This year, the popularity of the diabetes and weight-loss drug semaglutide has continued to surge. You’ve probably seen ads on social media or heard from friends who’ve tried top-selling brand-name versions, Ozempic and the higher-dose variety Wegovy (SN: 6/29/24, p. 5), or read accounts of people microdosing these drugs.

Semaglutide and its many relatives mimic the gut hormone GLP-1. But this drug family is nothing new. The U.S. Food and Drug Administration approved an early cousin of semaglutide for diabetes nearly 20 years ago, and another, liraglutide, for weight loss a decade later. Liraglutide’s approval was important, says endocrinologist Daniel Drucker of the University of Toronto, because “it showed that maybe these drugs have another utility beyond glucose control.”

In the last few years, that promise has panned out. Clinical trials in people with diabetes and obesity have shown that semaglutide and its newer cousins can help people shed a lot of weight, relatively safely. That’s not the norm, historically. Before these drugs, obesity therapeutics were “riddled with safety issues,” Drucker says. The drug regimen known as fen-phen, for example, could cause leaky heart valves (SN: 10/18/97, p. 252). These and some other drugs for weight loss have been pulled from the market.

The story of GLP-1 drugs may have a different ending. And their potential benefits seem to go well beyond weight loss. Though the drugs tend to make people feel full and eat less, there’s evidence they may also help treat diseases that affect the heart, kidney, liver and more. It’s not yet clear all the ways these drugs might aid the body, but some effects may be independent of weight loss. Studies suggest semaglutide could even curb addiction and inflammation (SN: 10/19/24, p. 6). And clinical trials testing if the drugs have neuroprotective effects in people with Parkinson’s and Alzheimer’s are in the works. So are more powerful medications. The FDA has already approved one such drug — tirzepatide (sold as Mounjaro and Zepbound) — which acts like two gut hormones, GLP-1 and GIP (SN: 12/6/24). And drugs that mimic three or even four hormones are coming.

To get a sense of where the field is heading, Science News spoke with Drucker and three other experts: physician-scientist Lorenzo Leggio of the National Institute on Drug Abuse in Baltimore, exercise physiologist Glenn Gaesser of Arizona State University in Phoenix and endocrinologist Maria Daniela Hurtado Andrade of the Mayo Clinic in Jacksonville, Fla. The conversations have been edited for length and clarity.

GLP-1 drugs have been studied for decades, but they became household names only recently. What changed?

Drucker: It was really the clinical trial data on semaglutide. That’s where we saw for the first time many people getting double-digit weight loss. [People taking semaglutide for obesity can lose about 15 percent of their body weight, on average.] Prior to that, that simply had not been achievable in the obesity therapeutic space, unless you went for bariatric surgery.

Semaglutide was the first medicine that said to people, wow, this is something different.

Now there’s evidence that it can have cardiovascular benefits and potentially even help people with addiction.

Drucker: The SELECT trial in overweight or obese people [reported in 2023] showed a 20 percent reduction in heart attack, strokes and cardiovascular death, and a 19 percent reduction in all-cause mortality. So this has really changed the game. We have never seen anything like this in obesity medicine.

Leggio: It seems that this class of drugs has a broad effect across multiple addictive disorders. This work is very promising, but it is work in progress.

The obesity clinical trials clearly show these medications are effective. But that doesn’t mean that everybody responded. You have patients who have profound weight loss, and patients who do not.

I anticipate that even if this medication works for Parkinson’s, Alzheimer’s and addictions, not all patients will respond. We will have to understand who may or may not respond, and for what patients [the drugs] may be unsafe to take.

Are there other hints about the potential of these drugs that intrigue you?

Hurtado Andrade: We already have evidence on tirzepatide and obstructive sleep apnea, and there is more data coming out about the beneficial effects of these medications on metabolic-associated liver dysfunction.

I’m sure we’re going to hear more as time goes by. There will probably be data on osteoarthritis. I’m sure there will be data on cancer.

Drucker: I find the inflammation story really exciting. I get emails every week or so from people with some disease, generally inflammation related.

This week’s email was from a woman with lipedema, which is inflammation of fat in your lower extremities. It can be very disabling. She said she took one dose of semaglutide and started to feel better immediately. She started to see her inflammation go away. Then she had to stop the drug because she lost her insurance, and everything came right back.

There’s still a ton of fascinating science to explore, whether it’s inflammation or alcohol dependence or narcotics or smoking, compulsive behaviors, neuropsychiatric conditions. But it’s very early days.

