Dr. Lotte Knudsen started her scientific career with research into detergents that would prevent red dyes from ruining white clothes.
Decades later, she is the scientist behind semaglutide, the active ingredient in the successful weight-loss drugs Ozempic and Wegovy – and now she hopes to use the drug to prevent dementia.
The self-proclaimed socialist from a small town outside Copenhagen, who relinquished intellectual property rights to semaglutide and did not cash in on its enormous success like Novo Nordisk executives, led the development of Ozempic, which was initially designed to treat type 2 diabetes.
The Danish scientist pioneered research into the drug’s predecessors, culminating in groundbreaking findings on their ability to reduce cognitive decline in dementia patients.
Several studies she co-authored have provided compelling evidence that Ozempic-like drugs can prevent hallmark symptoms such as memory loss before they cause permanent brain damage.
Dr. Knudsen believes they can do even more.
Of the approximately seven million Americans who currently have Alzheimer’s disease, it is estimated that approximately 81 percent have type 2 diabetes. The metabolic disease is known to increase the risk of developing the memory-robbing disease up to 77 percent.
Dr. Lotte Knudsen pioneered the research into semaglutide and its older cousins, which gave the world Ozempic and Wegovy, groundbreaking drugs that have helped about five million people lose weight
The drug she has been researching for years is GLP-1, which mimics a hormone in the brain that regulates appetite and makes people feel full.
Dr. Knudsen helped develop liraglutide, a synthetic version of GLP-1.
Because natural GLP-1 doesn’t last long in the body, Knudsen and her team added a ‘spacer’ to increase its ability to dissolve in the body and help it attach to a protein called albumin named. This allowed it to stay in the body longer.
Building on the foundational work done with liraglutide, Dr. Knudsen and her team focused on creating a next-generation GLP-1 analog that would offer improvements including longer duration of action.
Thus, semaglutide, the active ingredient in Ozempic and Wegovy, was born.
Today, semaglutide is linked to better outcomes for people with heart disease and heart failure, high blood pressure and dementia.
It is marketed as Ozempic and is approved for the treatment of type 2 diabetes, but is often prescribed off-label for weight loss.
Wegovy is a higher dose version approved for weight loss in people with a body mass index of at least 30, or in overweight people with a BMI of 27 or higher, who also have a medical condition caused by their weight .
The search for a drug against dementia is not going well. Part of this is due to a general lack of understanding of what exactly in the brain causes the characteristic cognitive decline.
Most research, including the research that has led to controversial, expensive treatments, has focused almost exclusively on a protein called beta-amyloid. This protein creates the sticky buildup that clogs the spaces around brain cells.
But scientists are now coming to terms with the idea that they set their sights on the wrong target. A growing body of evidence suggests that twisted fibers that accumulate in brain cells, called tau tangles, could be behind the dementia.
A 2015 study published in the journal Journal of Alzheimer’s Disease co-authored by Dr. Knudsen investigated how mice given a semaglutide-like compound would be better able to prevent cognitive decline.
They followed the mice for four months. They all had a predisposition to Alzheimer’s disease.
The mice given the drug liraglutide for four months had more neurons in a key area of the brain (the hippocampus) linked to memory, suggesting that the drug could help preserve brain cells and improve memory function.
Dr. Knudsen said last spring: ‘The effectiveness against Alzheimer’s has not yet been proven, but it is a hypothesis that we are investigating.’
She continued to research the uses of liraglutide and co-authored a study in 2016 which showed that mice with a genetic tendency to develop tau tangles in their brains and movement problems showed better survival when given liraglutide, semaglutide’s older cousin.
Mice treated with the drug showed a 62 percent reduction in tau tangles compared to the untreated mice.
A few years later, in a study published in the journal Alzheimer’s and dementiaDr. Knudsen and colleagues studied nearly 16,000 people and gave one group a drug from the same class as Ozempic, while giving the other group nothing.
After three and a half years, they found that the risk of developing dementia was 53 percent lower in the experimental group.
Studies in both humans and mice found that those given the class of drugs that Ozempic is part of showed slower cognitive decline, linked to fewer deposits of harmful proteins in the brain.
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In the same study, they looked at a national cohort of more than 120,000 people with diabetes. Dr. Knudsen and fellow scientists followed them for seven years and four months and found that people who took these drugs for a long period of time had a lower risk of developing dementia.
In addition to the compelling evidence pointing to a link between diabetes and Alzheimer’s disease, obesity is a known risk factor.
Research has shown a link between body mass index (BMI) and brain size in people around the age of 60, finding that the higher a person’s BMI, the smaller their brain is.
Research shows that areas of the brain that shrink In Alzheimer’s disease, this also applies to obese people.
Obesity can reduce resilience to Alzheimer’s-related brain damage, worsening symptoms and accelerating disease progression. It can also cause chronic inflammation, which negatively affects the brain by overstimulating immune cells and damaging nerve cells, linking it to dementia.
Ozempic and Wegovy have now been shown to reduce a person’s body weight by five to twenty percent. Currently, between five and seven million people are taking one of these drugs or similar ones from Eli Lilly, and there are early signs that obesity rates in the US have declined for the first time.
A CDC report published in September found that 40 percent of U.S. adults were obese between 2021 and 2023, up from 42 percent between 2017 and 2020.
At the request of Pharma times what her goal for the future of these medicines was, Dr. Knudsen said: ‘Building new innovation in the field of cognitive disorders (dementia).
‘Have GLP-1 properly tested in neurodegenerative diseases, because a lot of science supports its potential usefulness there.’
However, there are perceived disadvantages to semaglutide. Hundreds of Americans have joined a class action lawsuit alleging that Novo Nordisk, the maker of Ozempic and Wegovy, failed to warn its millions of eager customers about the very real risk of serious gastrointestinal injuries, including gastric paralysis. gallbladder problems, colon removal, and more, and also make misleading claims about the safety of the drugs.
It’s also not yet clear, because the drugs haven’t been around long enough for researchers to collect long-term data, whether people who stop taking one of the blockbuster drugs will quickly regain all the weight they lost. will get back.
Dr. Knuden’s research focus has changed dramatically over the years. Before changing the landscape of obesity treatment, she studied at the Technical University of Denmark.
She began working with the Danish pharmaceutical company Novo on a project to discover enzymes that improve the performance of clothes detergent to prevent both color bleeding and pilling in clothes.
A research accident during her research into preventing dye bleeding, which resulted in a stink bomb-like explosion in a laboratory refrigerator, coincided with Novo’s acquisition of Nordisk, an insulin-making giant.
This transition saw industrial products moved to a new division, Novozymes, while Knudsen’s boss became head of a small research group focused on type 2 diabetes. Dr. Knudsen was then brought into the fold.
By chance she became a diabetes researcher. Repeated attempts to develop compounds that activated GLP-1 receptors failed.
But Dr. Knudsen’s determination pushed the project forward and laid the foundation for subsequent advances that would become a crucial breakthrough.