Alzheimer’s Disease Research Points Toward Diabetes Drugs as a Potential Future Treatment

Nov 4, 2018 | Alzheimer, Blog, Diabetes Type 2

The Growing Alzheimer’s Disease Menace

Alzheimer’s disease (AD) is a neurodegenerative disorder including cognitive, functional and behavioral alterations. As the world’s population grows, the disease affects greater numbers of people. By 2050, some estimate that one in every 85 people will struggle with AD. A vast number of people face exposure to preclinical AD, which includes the risk of it progressing to manifest the disease. It is imperative that drug developers commercialize disease-modifying therapies (DMTs) which act to delay or even prevent the disease itself given this dire situation. The state of the AD DMT was recently published by the NIH.

Presently, nearly 30 million battle the disease. Economic costs to the United States alone skyrockets to $277 billion dollars. According to the Alzheimer’s Association’s Alzheimer’s Impact Movementover 5 million Americans battle with the disease, and it is predicted that in the last five years of life, per person dementia costs in total more than $287,000, as compared to $175,000 for heart disease and $173,000 with cancer. AD research and development pipelines are growing. According to a recent report there are over 100 agents in the AD pipeline. See the table below for breakdown:

Phase Trials Agents
3 35 26
2 75 63
1 25 23

AD clinical pipeline agents are segmented into a) disease modifying therapies (63 percent) b) symptomatic cognitive enhancers (22 percent) and c) symptomatic agents involving neuropsychiatric and behavioral changes. A biomarker review reveals that amyloids are used as an entry criterion in 14 phase 3 disease-modifying agent trials and 17 disease-modifying agent trials in phase 2.  

Although the AD clinical trial pipeline is growing, due to a victory after decades of failure and underinvestment, individual trials struggle to find participants among other problems. In fact, the subject enrollment dilemma has been labeled a crisis by clinical industry participants. Moreover, a growing frustration exists with previous large, costly trials having failed to produce any treatments. Most recently, Johnson and Johnson announced that it was halting a new AD drug for safety reasons. Failure by academic, patient association or commercial sponsors to find sufficient numbers of willing study participants leads to complete failure. However, news sources have recently buzzed with a positive message—the AD drug development connection to type 2 diabetes.

The Connection to Type 2 Diabetes

Researchers point to a correlation between diabetes and Alzheimer’s Disease. A growing body of research indicates that type 2 diabetes raises the risk of AD (Xu et al., 2009), and the Alzheimer’s Association identifies a growing body of scientific research linking the two. Furthermore, an increasing number of clinical and epidemiological research supports that AD and type 2 diabetes are indeed linked. One of the first research outcomes bolstering evidence between type 2 diabetes and AD was the Rotterdam study

In late 2014 it was reported in the press that a pair of drugs frequently prescribed for diabetes type 2 were found work against AD in laboratory mice. In one case it was reported that lixisenatide (Sanofi) and liraglutide (Novo Nordisk) were shown to protect AD afflicted mice’s brain nerve cells from injury or degeneration. According to this pre-clinical animal study, the diabetes drugs were more effective against AD adverse degenerative impacts than any other treatments for the brain disorder. Given they are licensed already for diabetes treatment, why not test them for dementia

Liraglutide & University of Aarhus Study & Novo Nordisk Opportunity

In a first in-human study, based on the results of GLP-1 analog treatment and the effects on brain glucose metabolism, investigators studied the effects of liraglutide on three vital signifiers in AD, including a) cerebral glucose consumption b) fibrillary Aβ deposition and c) cognition. They tested the hypothesis that treatment with liraglutide prevents or reduces the decline of cerebral glucose consumption. Additionally, they tested if the 6-month liraglutide treatment would reduce the Aβ deposits in the brains of AD patients and determined commensurate changes of relevant cognitive scores.