What studies and clinical trial results are you watching for?

Drucker: I would be most excited if the Alzheimer’s trials came back positive.

We have hundreds of millions of people faced with the looming burden of Alzheimer’s disease, either in loved ones or themselves. We don’t have anything easy for them to take that’s safe yet might really delay the progression of their disease. I don’t know if semaglutide will do that. But it’s being studied in two trials [evoke and evoke+], which will probably report out at the end of 2025.

To me, that’s the most exciting, huge issue on the landscape. So that’s where I would watch.

Hurtado Andrade: I’m looking forward to seeing the cardiovascular outcomes with tirzepatide, because it seems to be a more effective [weight-loss] medication compared to semaglutide.

Gaesser: I would like to see studies that look at [individuals on] the drugs with and without exercise long-term. How active are they? How much time do they spend in sedentary behaviors? How much time do they spend in light-, moderate- and vigorous- intensity behaviors? I want to see if [the drugs] change behavior.

How does exercise factor in with these drugs?

Gaesser: One of the major health problems in this country and perhaps worldwide is not so much that we weigh too much, but that we aren’t active enough. And when you look at a number of populations across the board, it seems like fitness is more important than slimness in terms of health outcomes. So, what’s going to happen with the millions of people taking these GLP-1 drugs? They may lose a lot of weight, but is that going to make them any more active?

How many people do you foresee eventually taking these drugs?

Gaesser: I think that we’re going to have a lot more people wanting to take these drugs. I mean, the obsession with weight loss in our country is nothing new. Certainly in the United States, the cost and availability of these drugs are huge issues.

Drucker: If you’re living with type 2 diabetes or obesity, there’s substantial evidence that these drugs are helpful beyond controlling your blood sugar and body weight. But should the rest of us be taking them? Well, let’s see what the Parkinson’s trials show. Let’s see what the Alzheimer’s trials show. Let’s see what the metabolic liver disease trials show. Let’s just wait for the data. It’s going to come in steady buckets over the next couple of years.

We really want to make sure that the right people are using the medicines for the absolute best indications that are proven beyond a shadow of doubt.

As newer medications come out, do you have concerns about side effects?

Drucker: The safety of today’s GLP-1–based medicines is very well established. Side effects are predominantly nausea, vomiting and diarrhea. But once we start [targeting multiple hormones], then you have to step back and say, I don’t fully know the safety of these medicines. They’re manipulating additional circuits. So we must always scrutinize the safety in large trials and then look at the real-world data.

Hurtado Andrade: This family of medications has been around for more than two decades, and we haven’t had any surprises. That doesn’t mean that we are not going to have surprises with newer drugs, but we already know a lot about the potential adverse events.

Gaesser: There may be some adverse effects on muscle mass and bone density.

Leggio: For the addiction scientific community, one question is: [What happens when] you combine these medications with addictive drugs that may interact pharmacologically in the body? We have to be even more mindful of potential side effects.

What big questions would you like answered?

Drucker: We’re going to have like a half a dozen drugs that will produce 25 percent weight loss or more on average. [In a recent clinical trial of the experimental obesity drug retatrutide, participants lost more than 24 percent of their body weight, on average.] And then the question will be, what’s the difference between them? Will they all be equally effective for heart disease, kidney disease, metabolic liver disease, Parkinson’s, Alzheimer’s, sleep apnea, or are we going to start to see differences?

Hurtado Andrade: Most studies that have been done with these medications are biased towards middle-aged adults. We certainly need to have more data in different age groups.

[Also, recent data] suggest that the cardiovascular benefits of semaglutide may be weight independent. I’m not surprised by this. We have GLP-1 receptors all over our body and what these medications do is activate GLP-1 receptors. I’m interested in understanding if we can have other beneficial effects throughout our body that are also weight independent.

Leggio: The near-future question that we are trying to answer is, do these medications work for addiction? We are optimistic but also cautious, because we know from history that sometimes very promising medications fail to show efficacy. And so it’s important that we don’t put the cart before the horse.

Gaesser: The drugs haven’t really been studied in healthy populations — individuals who are absolutely free of disease and have no medical conditions, just excess weight. I don’t know what the new drugs will show once [scientists] start randomized controlled trials in individuals that are reasonably healthy but just want to lose weight.

And I don’t think taking the drug and losing weight makes unhealthy individuals equivalent to [healthy] individuals who have never taken it — and certainly not a healthy person who is exercising regularly and has a modest to high level of fitness. I don’t think the drugs will ever be able to match something like that.