4) and reported as hazard ratios for each year of increase in GLP-1 receptor agonist exposure for cases versus controls. Hazard ratios for each year of increase in the period were reported. The models were adjusted for age, sex, and calendar date via matching, as well as for diabetes duration at the start of the exposure window (years since first prescription of any secondary diabetes treatment), stroke, myocardial infarction, hypertension, chronic kidney disease, and educational attainment (Tables S1 and S2). Similar Cox regression models were employed for each of the other secondary diabetes treatments. Additionally, hazard ratios for dementia with exposure to GLP-1 receptor agonists were examined across subgroups including sex, age, insulin exposure, and cardiovascular status, where cardiovascular disease was defined as previous stroke or myocardial infarction. In the nationwide cohort, prespecified sensitivity analyses were performed to determine the effects of 1) reverse causation, where exposure 2 years prior to the case date was ignored, 2) diabetes duration defined as "time since first treatment with metformin or a second-line diabetes treatment," 3) shortening and lengthening the exposure window (3 and 10 years, respectively), 4) adjustment via matching only on age, sex, and calendar date, and 5) competing risks due to death. The level of statistical significance was set at 5%.

[0072] result Study population In total, 15,820 patients at high risk for or with established cardiovascular disease were randomized to GLP-1 receptor agonists or placebo in the pooled RCTs. Baseline characteristics are presented in Table 1.

[0073] In a nationwide cohort of 120,054 patients at least 5 years after initiation of secondary diabetes treatment, 4,849 patients developed dementia during follow-up from 2009 to 2017. Characteristics of case and control patients are presented in Table 2. Liraglutide accounted for 95% of all prescriptions for GLP-1 receptor agonists.

[0074] Dementia in pooled RCTs In the pooled RCTs, 15 patients randomized to GLP-1 receptor agonists and 32 patients randomized to placebo developed dementia during a median follow-up of 3.61 years (table S4).

[0075] Patients randomized to GLP-1 receptor agonists had a lower risk of developing dementia compared with patients randomized to placebo (hazard ratio, 0.47; 95% confidence interval (CI), 0.25 to 0.86) (Figure 1 and Table S5). The beneficial effect of GLP-1 receptor agonists was evident after 12 months of treatment (Figure 1).

[0076] Dementia in a nationwide cohort The median follow-up time in the national cohort was 7.4 years. The national within-cohort analysis was specifically designed to examine long-term effects by ensuring treatment with secondary diabetes therapies for at least 5 years. The result was a reduction in the hazard of dementia with increasing duration of GLP-1 receptor agonist exposure (Figure 2). Exposure to other secondary diabetes therapies was found not to be associated with a reduction in the hazard ratio (Figure 2). The reduction in the hazard ratio for dementia with exposure to GLP-1 receptor agonists was similar across subgroups stratified by sex, age, concurrent exposure to insulin, and cardiovascular status (Figure 3).

[0077] Results did not change by excluding exposure in the 2 years leading up to dementia diagnosis (Figure 5A), but when diabetes duration was assessed as "time from first treatment with metformin or second-line diabetes treatment", the association with DDP4 inhibitors was found to be protective against dementia (Figure 5B). Furthermore, dementia outcomes remained unchanged when exposure to GLP-1 receptor agonists within 3 and 10 years prior to dementia diagnosis was assessed (Figure 6A). Adjusting for age, sex, and calendar days only via matching yielded the same results (Figure 6B). Finally, an analysis of death as a competing risk evaluating the hazard ratio for death without a previous dementia diagnosis showed a lower hazard ratio for death with exposure to GLP-1 receptor agonists (Figure 6C).

[0078] In conclusion, treatment with GLP-1 receptor agonists was found to be associated with a reduced risk of dementia in patients with diabetes. [Table 1] [Table 2-1] [Table 2-2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8]

[0079] Example 2 - Semaglutide prevents cognitive decline in senescence accelerated prone 8 (SAMP8) mice The inbred senescence-accelerated mouse prone 8 (SAMP8) model is a non-transgenic mouse strain that displays a phenotype associated with sporadic (not driven by a defined genetic cause) Alzheimer's dementia, including measurable cognitive decline. SAMP8 mice display increased markers of oxidative stress and inflammation, indicative of accelerated aging and therefore model aging-related metabolic complications. Because cognitive impairment can be measured in this model prior to the presence of overt neuropathology such as the accumulation of amyloid plaques in the brain, this mouse model allows for the evaluation of drug effects on preventing cognitive decline, modeling an earlier stage of the disease in humans.

