GLP-1s like Ozempic are among the most important drug breakthroughs ever
IN THE HISTORY of medicine, a few drugs tower above all others. Humira for rheumatoid arthritis; Prozac for depression; statins to prevent heart disease and strokes. All have helped patients far beyond doctors’ initial expectations and continue to benefit millions of people every day. A new class of drugs is set to join their ranks and has the potential to eclipse them all—GLP-1 receptor agonists.
These drugs mimic the action of a naturally occurring hormone, glucagon-like peptide (GLP-1), and for decades have been used to treat diabetes. More recently they have become a wildly popular way for people to lose weight. But in March semaglutide (a GLP-1 receptor agonist sold as Ozempic for diabetes and Wegovy for weight-loss) was approved in America for cardiovascular disease in overweight people. In April tirzepatide (sold as Mounjaro and Zepbound) showed positive results in late-stage trials for sleep apnoea, a breathing disorder. In other trials it seems to reduce chronic kidney disease.
This is just the start. GLP-1 agonists are also being tested for everything from liver disease to substance-use disorders and addiction. One firm is even considering trials for those at risk of obesity—as preventive medications. Patients taking semaglutide may have a lower risk of overdose from opioids, suggesting that it could also be used to treat opioid-use disorder. The drugs have been mooted as a treatment for long-term infections, are being investigated for use in delaying Alzheimer’s, and some even talk of their anti-ageing effects and potential as a longevity drug. On X recently, Eric Topol, a cardiologist who leads Scripps Research, a non-profit research institute in San Diego, California, called GLP-1 drugs “the most important drug-class breakthrough in medical history”.
Drug companies are racing to find, test and market new versions and uses for these drugs. In the background, however, lies a question: how can GLP-1 agonists—drugs developed to work for diabetes—have such a diverse array of beneficial effects across the body? As they look for answers, scientists are finding surprising details about the many roles of GLP-1 hormone. These drugs seem to activate basic protective mechanisms in cells, such as reducing inflammation and clearing out junk, thereby keeping organs healthier. They also have powerful effects on the brain, through which they can both further influence the health of the rest of the body, and even affect behaviour.
GLP-1 is a short-lived hormone that is usually released in a person’s intestines, after a meal. Once in the blood it helps regulate glucose levels, by stimulating the pancreas to release insulin (which lowers blood-sugar levels) and suppressing glucagon (which normally increases them). It also promotes the feeling of fullness, partly by acting on the gut to slow down how fast food moves through it. But the hormone also acts on the brain: at the hypothalamus, a part that controls hunger and satiety; and also on the pathways that modulate cravings. GLP-1’s regulation of blood sugar explains the success of drugs that mimic it for treating diabetes; that GLP-1 agonists promote satiety and reduce the rewards associated with eating explains why they have been helpful to people wanting to lose weight.
At first glance, the wider effects seen from GLP-1 drugs might look like ancillary benefits from their effect on weight—the obese are much more prone to a range of other serious health problems, from heart disease to certain cancers, sleep apnoea and fatty liver disease, so losing weight should improve overall health. That does happen, of course, but research shows that it is not the full story. A study of more than 17,600 overweight and obese patients from 41 countries who took semaglutide found that participants lost about 10% of their body weight and had a 20% reduction in serious adverse coronary events, strokes, heart attacks and all-cause mortality. Crucially, these cardiovascular improvements long preceded any meaningful weight loss.
Multipurpose agonists
For patients living with cardiovascular diseases, GLP-1 drugs work partly by binding to their namesake receptors on heart cells and blood vessels. This contributes to better control of blood pressure and fat levels in the blood. The drugs also help heart cells use glucose more efficiently and reduce oxidative stress, in other words the damage caused by highly reactive molecules that are the by-products of metabolism in cells. Semaglutide has been shown to stimulate the production of nitric oxide, which relaxes vessels and helps improve blood flow to the heart.
This ability of GLP-1 drugs to act on different problems at once is what makes them so interesting. Many people at risk of heart disease or diabetes may be carrying extra weight, have high blood pressure, or have too much sugar or unhealthy fats in their blood. Drugs exist to tackle each of these problems individually, but GLP-1 agonists behave like a molecular Swiss Army knife. (Endocrinologists have noticed something similar in type-2 diabetes: GLP-1 agonists improve most of eight core defects of the condition—known as the “ominous octet”—which include decreased insulin secretion and its uptake in peripheral tissues such as muscle.)
