Identifying Potential Effects of Liraglutide on Degenerative Changes
Condition: Alzheimers Disease
MeSH terms: Alzheimer Disease
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Liraglutide; non-active study drug
Intervention type(s): Drug; Drug
Intervention description(s): 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
Intervention MeSH terms: Liraglutide
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Alzheimers disease