Repurposing Type 2 Diabetes Mellitus Drugs for Alzheimer’s Disease
Written By Fiona Chisholm, Analyst for GBI Research
The public healthcare crises of Type 2 diabetes mellitus and Alzheimer’s disease
Type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) represent major public healthcare crises, on a global scale. With the prevalence of both diseases escalating rapidly, the already substantial human, societal and economic costs will be amplified over the coming decades.
Both T2DM and AD are chronic, progressive multi-factorial diseases resulting from interacting environmental, lifestyle and genetic factors. T2DM is a metabolic disorder characterized by hyperglycemia (high blood glucose levels) that results from impairments in the secretion and activity of insulin, a hormone that contributes to the regulation of blood glucose levels. Having a poor diet and carrying excess weight represent particularly strong risk factors for T2DM, with the majority of patients being obese (Eckel et al., 2011). The risk of developing T2DM also increases markedly with age (CDC, 2014).
AD is a neurodegenerative disease associated with cognitive impairment, memory loss and functional decline that affects a person’s ability to undertake everyday activities. The greatest risk factor for AD development is advancing age, as the vast majority of patients are aged 65 and older at diagnosis (Alzheimer’s Association, 2016). This is attributable to a series of age-related changes in the brain that occur over decades (NIH, 2016). In particular, two classes of abnormal structures accumulate in the AD brain – extracellular amyloid plaques comprising amyloid beta peptide, and intraneuronal neurofibrillary tangles comprising tau proteins (Bloom, 2014).
In 2006, 26.6 million people were estimated to be living with AD worldwide, a number that is expected to quadruple by 2050, and similar epidemiological trends of rising prevalence are also apparent for T2DM (Brookmeyer et al., 2007). These trends have been attributed to multiple factors, including economic development, increased urbanization and aging populations.
Within this context, research into pathophysiology and drug development for these indications is highly active. In particular, increasing evidence indicates many commonalities between T2DM and AD. It is well-established that having one of these conditions increases a person’s risk of developing the other. Patients with T2DM have a 50–75% increased risk of developing AD in comparison to age and gender-matched controls, and rates of T2DM among AD patients are approximately twice as high as rates observed among control subjects (Janson et al., 2004; Kim et al., 2009).
Is Alzheimer’s disease diabetes of the brain?
Evidence relating to a shared pathophysiology between T2DM and AD has become so compelling in recent years that AD has been described by some researchers as ‘brain-specific diabetes’ or ‘type 3 diabetes’ (Sebastião et al., 2014). In particular, this reflects the role of insulin in the two diseases.
Insulin’s role in maintaining glucose homeostasis is well-established. The hormone is released in response to increased blood glucose levels following food consumption, and in turn triggers the absorption of glucose by insulin-sensitive target tissues. This provides a fuel source for cells to carry out essential glucose metabolism, and lowers the blood glucose concentration to the point where it reaches a homeostatic level, in turn decreasing the rate of insulin secretion.
However, this process is impaired in T2DM as a result of insulin resistance. This is characterized as the reduced responsiveness of target tissues – predominately peripheral tissues such as skeletal muscle and adipocytes – to normal circulating concentrations of insulin, which leads to impaired glucose homeostasis. Insulin resistance is considered to be the primary defect in T2DM, and due to the slowly progressing nature of the disease it can occur years or even decades before patients become symptomatic.
At the cellular level, insulin resistance results from dysregulated signaling from the insulin receptor to its downstream substrates (Draznin, 2006). Insulin and insulin receptors are ubiquitously expressed in the brain, as well as in peripheral tissues. However, research on the role of insulin in the brain has been very limited in comparison to its role in peripheral tissues, although it is known to have neuro-modulatory effects.
Processes impacting learning and memory such as dendritic sprouting, neuronal stem cell activation, cell growth and repair, synaptic maintenance and neuroprotection are all regulated in the brain by insulin, insulin-like growth factors and their receptors (Bedse et al., 2015). For this reason, an insulin-resistant brain state has been proposed as a key contributor towards cognitive impairment and AD.
For example, brain insulin resistance is associated with decreased signaling via phosphoinositol-3-kinase, Akt and Wnt/β-catenin, and increased activation of glycogen synthase kinase 3β. These effects can impair tau gene expression, resulting in tau hyper-phosphorylation, mis-folding, aggregation and neurofibrillary tangle deposition.
Additionally, inadequate insulin activity in the brain reduces glucose transporter 4 gene expression and protein trafficking from the cytosol to the plasma membrane. This decreases glucose transporter 4-mediated glucose uptake and utilization, culminating in disrupted neuronal cytoskeleton and synaptic connections (Matioli and Nitrini, 2015). The onset of AD-type symptoms following experimentally-induced insulin resistance in animal models provides support for this hypothesis (Kamat, 2015; Lester-Coll et al., 2006; Sachdeva et al., 2013). Furthermore, postmortem analyses indicate that insulin signaling is impaired in the brain tissue of AD patients (Morris and Burns, 2012).