[0080] Here, we utilized SAMP8 mice to characterize the impact of semaglutide treatment on memory impairment and cognitive decline. Two behavioral tests commonly used to assess cognitive impairment in rodents were used to assay effects on short-term memory (Y-maze test) and long-term memory (step-through passive avoidance test). The Y-maze is a test of short-term memory and assesses spatial working memory and exploratory behavior by measuring spontaneous alternation, the frequency of entering a new arm of the maze rather than returning to a previously visited one (described in Methods). The step-through passive avoidance test measures associative long-term memory by assessing learning regarding the association of an aversive stimulus to a specific context (described in Methods). SAMP8 mice have measurable impairments in both tests with age.

[0081] method The experiment was carried out using SAMP8 mice with the following treatment groups: vehicle-treated SAMP8 (n=24) and semaglutide (30 nmol / kg)-treated SAMP8 (n=11). Treatment began at 6 weeks of age. Treatment was delivered subcutaneously once daily, progressing with an initial titration period of 3 nmol / kg semaglutide on the first day of dosing, 10 nmol / kg on the second day of dosing, and 30 nmol / kg thereafter.

[0082] Testing in the Y-maze was performed at 8 and 16 weeks of age, approximately 15 and 71 days after the start of treatment, respectively. The Y-maze consisted of grey polyvinyl chloride with three arms 40 cm long, 13 cm high, and 3 cm wide at the bottom, converging at equal angles and with an upper part 10 cm wide. Each mouse was placed at the end of one arm and allowed to move freely throughout the maze during an 8-min session. A sequence of arm entries, including a possible return to the same arm, was monitored, and an alternation was defined as an entry into all three arms on consecutive occasions. Thus, the maximum number of alternations was the total number of arm entries minus 2, and the percentage of alternations was calculated as (actual alternations / maximum alternations) × 100.

[0083] Step-through passive avoidance behavior was performed at 18 weeks of age. Testing was performed in an apparatus consisting of a two-compartment box (15 x 20 x 15 cm high), where one compartment was illuminated with white polyvinyl chloride walls and the other was darkened with black polyvinyl chloride walls and a grid floor. A guillotine door separated the compartments. A 60 W lamp positioned 40 cm above the apparatus illuminated the white compartment during the experiment. A shock generator Scrambler (Lafayette Instruments, Lafayette, USA) was used to deliver a scrambled foot shock (0.3 mA for 3 seconds) to the grid floor. A training session was performed first, in which the guillotine door was first closed and each mouse was placed in the white compartment. After 5 seconds, the door was lifted. When the mouse entered the dark compartment and placed all four paws on the grid floor, the door was closed and a foot shock was delivered for 3 seconds, associating the dark chamber with the foot shock. Retention testing was performed 24 hours after training. Each mouse was placed again in the white compartment and after 5 seconds the door was lifted. Step-through latencies were recorded up to 300 seconds and were defined as the time it took the mouse to enter the dark compartment during the retention test. Escape latencies were recorded and were defined as the time in the retention test to escape from the dark chamber after the application of the footshock.

[0084] result The data in Figure 7 show that vehicle-treated SAMP8 mice had a significantly reduced rate of alternation behavior in the Y-maze at 16 weeks of age (mean ± SEM: 42.8% ± 2.1%) versus 8 weeks of age (mean ± SEM: 69.1% ± 1.3%), as expected (p<0.0001, 2-way ANOVA, Sidak's multiple comparison test). Semaglutide-treated SAMP8 mice at 16 weeks of age had significantly improved alternation behavior (mean ± SEM: 79.1% ± 1.6%) compared to vehicle-treated SAMP8 (mean ± SEM: 42.8% ± 2.1%) controls (p<0.0001, 2-way ANOVA, Sidak's multiple comparison test). These data show that semaglutide has a positive effect on the preservation of short-term memory function in SAMP8 mice, as measured in the Y-maze test.

[0085] Semaglutide also improved long-term memory in SAMP8 mice, as measured in the step-through passive avoidance test (Figures 8-9). Semaglutide-treated SAMP8 mice had significantly increased step-through latencies into the dark chamber during the retention phase, which was previously associated with footshock (Figure 8; vehicle-treated SAMP8 mean ± SEM: 109.8 s ± 5.8 s; semaglutide-treated SAMP8 mean ± SEM: 260.5 s ± 14.5 s, p<0.0001, Mann-Whitney test). Semaglutide-treated SAMP8 mice also had significantly lower escape latencies from the dark chamber (Figure 9, vehicle-treated SAMP8 mean ± SEM: 88.8 s ± 4.6 s; semaglutide-treated SAMP8 mean ± SEM: 19.0 s ± 3.0 s, p=0.01, unpaired t-test).