Daniel Drucker, a senior scientist at the Lunenfeld-Tanenbaum Research Institute at Mount Sinai Hospital in Toronto, says that having GLP-1 receptors “seems to allow cells to be maintained in a healthier state and to be less susceptible to death”. This protective effect works across many organs whose cells have GLP-1 receptors and which the hormone (or a drug) can reach—in the liver it may improve function and reduce fat levels; in chronic kidney disease it can reduce adverse outcomes and death, independent of the ability to control blood glucose.
GLP-1 agonists also act on certain immune-system cells around the body to reduce their production of inflammatory molecules, known as cytokines. Inflammation is part of the body’s natural immune response to injury or infection. But chronic inflammation can end up damaging tissues and is a powerful driver of health problems such as cancer and cardiovascular, neurodegenerative and autoimmune diseases. So reducing it would be progress.
GLP-1 is already known to have a role in dampening inflammation in the gut, which is highly susceptible to infection after a meal. But when people have Shigella, Salmonella or any kind of infectious diarrhoea, Dr Drucker says that GLP-1 levels go up “ten- or 20-fold”. The hormone binds to immune cells that are present in the organ to keep inflammation down.
The reduction of inflammation is the common thread that explains why patients taking GLP-1 agonists for diabetes or obesity also report improvements in other conditions, such as arthritis, ulcerative colitis or post-covid brain fog. Fatima Stanford, a physician who researches obesity at Massachusetts General Hospital and Harvard Medical School, says that patients with a history of gout and other rheumatic diseases have also seen their symptoms improve after taking GLP-1 drugs for weight loss. There is also evidence that they work on inflammation in the skin, liver and kidneys, and even in the brain itself.
Not all these organs have GLP-1 receptors on the surfaces of their cells, nor do they have GLP-1-activated immune cells nearby. The answer to how they benefit even so from the anti-inflammatory effects of GLP-1 agonists lies in how these drugs work in the brain.
The brain has GLP-1 receptors in abundance and, though very little drug seems to be able to cross the blood-brain barrier (the filter that protects the brain from harmful substances), experiments have shown that GLP-1 agonists can nevertheless activate pathways that transmit signals to these receptors deep in the brain.
It is unclear exactly how this works, but it has been shown that if GLP-1 receptors in the brains of mice are blocked, the drugs lose their ability to tamp down inflammation in the body. That finding, published in January by Dr Drucker and colleagues, points to the existence of a communication network between the gut, the brain and the immune system that can control systemic inflammation. This then influences the health of organs—such as the skin, lungs or muscles—that do not have many (or any) of their own GLP-1 receptors.
Because they reduce inflammation and improve the health of neurons in the brain, GLP-1 drugs have also attracted interest as treatments of neurodegenerative conditions such as Alzheimer’s. So far, research shows that GLP-1 drugs can improve learning and memory and reduce the build-up of proteins called amyloids in the brains of rodents. The drugs also reduce inflammatory responses and oxidative stress—two contributory factors to Alzheimer’s disease. A recent (small and preliminary) study from Imperial College London, involving more than 200 patients with mild Alzheimer’s disease treated with liraglutide, a GLP-1 drug, found that, after a year, brain shrinkage had reduced by almost 50%, and cognitive decline by up to 18%.
Brain gain
Data like these have made endocrinologists such as Caroline Messer, founder of the Well by Messer, a metabolic and weight-loss clinic in New York, bullish about GLP-1 drugs. She feels the onus to use them to treat patients where she thinks appropriate, and is happy to offer semaglutide and tirzepatide to those with mild cognitive impairment or early Alzheimer’s.
That is ahead of evidence on efficacy from the sorts of clinical trials that regulators consider as proof. But Dr Messer argues that patients who are actively declining have no time to wait, and GLP-1 drugs already have a good safety profile. Even if these drugs are ultimately proved to be ineffective for memory loss, she says they are already known to reduce the risk of cardiovascular disease and stroke. She says there are many connections between diabetes and Alzheimer’s, which makes this class of drug promising, such as an increase in insulin resistance and an increase in oxidative stress. Some have even termed Alzheimer’s “type 3 diabetes”, as it seems to involve insulin resistance in the brain.
Another promising avenue for GLP-1 agonists stems from the core reason for their astonishing success as weight-loss treatments—their ability to interact with mechanisms in the brain related to cravings and feelings of reward. Analysis of electronic health records suggests lower rates of new or recurrent cannabinoid-use disorder in those taking semaglutide for other reasons. And a recent study found that patients who abused opioids or alcohol, given GLP-1 medications for other reasons, had lower rates of opioid overdoses and got drunk less often. Research on monkeys has shown that liraglutide can reduce alcohol consumption, though trials involving human drinking have been inconclusive.