Type 2 diabetes mellitus drugs show potential for treatment of Alzheimer’s disease
The linked underlying role of dysregulated insulin signaling in T2DM and AD pathophysiology is becoming increasingly apparent. This suggests that therapeutic approaches established within T2DM could also prove to be beneficial for the treatment of AD. This is an area of high unmet need, as there are no drugs available that can prevent or slow disease progression in AD (Chen et al., 2016).
One area of research that has received a large amount of attention in recent years is the use of insulin therapy for AD. Insulin therapy is administered to many T2DM patients in order to supplement physiological levels of insulin in the body and overcome the insulin resistance found in the disease, leading to potent reductions in blood glucose concentration. In most cases these therapeutics are synthetically produced and are administered via subcutaneous injection.
Amplifying insulin activity in the brain has also been proposed as a means to improve cognitive function in AD. However, in order to achieve functionally effective insulin concentrations in the brain, AD patients would need to be injected with very high doses of insulin, which may induce or exacerbate strong side effects in the peripheral tissues, such as induction of hypoglycemia (low blood glucose levels).
Intranasal administration of insulin could provide a means to rapidly deliver insulin to the central nervous system, selectively enhancing insulin levels in the brain while avoiding deleterious side effects in the peripheral tissues (Bedse et al., 2015).
Positron emission tomography (PET) scans of AD patients treated with intranasal insulin demonstrate enhanced radioactive glucose uptake in multiple brain regions. This finding is encouraging, as reduced glucose uptake is indicative of cerebral metabolic dysfunction and is consistent with AD progression (Yarchoan and Arnold, 2014).
There are several intranasally administered insulin products in development for AD, among which Impel Neuropharma’s INP-102, which is currently in multiple late-stage trials, is the most developmentally advanced. Preliminary clinical data indicate that delivery of INP-102 is associated with minimal systemic exposure – although there is currently no data available on the safety profile. Treatment over a period of four months resulted in cognitive improvements from baseline at the end of the treatment period and sustained cognitive improvements following treatment cessation (Impel Neuropharma, 2016).
In addition to insulin therapies, T2DM agents that enhance patients’ sensitivity to insulin could also prove to be beneficial in AD. These include metformin, a generic orally administered drug that is used as first-line therapy in T2DM. Metformin has been used in T2DM for decades and has very well-characterized safety and efficacy profiles. It reduces peripheral insulin resistance, possibly by modulating insulin receptor expression and tyrosine kinase activity (Viollet et al., 2012).
Metformin has also attracted interest as a means to improve insulin sensitivity in the brain, as the drug can cross the blood–brain barrier. In a trial of 80 patients with amnestic mild cognitive impairment, a condition that often precedes AD, treatment with metformin over 12 months significantly improved memory scores on recall tests (Luchsinger et al., 2016).
Takeda’s Actos (pioglitazone) is also a well-established insulin sensitizer within T2DM. By activating peroxisome proliferator-activated receptor-gamma receptors, the drug stimulates insulin-sensitive genes, and increases the production of insulin-dependent enzymes, which work to increase systemic insulin sensitivity.
In a trial of patients with mild AD and T2DM, Actos treatment over six months resulted in improved cognition and regional cerebral blood flow in the parietal lobe (Chen et al., 2016). Additionally, an ongoing Phase III trial is investigating the potential of Actos to delay the onset of mild cognitive impairment due to AD in cognitively normal high-risk elderly subjects.
Glucagon-like peptide-1 (GLP-1) receptor agonists also represent promising contenders for AD repositioning. These drugs stimulate the synthesis and release of insulin and have been used to treat T2DM for over a decade, with Novo Nordisk’s Victoza (liraglutide) representing the current market leader among the drug class.
In a mouse model of AD, treatment with liraglutide delayed or partially halted the age-associated progressive decline in spatial memory function (Hansen et al., 2015). Recent findings from a first-in-human placebo-controlled 26-week trial comprising 38 AD patients are also promising. Although the study was underpowered to detect differences in cognition between the placebo and treatment groups, liraglutide treatment prevented the expected decline in glucose metabolism indicative of disease progression, cognitive impairment and synaptic dysfunction (Gejl et al., 2016).
Multiple streams of evidence from epidemiological, preclinical, clinical and postmortem studies suggest that pathologies characteristic of T2DM also play an important role in AD onset and progression. Although the role of insulin in AD has historically been marginalized, over the past decade this area of research has gained precedence, with many important discoveries being made. Additionally, with a rapidly expanding prevalence population and a disease market characterized by high unmet need, identifying new treatments for AD has become increasingly important.
T2DM therapies are capable of modifying the activity of insulin in the brain, and therefore address what is now considered to be one of the underlying features of AD pathophysiology. Recent findings suggest that these drugs could be used to alleviate symptoms among AD patients or even exert potential disease-modifying effects. Future research efforts are therefore essential in order to fully characterize the implications of treating AD patients with T2DM drugs. In particular, drugs with established efficacy in AD may prove to be especially beneficial for the treatment of patients with co-morbid T2DM and AD, or for T2DM patients with a high risk of developing AD.
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