[0086] Semaglutide treatment did not result in differences in body weight (16 weeks of age; vehicle-treated SAMP8 mean ± SEM: 31.0 grams ± 0.43 grams or 148.0% ± 4.6% change in body weight from baseline; semaglutide-treated SAMP8 mean ± SEM: 29.2 grams ± 0.7 grams or 145.4% ± 4.2% change in body weight from baseline) or blood glucose (vehicle-treated SAMP8 mean SEM: ± 137.1 mg / dL ± 5.6 mg / dL; semaglutide-treated SAMP8 mean ± SEM: 133.1 mg / dL ± 2.2 mg / dL) compared to vehicle-treated animals.

[0087] conclusion Chronic semaglutide treatment prevents cognitive decline in SAMP8 mice.Semaglutide prevents the decline of alternation behavior in the Y-maze and shows improved short-term and spatial memory compared to vehicle-treated SAMP8 controls.Semaglutide also increases step-through latency and shortens escape latency in step-through passive avoidance test, which are positive indicators of longer-term memory performance and associative learning.These positive effects on cognitive parameters also appear to be novel effects of semaglutide that are not driven by changes in blood glucose or body weight.Example 2 surprisingly shows the effect of semaglutide better than that published for liraglutide in the same animal model.

[0088] Example 3 - Semaglutide reduces brain inflammation (neuroinflammation) in a lipopolysaccharide (LPS) inflammation mouse model Neuroinflammation is part of pathology including dementia and Alzheimer's disease, human brain imaging studies highlight increased markers of inflammation in Alzheimer's disease (e.g., translocator protein 18 kDa levels) and genetic association studies in humans highlight that genes associated with Alzheimer's disease are part of the inflammatory pathway. Inflammation is also associated with metabolic disease in humans (obesity, type 2 diabetes, cardiovascular disease) and therefore may influence cognitive decline and dementia progression in people with metabolic disease.

[0089] LPS-induced neuroinflammation is used as a non-genetic model of Alzheimer's disease in rodents. LPS is an endotoxin derived from Gram-negative bacteria that provides a sustained inflammatory stimulus that activates brain immune cells (neuroimmune cells). Microglia are the brain immune cell type that is activated by LPS, and the degree of neuroinflammation can be assessed by the area of ​​microglia in brain tissue as measured by the microglia-specific marker ionized calcium-binding adaptor molecule 1 (Iba1).

[0090] Here, using LPS-induced neuroinflammation in mice, we assessed the effect of semaglutide on attenuating brain inflammation in the hippocampus, a region of the brain involved in memory and learning that is deteriorated in Alzheimer's disease.

[0091] method Experiments were performed using 8-10 week old C57BL / 6 mice. Mice were treated with semaglutide (30 nmol / kg, subcutaneously once daily) or vehicle from days 1 to 28 of the study. To induce inflammation, LPS was administered (1.0 mg / kg, intraperitoneally once daily) to vehicle-received control animals for 3 days on days 15-17 of the study. Induction of inflammatory cytokines was confirmed by measuring plasma tumor necrosis factor alpha levels 1 hour after LPS administration on day 15. Animals were sacrificed either on day 19 (day 2 after LPS treatment) or day 28 (day 11 after LPS treatment) to measure markers of neuroinflammation. All treatment groups had n=8-12.

[0092] Immediately after sacrifice, whole brains were collected for immunohistochemistry (IHC) analysis of neuroinflammatory markers. Brains were immersion fixed in 10% neutral buffered formalin for approximately 48 hours, then transferred to 70% ethanol and stored at 4°C until paraffin-embedded into blocks. Serial sections representing the rostrocaudal axis of the dorsal hippocampus were cut at 4 μm and collected on Superfrost plus slides. Paraffin-embedded sections were deparaffinized in xylene and rehydrated in a graded series of ethanol. IHC for Iba1 was performed using Iba1 primary antibody (Abcam, Cat. No. Ab178845). Following antigen retrieval and blocking of endogenous peroxidase activity, slides were incubated with primary antibody. Primary antibodies were detected using a linker secondary antibody followed by amplification using a polymeric HRP-linker antibody conjugate. Primary antibodies were then visualized with DAB as a chromogen and counterstained in hematoxylin.