As more and more patients go onto GLP-1 drugs, anecdotal reports of their benefits (as well as side-effects) have spread. A very common one is that they work wonders in improving dependence-related behaviour, such as drug and alcohol addiction. Dr Messer says she has lost count of how many people have told her that the drug has saved their marriage.
If these drugs are indeed shown to attenuate addictive behaviours, they would find widespread use in treating the abuse of alcohol, tobacco and many other drugs. Last year Leandro Vendruscolo, a neuropharmacologist at America’s National Institute on Drug Abuse, described semaglutide to Science as the “most exciting drug for the last few decades”. Kyle Simmons, a pharmacologist at the Oklahoma State University Centre for Health Science, wondered if positive trials would bring addiction science its own “Prozac moment”—a reference to the arrival of selective serotonin reuptake inhibitors (SSRIs) to treat depression, and its expansion into many other areas of psychiatry.
There is yet one more emerging field of medicine in which GLP-1 agonists are generating buzz—ageing. The refrain is now familiar: scientists know that these drugs keep cells healthy, reduce inflammation, oxidative stress and cell death. These are exactly the problems that have been identified as the biggest risk factors of ageing and its associated diseases. In February Michael Leone and Nir Barzilai at the Albert Einstein College of Medicine in New York reviewed drugs that had been approved by regulators and which were thought likely to extend lifespans. They ranked each according to its ability to target the hallmarks of ageing. Out of 12 drugs or drug classes, GLP-1 drugs came fourth. Two of those that rated higher—metformin and SGLT2 inhibitors—are also drugs for diabetes.
More, cheaper, better
Cost looms large in any discussion about these drugs, as well as the need to take them for a lifetime. Both concerns are likely to prove temporary. In years to come the growing level of competition and the arrival of generic copies will lower prices and broaden access. Countries will negotiate discounts. Indian and Chinese companies are already racing to make copycat versions of GLP-1 drugs when patents expire in their countries.
It is also hoped that new formulations will improve the efficacy of current drugs, and that ways will be found to reduce their shortcomings, whether this is in the loss of muscle mass and unpleasant gastro-intestinal side-effects—or even the need to inject medicines. Several firms are exploring the production of pills, which would be a big step forward and, being cheaper to produce and distribute, would probably greatly expand the numbers using them.
As GLP-1 drugs are shown to work on a wider range of conditions, so the demand for them from both clinicians and patients will grow. When supply shortages are overcome, governments will have to grapple with complex calculations to work out which conditions they are cost-effective for treating, and the overall impact the prescription of the new drugs will have on stretched health budgets.
It is still unknown if patients will need to remain on these medicines for the long term, and at what cost and benefit. (The risks of long-term use in patients who are not diabetic, for example, are not fully understood.) So estimates of how much they will be used remain guesswork. Moreover, their prophylactic uses could save money years into the future from the prevention or amelioration of long-term conditions. But that benefit is hard to quantify, and existing budgets for prevention are a tiny fraction of what is available for the treatment of existing conditions. Public-health systems are likely to be very slow to adopt the drugs as preventive treatments.
GLP-1 drugs are already having a huge impact in the pharma industry, with a large number of new drugs in the pipeline (see chart). But many other sorts of business are also feeling the effect. Some are obvious: the food industry, for example, is looking on nervously, fearing that the drugs’ success may lead to thinner profits, as well as slimmer waistlines. Last year Morgan Stanley published a survey of 300 patients, entitled “Could obesity drugs take a bite out of the food industry?” It found that they lead to a reduction in calorie intake per patient of between 20% and 30%, and that this could have long-term implications for food-related businesses, particularly those selling unhealthier foods such as high-fat, sweet and salty products. But eating habits will not change overnight. The food and hospitality industry has time to adapt by offering smaller portions and healthier options.
Other analysts have projected a rise in interest in physical fitness and sportswear by those who were once overweight who wish to maintain fitness and muscle mass. Some also speculate that the psychological impact of weight loss could extend to an increase in interest in cosmetics.
The commercial implications for other businesses are only just beginning to be recognised. Take a less than obvious one: aviation. Analysts at Jefferies, an investment bank, calculated in 2023 that if the average United Airlines passenger were to lose 10lbs (4.5kg), it would save the airline $80m a year in fuel costs.
The arrival of GLP-1 drugs has also shifted the way in which obesity is viewed: no longer as a disease of failing willpower but as a lifelong chronic condition from which the body never truly escapes. But diabetes and obesity have been just the start. Few drugs, if any, have promised to have such a revolutionary impact on human health, longevity and happiness. ■