Leading GLP-1 researcher says while drugs like semaglutide do appear to have longevity benefits, they won’t make healthy people healthier.
Semaglutide, the so called “skinny jab”, marketed around the world as Wegovy, Ozempic and Rybelsus, is rarely out of the news these days. Gossip columns are awash with claims of celebrities using the drug to achieve their weight-loss goals, alongside warnings around side-effects, the surge in black market knockoffs, and the drug’s potentially detrimental effects on things like muscle mass and bone density.
Having secured regulatory approvals all over the world, semaglutide’s maker, Danish pharma company Novo Nordisk, now valued at more than $500 billion, has become the most valuable company in European Union, prompting speculation in longevity circles about what a successful aging drug could mean for the pharma industry.
From a clinical perspective, the results have been impressive, and not just in promoting weight loss and preventing diabetes. Semaglutide has also demonstrated efficacy in reducing cardiovascular complications in human studies, as well as showing neuroprotective effects in mouse studies, leading to suggestions that it could be considered a “longevity drug.”
Longevity.Technology: Semaglutide is part of a class of drugs that work by activating the GLP-1 hormone receptor, mimicking certain biological actions that occur in the gut after eating, helping combat our urge to eat. We spoke exclusively to one of the world’s leading GLP-1 researchers, University of Copenhagen professor Jens Juul Holst, to find out what the experts think about the longevity potential of the skinny jab.
To answer the question, Holst, who discovered the GLP-1 hormone more than 30 years ago, begins by highlighting some of the key evidence supporting semaglutide’s longevity credentials. He says that he and his fellow researchers have been blown away by the results achieved by the drug in obesity trials.
“I think it’s important to note that these weight losses are completely unbelievable. We never expected that it could go so high. With some of the newer combinations, we’re now seeing weight loss of 25%, which is almost comparable to bariatric surgery.”
“And the important thing about that is that we have a lot of experience from bariatric surgery, which we know results in increased longevity. Obese individuals typically see up to nine years of extended life expectancy after the operation, and at least five years for people with diabetes.”
A longevity drug?
Holst, who is also affiliated with the Novo Nordisk Foundation Center for Basic Metabolic Research, then cites the recent SELECT trial, where treatment with semaglutide demonstrated a 20% reduction in the incidence of major adverse cardiovascular events.
“This included mortality,” he says. “So, we now know that treatment with a GLP-1 agonist, for a timeframe of four years, is associated with reduced mortality, or increased longevity, as well as reduced risk of stroke, myocardial infarction, and things like that.”
And, with Novo Nordisk now pursuing clinical trials of semaglutide in early Alzheimer’s, Holst says he personally believes that the drug’s impact on metabolism is also likely driving its potential in neurodegenerative disease.
“What these compounds do is normalise lipids, glucose and inflammation,” he says. “And obesity is also associated with a kind of diffuse inflammation throughout the body, so it is not such a stretch to imagine that this will also translate into fewer problems in the vasculature of the brain.”
“Once you put all this evidence together, then I think it’s more probable than not that you will have an effect on longevity with these agents.”
So that’s a “yes” to GLP-1 drugs improving longevity. But could Holst ever envisage a point at which the drugs might be prescribed to healthy individuals? (We’re looking at you, Elon Musk!)
“Definitely not,” he says. “While I think you can prevent the complications of major population health problems with these drugs, I would never say that they can make you more healthy than healthy.”
What’s next for GLP-1?
With pharma companies all now scrambling to get new GLP-1 drugs into the market, Holst says a battle is on to demonstrate the most compelling results.
“Currently, all the companies are competing like crazy to get the greatest weight loss,” he says. “They’re trying all sorts of combinations and all sorts of interesting molecular changes.”
A key development, says Holst, will be the approval of more simple molecules that can be taken orally. He points to Lilly’s development of orforglipron, which is designed to be taken as a daily tablet.
“Semaglutide is also available orally as a tablet, but it’s still a complicated molecule and it’s a complicated procedure, so it’s expensive and will remain expensive,” he explains. “But a small molecule like orforglipron is much easier to produce, so it will be much easier to provide large amounts of such a compound to a very large population.”
A pleasure killer?
Holst believes that one of the biggest challenges for pharma companies is getting people to stay on the drugs once they are prescribed.
“More people stay on GLP-1 agonists than on any of the other weight loss compounds out there, but still only something like 40% of those that have been prescribed stay on after a year. That’s not very long, so one starts to wonder, why is that?”
One factor could be the high cost of the drugs, or side-effects, or potentially people quitting after they reach a certain weight, but Holst suspects that the intended effect of GLP-1 drugs on our reward system may be the real kicker.
“One of life’s greatest pleasures is to eat, and these drugs, to some extent at least, take away the pleasure of meal ingestion,” he says. “And so, if you are a person whose greatest pleasure in life has been to eat, and you take a GLP-1 agonist, then you might have a problem!”
“I don’t have any statistics for this because the companies have been reluctant to go into it, but I think there’s something to it. So, before we make fantastic prophecies about the future use of these compounds, let’s have a look at how many people will actually continue once they’re prescribed the drug.”
Pharma’s shift towards prevention
There is little doubt that the GLP-1 revolution shows pharma’s view on preventative medicine is changing. And “prevention is better than cure” has been Holst’s mantra for many years.
“Prevention was one of my personal main motives for engaging in this research,” he says. “It was about showing that we could largely prevent the most important and most frequent complication of obesity. I realised quite early that the anti-obesity effects of a GLP-1 therapy would have a tremendous effect in preventing diabetes from occurring in overweight people.”
This was proven to be the case in the SCALE studies, where the incidence of diabetes occurrence was reduced by 80%.
“Looking at that study, you can say, yes, we can prevent a hell of a lot of diabetes from occurring,” says Holst. “And, of course, diabetes is just one of the components of what we call the metabolic syndrome, which affects something like a quarter of the adult population in the Western world. These individuals have double or triple the risk of death from myocardial infarction and stroke, so a huge number of people are at risk.”
Ultimately, though, Holst hopes that his work will simply help people to make changes in their lives that will ensure they don’t need further treatment.
“The thing that I emphasise all the time these days is that it’s important to use the one and a half years on a GLP-1 drug to change your lifestyle, to change your habits,” he says. “And not just your dietary habits, but also with physical activity. After some weight loss, even very obese individuals can start to build in new exercise habits – nothing crazy, but daily routines, walking and biking and things like that. I think that’s hugely important for the future use of these drugs.”