[0093] Quantitative assessment of Iba1 signal was performed to measure the area of ​​microglia in the hippocampus of tissue sections. Assessment was performed using a two-step protocol with VIS (Visiopharm, Denmark) software. First, a crude detection of the tissue at low magnification (1x objective) and delineation of the region of interest (ROI) were obtained. Then, detection of IHC positive staining was performed at higher magnification (10x objective) within the ROI. Quantitative estimates of IHC positive staining were calculated as the area fraction (AF) of the total tissue area, which is:

number

[0094] result Semaglutide reduced the microglial inflammatory marker Iba1 in the hippocampus after LPS administration. The results in Figure 10 show that LPS significantly increased hippocampal Iba1 area on day 19 in mice receiving LPS+vehicle compared to vehicle / vehicle-treated controls (p<0.001, Dunnett's test one-factor linear model; day 19 vehicle / vehicle mean ± SEM: 8.98% ± 0.34%, day 19 LPS+vehicle mean ± SEM: 14.25% ± 0.54%), indicating that neuroinflammation was induced by LPS. At day 28, LPS+vehicle treated mice continued to have significantly higher hippocampal Iba1 area (p<0.05, vs. vehicle / vehicle control, Dunnett's test one-factor linear model; day 28 vehicle / vehicle mean ± SEM: 9.77% ± 0.54%, day 28 LPS+vehicle mean ± SEM: 12.17% ± 0.88%), whereas semaglutide treatment significantly reduced Iba1 area in LPS+semaglutide treated mice (p<0.01, vs. LPS+vehicle treated mice, Dunnett's test one-factor linear model day 28 LPS+vehicle mean ± SEM: 12.17% ± 0.88%, day 28 LPS+semaglutide mean ± SEM: 8.53% ± 0.49%).

[0095] On day 28, there was no significant difference in body weight between mice receiving LPS + vehicle (mean ± SEM: 23.83 g ± 0.33 g) and mice receiving LPS + semaglutide (mean ± SEM: 22.98 g ± 0.70 g).

[0096] conclusion In an LPS-induced neuroinflammation model, semaglutide reduced neuroinflammation in both hippocampi as measured by the area of ​​microglia (Iba1).Semaglutide treatment reduced neuroinflammation, suggesting that this may be a novel mechanism by which semaglutide may have effects on cognition.

[0097] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those skilled in the art, and it is therefore to be understood that the appended claims are intended to cover all such modifications and changes that fall within the true spirit of the invention.

Claims

1. 1. A pharmaceutical composition comprising the GLP-1 receptor agonist semaglutide for use in the treatment of Alzheimer's disease, said use comprising administering semaglutide to a subject in need thereof.

2. 1. A pharmaceutical composition comprising the GLP-1 receptor agonist semaglutide for use in the treatment of preclinical Alzheimer's disease, mild cognitive impairment of the Alzheimer's type, early-onset familial Alzheimer's disease, or prodromal Alzheimer's disease, said use comprising administering semaglutide to a subject in need thereof.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein the GLP-1 receptor agonist is the only pharma- ceutical active ingredient in the pharmaceutical composition administered to the subject.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the GLP-1 receptor agonist is administered subcutaneously.

5. 5. The pharmaceutical composition of claim 4, wherein the GLP-1 receptor agonist is administered in a dose ranging from 0.1 to 5.0 mg.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the GLP-1 receptor agonist is administered once a week.

7. The pharmaceutical composition according to any one of claims 1 to 3, wherein the GLP-1 receptor agonist is administered orally.

8. 8. The pharmaceutical composition of claim 7, wherein the GLP-1 receptor agonist is administered in the form of a tablet comprising at least 30% (w / w) of a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid.

9. 9. The pharmaceutical composition of claim 8, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is SNAC.

10. The pharmaceutical composition according to any one of claims 7 to 9, wherein the GLP-1 receptor agonist is administered in a dose ranging from 1 to 30 mg.

11. 11. The pharmaceutical composition of claim 10, wherein the GLP-1 receptor agonist is administered in a dose of 3, 7 or 14 mg.

12. The pharmaceutical composition according to any one of claims 7 to 11, wherein the GLP-1 receptor agonist is administered once a day.

13. A pharmaceutical composition according to any one of claims 1 to 12, wherein the administration of a GLP-1 receptor agonist is a chronic treatment in which semaglutide is administered for at least 12 months.

14. The pharmaceutical composition according to any one of claims 1 to 13, wherein the subject is a human.

15. A pharmaceutical composition according to any one of claims 1 to 14, comprising one or more pharma- ceutically acceptable excipients.

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