At the University of Aarhus in Denmark, the investigator and sponsor sought to study the potential effects of liraglutide on degenerative changes. Led by Dr. Birgitte Brockthe Danish group claimed that AD currently has no cure. However, they highlighted that animal studies have evidenced the promise of hormone GLP-1 to support improved memory in AD-prone mice. Dr. Brock and the team’s summarized research question is: can a 6-month treatment of GLP-1 receptor stimulating drug liraglutide reduce the intracerebral amyloid deposition in the central nervous system (CNS) in AD patients, and thereby reduce AD clinical symptoms? The study was summarized in a published article.

They completed a 26-week, randomized, placebo-controlled, double-blinded intervention with liraglutide (VICTOZA) or placebo in patients with AD. They set up an independent safety monitoring board, and their study protocol was approved by the Danish Data Protection Agency, and the Danish Medicines Agency. The Danish research team led by Dr. Brock concluded that in AD patients, the 26 week liraglutide treatment “prevented the expected decline of CMRglc that reflects disease progression, as observed in the placebo group. We found no differences between the groups treated with liraglutide and placebo with respect to amyloid deposition or cognition.” The investigator-initiated and led study was supported by an unrestricted research grant from Novo Nordisk as well as from Aarhus University. The researchers disclosed that no funding source has any role or influence on trial design, data collection, etc.

Interestingly, investment analyst website Seeking Alpha picked up on this important Danish trial. First, they pointed that a link between diabetes and AD has been well established. Second, they observed liraglutide prevented the decline of brain glucose metabolism in the small phase 2a study. Finally, they reported other results are being tested in larger phase 2b study to determine if AD progression can be halted or slowed down at an earlier age. 

Leonora Beck of Danish Medwatch reported that the clinical results raised the possibility that liraglutide (Victoza) could potentially be used to slow down AD. Ms. Beck wrote that a new large-scale patient trial was being organized to determine whether Novo Nordisk would attempt to move into the multi-billion-dollar AD market. Novo Nordisk CSO Mads Krogsgaard was quoted in the article, “as soon as we have indications that humans are a species in which we can expect liraglutide to have beneficial effects, we will seriously consider going actively into this on our own.”

Dr. Paul Edison of Imperial College London is leading the previously mentioned large-scale clinical trial to study liraglutide’s effect on humans. According to a review on ClinicalTrials.govthe trial sponsor is actively recruiting patients for the 12 month multicenter, randomized, double-blind, placebo-controlled phase 2b study. The targeted trial completion date is March 2019. Positive results may trigger the entrance of Novo Nordisk into the AD drug market. If all goes according to plan, spring of 2019 may lead to intensified investment activities in this field.

University of Ulster and Lancaster University Research

Another group of investigators seek to understand the correlation between Sanofi’s diabetes type 2 drug lixisenatide and the slow down or prevention of AD. Paula L McClean, Clinical Translation Research and Innovation Centre, University of Ulster and Christian Holscher Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, UK published an article in late 2014 showcasing lixisenatide’s positive neuroprotective effects in a mouse model.                                                                    

The pre-clinical research revealed that the GLP-1 receptor agonists liraglutide and lixisenatide—currently on market as type 2 diabetes treatments, represent potential AD treatments. The researchers reported that “lixisenatide was equally effective at a lower dose compared to liraglutide in some of the parameters measured.”

UK & China Research Collaboration

Additional research reported in 2018 represents a collaboration between Dr. Holscher of Lancaster University as well as Shanxi Medical University and Shaoyang University of China. The Anglo/Chinese researchers report diabetes drugs evidence a “clear promise” as a future potential treatment for AD and other neurodegenerative disorders. Their study confirmed that AD-afflicted mice treated using a triple-receptor agonist (TA) showed “significantly reversed memory loss.” In addition to reduced neuroinflammation and oxidative stress, there was a reduced amyloid plaque load as well as increased levels of brain-derived neurotropic factor (BDNF)—a core growth factor protecting synaptic function. Holscher and the collaborative team in China understood and acknowledged that further dose-response testing as well as intensive drug comparisons will be needed to determine if new TA is more effective against neurodegenerative disorders than previously developed treatments. However, they conclude that the novel triple GLP-1/GIO/Gcq receptor agonist holds clear promise as an applied treatment for chronic neurogenerative disorders such as Alzheimer’s disease.

