Identifying Potential Effects of Liraglutide on Degenerative Changes
Today Alzheimers disease can not be cured. Animal experiments have shown that the hormone GLP-1 can improve memory in Alzheimer-prone mice.
The investigators hypothesis is that a 6-month treatment with the GLP-1 receptor stimulating drug liraglutide will reduce the intracerebral amyloid deposition in the central nervous system (CNS) in patients with Alzheimer's disease (AD) and thereby reduce the clinical symptoms of the disease.
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Neurodegenerative Changes in Alzheimer's Disease: Identifying Potential Effects of Liraglutide on Degenerative Changes|
- PIB PET scan [ Time Frame: PIB PET-scan at baseline and after 26 weeks ]Primarily to investigate whether 26 weeks of treatment with GLP-1 receptor liraglutide (Victoza ®) will change the intra-cerebral amyloid deposit in the CNS in patients with Alzheimer's disease assessed by PIB PET scan.
- Neuro-psychological tests [ Time Frame: At baseline, after 12 weeks and after 26 weeks ]To validate the cognitive functions using specific neuro-psychological test battery before and after treatment with liraglutide/placebo.
- FDG PET Scan [ Time Frame: FDG PET-scan at baseline and after 26 weeks ]To examine changes in glucose uptake in the CNS by FDG PET scan before and after 6 months of treatment with liraglutide/placebo
|Study Start Date:||January 2012|
|Study Completion Date:||April 2013|
|Primary Completion Date:||April 2013 (Final data collection date for primary outcome measure)|
Active Comparator: Drug
the GLP-1 receptor analog liraglutide is the active drug. The dose is 1.8mg daily
Liraglutide (Victoza ®), human GLP-1 analog produced using recombinant DNA technology in saccharomyces cerevisiae. Victoza ® is registered and approved for the treatment of type 2 diabetes.
Victoza ® stimulates glucose-dependent insulin secretion from β-cells and inhibits glucagon secretion, slows ventricle emptying and reduces body weight and body fat mass by affecting appetite regulation.
Form of administration: Liraglutide is a clear injection fluid, which comes in a prefilled disposable pen.
1 ml contains 6 mg of liraglutide in sterile water. There is added disodium phosphate and propylene glycol and the preservative phenol. A filled pen contains 18mg liraglutide in 3ml. NovoFine® needles are used.
Placebo Comparator: placebo
non active intervention
Drug: non-active study drug
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The incidences of both type 2 diabetes (DM-2) and Alzheimer's disease (AD) have increased during the last years, resulting in an increase in morbidity and mortality. DM-2 is a risk factor for both AD and vascular dementia. In addition, an increased incidence of DM-2 in Alzheimer's patients has been observed. The understanding of the underlying mechanism behind this linkage is so far very sparse.
In both diseases premature cell degeneration develops. DM-2 is characterized by a loss of β-cell function and β cell mass in the pancreas, whereas AD shows a loss of neuronal function as well as neuronal cell death. General metabolic risk factors such as hyperglycemia and hypercholesterolemia are evident in both diseases.
Glucagon-like-peptide-1 (GLP-1) is an incretin hormone with numerous documented effects on the glycaemic response. It is released as a response to food ingestion and consequently exerts a glucose-dependent stimulation of insulin secretion while inhibiting glucagon secretion. In animal experiments as well as cell experiments β-cell neogenesis, growth and differentiation are stimulated by GLP-1, and inhibition of β-cell apoptosis has been demonstrated in cell studies. In addition to α- and β-cells of the pancreas, GLP-1 receptors (GLP-1R) have been localized to the CNS, where GLP-1R are distributed corresponding to the hypothalamus and hippocampus. Experimental investigations on mice where GLP-1 was given intra-cerebroventricularly, GLP-1R stimulation reduced nerve cell damage caused by neurotoxic stimuli. Furthermore, GLP-1R stimulation in hippocampus induced learning ability and memory and it has been shown that GLP-1R stimulation leeds to neurite outgrowth and protects against nerve cell apoptosis.
In connection with hyperinsulinaemia in early stages of DM-2, studies suggest that stimulation of insulin receptors represented in the brain produce an increased level of β-amyloid and an increased number of neurofibrillary tangles. AD is pathologically characterized by an increased level of β-amyloid as well as an increased number of neurofibrillar tangles. Accumulation of β-amyloid in the brain is localized to areas with cognitive functions. A recent animal experimental work has shown reduced memory in GLP-1 receptor KO mice and mentions the lack of a possible neuroprotective effect as a potential explanation for the observation. In studies of humans a worsening of the cognitive functions has been shown to be associated with dementia and DM-2, even though an actual causal relation has not yet been found. The investigators have recently shown that GLP-1 has a neuroprotective function in patients with DM-2.
Positron emission tomography (PET) scanning has been well evaluated in clinical demonstration of CNS changes following AD including changes in amyloid deposits.
Presently there are no registered drugs which change the deposition of amyloid and there are no drugs with convincing effect on the progression of the disease in patients with Alzheimer's. Moreover the drugs which have been marketed for treatment have a disadvantageous side effect profile. Besides insulin, β-cells secrete amylin, amyloid or IAPP (islet amyloid polypeptide) and these thus share certain characteristics with β-amyloid. Previously IAPP was considered to be non-toxic but recent studies have indicated a possible conversion to toxic β-amyloid.
The insulin-producing β-cells have been found to be characterized by accumulation of amyloid in several DM-2 models. A recent study with treatment with DPP-4 inhibitors (increasing endogenous GLP-1) improved glucose tolerance, increased GLP-1 levels and normalized the topography of the islets of Langerhans in a mouse model with β cell specific over expression of human amyloid.
The investigators hypothesis is that a 26 week treatment with the GLP-1 receptor stimulating pharmaceutical liraglutide will reduce the intracerebral amyloid deposition in the CNS in patients with Alzheimer's disease, as demonstrated by PET.
The investigators aim is that this clinical study will be able to give new information about the effect of the GLP-1 axis in the CNS and explore the potential for treatment of large groups of patients who cannot be offered effective drugs today. Altogether the results from the studies will contribute to the development of future treatment options for AD.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01469351
|Aarhus, Denmark, 8000|
|Principal Investigator:||Birgitte Brock, MD phD||University of Aarhus|