From his office at the Hammersmith Hospital in west London, Dr Paul Edison has begun the search for patients to participate in a counter-intuitive clinical trial. He wants people who do not themselves have diabetes to take diabetes drugs.
His efforts, in a trial known as the Elad study, are prompted by the work of a growing minority of medical researchers seeking a radical new way to tackle Alzheimer’s and other neurodegenerative diseases such as Parkinson’s.
He runs one of several modestly funded research projects that have developed over the past decade and challenge a longstanding orthodoxy about the causes and best ways to tackle Alzheimer’s, into which drug companies have invested billions of dollars with scant results.
He is also part of a broader and growing interest in “repurposing” existing medicines for new applications, as scientists seek ways to slow deterioration and even reverse the cognitive decline in Alzheimer’s patients, one of the biggest health burdens of the coming years.
Currently, a handful of older drugs have a marginal impact on slowing the progression of the disease for a few months at best. Most pharmaceutical industry research has focused on developing experimental treatments seeking to reverse impairment by tackling the beta-amyloid plaques that build up in the brains of sufferers.
Yet Dr Edison cautions: “Most treatments that seek to clear the amyloid haven’t worked. Anti-diabetic agents have shown a significant effect in laboratory studies on memory and in reducing the abnormal protein that causes the problem.”
His study, partly funded by charities including the Alzheimer’s Society, aims to recruit 200 people in half a dozen study sites across the UK. Over 12 months, they will receive liraglutide (Victoza), one of several Glucagon-like peptide 1 (GLP-1) receptor agonists that are widely used for type 2 diabetes.
Novo Nordisk, the Danish company that developed the drug, is also providing support. Other studies have examined the role of older diabetic drugs such as metformin, inhaled insulin and more recent patented GLP-1 analogues produced by Eli Lilly and Sanofi.
Dr Edison’s research builds on the work of academics, including Christian Holscher from Lancaster University, who recalls first being struck with the potential of the approach in the middle of the last decade. He had read several papers identifying a far higher risk of Alzheimer’s in people who were diabetic. “The risk factors tell you a story, point a finger,” says Mr Holscher. “I wanted to know more.”
Past research has shown that the amyloid plaques in the brain associated with Alzheimer’s are also present in diabetics. There are other links too. One study suggested 85 per cent of those with Alzheimer’s disease also had type 2 diabetes, compared with 42 per cent among those without dementia.
Another study found that women without diabetes were twice as likely to have good cognitive function as those with the condition.
A more recent paper studying patients in France identified diabetes, alongside depression, as among the most important risk factors that could be influenced to reduce the risk of Alzheimer’s. That has led some to dub Alzheimer’s as diabetes of the brain. “There’s a theory that Alzheimer’s is type 3 diabetes,” says James Pickett, head of research at the Alzheimer’s Society in London.”
It has long been known that diabetes affects the body – damaging blood vessels, the kidneys, and peripheral nerves. More recently, however, attention has focused on the illness’s effect on the brain. Since diabetes drugs stimulate the pancreas to produce insulin, some studies have suggested that those who take them are less at risk of cognitive decline. This is because insulin, which allows cells to take up glucose for energy, seems to be important in activating new cell growth, also enhancing attention, memory and cognition.
The problem with older generation diabetes drugs is that they also affect blood sugar levels, making them unsuitable for those who are not diabetic.
By contrast, the newer GLP-1-type drugs do not affect glucose, offering scope for broader application in Alzheimer’s. They also cross the blood-brain barrier, offering potential to be active in the brain. Mr Holscher has tested the compounds in mice, and identified cognitive improvement.
“Amyloid is probably involved in Alzheimer’s, and causes inflammation,” he says. “But it may not be at the core of the disease, rather a side effect and probably not the main reason for it.”
Much work is yet to be done in larger clinical trials of the different compounds to study their safety, efficacy and appropriate dosage – let alone to understand their mechanism. But given the setbacks with current mainstream approaches, the field offers potential – a fact reflected by interest from the diabetic drug manufacturers themselves.
The links between diabetes and neurological degeneration may offer new scope for other existing and experimental treatments. These drugs are likely failing to combat Alzheimer’s because they are administered too late, once the condition has become irreversible. So it may be fruitful to explore their application far earlier – especially in groups at highest risk, such as diabetics.
Geographical burden: Cases are on the increase, yet many millions remain undiagnosed
The geographical burden of diabetes varies around the world, but the trend is clear: the number of people affected is high and continues to rise.
Poor diet, too little physical activity and rising life expectancy point to a sharp increase in the cost to healthcare systems in the years to come.
Very few countries, notably Japan, have shown a slight decline in prevalence, but the International Diabetes Federation suggests any reductions are more a reflection of the increasing accuracy of predictions than any sign of a reversal in the condition.
More than three-quarters of cases globally are in low and middle income countries, led by China and India. The US remains the country with the third largest number of cases. Even since last year, the 2014 edition of the World Diabetes Atlas estimates that there have been a further 5m cases of diabetes including 4m that are undiagnosed.