Mount Sinai Health System Postmortem Studies

As recently reported in EurekAlert!, a recent Mount Sinai Health System news article stated that AD patients on diabetes drugs may have fewer signs of dementia in the brain than comparable patients on any diabetes drugs. Funded by the National Institutes of Health and U.S. Department of Veteran’s Affairs, the Mount Sinai team and lead investigator, Vahram Haroutunian found individuals with AD who were on diabetes drugs had less AD disease markers—including abnormal microvasculature and dysregulated gene expressions in the brain compared to AD patients without diabetes treatment. 

Dr. Haroutunian and the team conducted the study on autopsied brains. In the process, they utilized a way to separate capillaries in the brain from nearby brain tissue. They used this method on the brains of 34 individuals who had been diagnosed with AD and diabetes type 2, and who had been on standard diabetes drugs during life. They compared these findings to a study of 30 brains from deceased people that had AD without type 2 diabetes. The results suggested that diabetes medications had a protective effect on the brains of AD patients, which may intensify the quest for effective therapies.

Haroutunian was quoted that “most modern Alzheimer’s treatments target amyloid plaques and haven’t succeeded in effectively treating the disease.” He continued, “insulin and diabetes medications such as metformin are FDA approved and safely administered to millions of people and appear to have a beneficial effect on people with Alzheimer’s. This opens opportunities to conduct research trials on people using similar drugs or on drugs that have similar effects on the brains’ biological pathways and cell types identified in this study.” The Mount Sinai research team will continue to study these drugs and their molecular pathways in further detail, utilizing combinations of postmortem human brain cells and mouse models.

Conclusion & Summary List of Sample Players

The news has buzzed of late with promising opportunities for AD treatment research agenda. Although not new news, TrialSite News research staff point out that connections between type 2 diabetes and AD are made as far back as the Rotterdam study in 1997. However, over the past few years there may be a growing momentum to connect the dots between AD and type 2 diabetes.  Mounting evidence points in the direction of type 2 diabetes drugs as a potential basis for AD disease modifying therapies. Some key research sites and investigative leads are included in the table below. TrialSite News will continue to monitor these groups and provide updates to our online reader community. AD represents a mounting crisis and is too important not to monitor and understand moving forward.

Institution Investigators Website Link
Imperial College London Paul Edison

Victoria Scott

https://www.alzheimers.org.uk/research/our-research/research-projects/testing-effect-diabetes-drug-liraglutide-alzheimers-disease
Mount Sinai, Icahn School of Medicine Vahram Haroutunian https://icahn.mssm.edu/research/nih-brain-tissue-repository/team
Lancaster University Christian Holscher http://www.research.lancs.ac.uk/portal/en/people/christian-holscher(7298c0ae-27d0-4941-a91a-8612ec3a9a0f).html
University of Aarhus Birgitte Brock https://www.researchgate.net/profile/Birgitte_Brock2
University of Ulster Paul L. McClean https://www.ulster.ac.uk/staff/pl-mcclean
Shanxi Medical University, Shanxi, China Weizhen Liu

Lin Li

Jingjing Ta

https://www.researchgate.net/scientific-contributions/2107248870_WeiZhen_Liu
Shaoyang University of China Yanwei Li https://www.researchgate.net/profile/Yanwei_Li10

 

Author

Daniel O’Connor

Mr. O’Connor has spent nearly 20 years providing technology and services to the clinical trials and health technology industry. An entrepreneur, he has been instrumental in building a few different ventures focusing on FDA 21 Part 11 enterprise document management, technology-enabled patient recruitment services, clinical document and safety data exchange, as well as population health and community care coordination for at-risk populations.  Mr. O’Connor has built a comprehensive research center data base and intelligent clinical research site new curation engine with TrialSite News.

 

 

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