Ozempic, Wegovy, GLP-1 – they have all become online buzzwords. A miracle drug for weight loss that makes you feel full and has apparently minimal side effects? But there is more. A flood of studies and clinical trials are investigating whether Ozempic and its sister drugs could treat an assortment of heart, kidney, and liver diseases, as well as having neuroprotective effects in neurodegenerative disease and dampening compulsive behaviors. It seems to be the drug that does it all, but is it too good to be true?
What are GLP-1 drugs?
Glucagon-like-peptide-1 (GLP-1) is naturally secreted in the body after a meal, stimulating insulin production to control glucose levels in the blood. When its effects on insulin were first found in the late 1980s, it seemed promising as a new treatment for diabetes, if it wasn’t for how quickly it gets broken down in the blood.
In comes the Gila monster, an impressive name for a venomous slow-moving lizard with bad breath. One of the compounds in its saliva is about 50 percent similar to GLP-1, enough to bind to GLP-1 receptors, but with the added benefit of a longer half-life allowing it to be effective over longer timescales. It was synthesized under the name exenatide and became the first GLP-1 receptor agonist (GLP-1RA) drug approved for treatment of Type 2 diabetes.
What are GLP-1RAs good for?
GLP-1RAs don’t just stimulate insulin production. They also slow the emptying of the stomach into the intestine after a meal, one way in which they make you feel full. These are the pathways that in addition to controlling blood sugar levels have led to the main side-effect of these drugs: weight loss. After 68 weeks of treatment overweight or obese people lost an average of 12 percent body weight due to the effects of the drug alone, according to a 2021 study. These effects were seen with the next generation of GLP-1RAs: semaglutide, most popular under the names Ozempic, Wegovy, and Rybelsus.
That’s when GLP-1RAs really started taking off. After inducing weight loss in people with obesity, it was flying off the shelves with the promise of weight loss for everyone.
Approved in the USA in 2017, and in the EU, Canada, and Japan in 2018, the popularity of Ozempic has been growing ever since. In recent years, it seems to be everywhere, with a surge in online interest in Ozempic and Wegovy (FDA approved in 2021) at the end of 2022, not long after Elon Musk claimed to be using the latter. It is unclear how many non-obese or overweight people are taking GLP-1RAs now, but the manufacturers of Ozempic report increasingly high demand.
Now it also seems to be good for everything. It is not uncommon for a drug to be multipurpose. Gabapentin, initially prescribed for epilepsy, is often used as a painkiller. Sildenafil, developed as a blood pressure medication, is best known as an erectile dysfunction drug.
As reported by Dr Daniel Drucker, a clinician-scientist and diabetes treatment expert based at The Lunenfeld-Tanenbaum Research Institute, in a new Perspective article, clinical trials are now being carried out to test the effectiveness of GLP-1RAs as medications for peripheral artery disease, to prevent major cardiovascular events, stroke, kidney disease, and heart attacks, to treat metabolic liver disease, as well as Parkinson’s disease. Initial studies are testing its potential as a therapy for dependence-related behaviors.
If that seems like an overwhelming list of unrelated diseases… it kind of is.
What do we know about how it works?
How could one drug, or even one family of drugs, do all of this? The receptor that these drugs bind to, GLP-1R, has been found in many different tissues and organs. Its expression in the pancreas is how it mediates its originally targeted effect on insulin secretion. It is also expressed in many different groups of neurons: for example, in peripheral neurons that control the emptying of the stomach, and in central nervous system neurons that control food intake. For these pathways, scientists have proposed mechanisms of action of these drugs.
GLP-1Rs are also expressed in the heart, liver and kidney. However their mode of action in these tissues is not clear, leaving scientists with correlation between GLP-1RA administration and disease outcomes without a mechanistic understanding.
That’s in part why some theories of GLP-1RA magical mode of action have turned to its role in inflammation. Taking GLP-1RAs seems to reduce inflammation in the whole body, from the gut to the brain, even in tissues that don’t express the receptor. The reduction in neuroinflammation is thought to underlie the therapeutic effects for neurodegenerative disease.
Low-grade inflammation accompanies Type 2 diabetes and obesity; is the anti-inflammatory action of GLP-1RA necessary for its beneficial effects? It should be noted that several of these studies reporting therapeutic effects on the heart, liver, and kidney were carried out only in people with Type 2 diabetes and/or obesity. Reducing inflammation in these tissues could reduce the risk of complications in these patients.
Is it all good?
Are GLP-1RAs being overused, and are the potential downsides not being sufficiently weighed? For all the many tissues and organs they target, they seem to have surprisingly few adverse effects, at least in the short term. Patients often report gastrointestinal discomfort, as well as nausea, vomiting, diarrhea, abdominal pain, and constipation. Not pleasant, but potentially treatable.
Of greater concern is the loss of muscle mass. Despite their powerful efficacy, GLP-1RAs are not magic bullets, and taking them has to be accompanied by lifestyle changes, particularly diet and exercise. Because GLP-1RAs make you lose weight by reducing your appetite, if not paired with exercise this can actually lead to significant loss of muscle mass. People report that taking these medications is making it easier to stick to diets and exercise.
Rarer, but more serious side-effects include pancreatitis, retinopathy, gallstones, and malnourishment. It also seems to be tied to cancer risk, but results are still unclear about this.
In the long term, however, we simply don’t know. We’re living through the “great Ozempic experiment”, as the New York Times put it. The trick with these drugs is that once you start, you are taking them for life. Their effects wane after consumption is interrupted. We simply don’t know what happens if you take them for 10, 20, 50 years. Or if you stopped taking them after a long period of administration.
Added to all this is the growing problem with counterfeit GLP-1RAs – with potentially even more dangerous side-effects – being circulated on the black market, leading the World Health Organization to issue a warning in June 2024.
GLP-1RAs have been used for treatment of Type 2 diabetes for 20 years, suggesting their safety in that context. They were approved for obesity only 10 years ago, and are still under investigation for all their other potential uses. The risk vs. benefit analyses will also have to be expanded to identify which patients may be most responsive to these treatments.
The Perspective is published in Science.
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