Health

What the GLP-1 medications actually do, three years into the rush

Ozempic, Wegovy, Mounjaro, Zepbound — a working journalist's explainer of how the drugs work, what the evidence shows, and what is still in dispute as the second wave of these medications enters wide use.

By Aaron Lindholm

Published April 7, 2026 · 9 min read

The bottom line

GLP-1 receptor agonists have produced the most consistent weight-loss results of any pharmacological intervention in modern medicine. The longer-term questions — durability after discontinuation, cardiovascular benefit beyond weight loss, the cost picture, and the lean-mass loss debate — are still being answered as the second-wave drugs come to market.

Three years into what is by any honest measure the largest pharmacological intervention in chronic disease since statins, the GLP-1 receptor agonists are everywhere — in the prescriptions of cardiologists, the social-media feeds of celebrities, the boardrooms of pharmaceutical companies whose stock prices have moved by tens of billions of dollars on quarterly results. The headlines have outpaced the science by a wide margin, and the science itself, while genuinely impressive, has more open questions than the headlines admit.

This piece is a working journalist’s explainer of what the drugs actually do, what the evidence currently supports, and what is still in dispute as the second-wave drugs enter wide use.

What the drugs are

GLP-1 — glucagon-like peptide 1 — is a hormone the body releases from the small intestine after a meal. It does several things at once: it tells the pancreas to release insulin, it tells the stomach to empty more slowly, and it acts on receptors in the brain to reduce appetite. The hormone has a half-life of about two minutes in the bloodstream, which makes it useless as a drug in its native form.

The class of medications collectively called GLP-1 agonists are engineered analogs of the hormone, modified to resist enzymatic breakdown, that can be injected once a week and produce sustained activation of the receptor. The first generation includes liraglutide and exenatide, which were approved for type 2 diabetes in the late 2000s. The second generation — semaglutide, sold as Ozempic for diabetes and Wegovy for obesity — produced large enough weight loss in trials to expand the indication. The third generation, tirzepatide, sold as Mounjaro for diabetes and Zepbound for obesity, adds a second receptor — GIP — and produces larger weight loss still.

A fourth generation is in development: triple agonists that hit GLP-1, GIP, and glucagon. Phase 2 trial data have been encouraging. Whether the additional pharmacology produces materially larger weight loss in real-world use is not yet known.

What the evidence shows on weight loss

The headline trial for semaglutide in obesity was STEP-1, which followed about 1,900 adults with obesity for 68 weeks. The semaglutide arm lost an average of 14.9 percent of starting body weight; the placebo arm lost 2.4 percent. Replication trials have produced similar figures. For tirzepatide, the SURMOUNT-1 trial followed about 2,500 adults for 72 weeks and reported an average weight loss of 20.9 percent on the highest tested dose.

Both numbers are dramatically larger than what any earlier weight-loss drug produced, and they are larger than what nearly any non-surgical intervention has produced in well-controlled trials. They are also averages over heterogeneous populations: the trials show wide individual variation, with a meaningful fraction of participants losing more than 25 percent of starting weight and another meaningful fraction losing very little.

The cardiovascular evidence is more recent and, on the whole, encouraging. The SELECT trial, published in 2023, showed a 20 percent reduction in major adverse cardiovascular events in patients with established cardiovascular disease and obesity treated with semaglutide for an average of three and a quarter years. That benefit appears to be partially independent of weight loss — that is, it is not fully explained by the weight reduction itself — though the size of the independent component is still under investigation.

What discontinuation does

This is the part of the evidence base that has been most aggressively under-reported in popular coverage. The available randomized trials in which patients were taken off the medication after a successful weight-loss phase consistently show substantial regain. The STEP-4 trial, which randomized patients who had successfully lost weight on semaglutide to either continued treatment or placebo for an additional 48 weeks, found that the placebo group regained, on average, two-thirds of the weight they had lost.

The clinical implication is that GLP-1 treatment for obesity is, on the available evidence, an ongoing therapy rather than a course of treatment with a defined endpoint. Whether to interpret that as a problem of the medication or as evidence that obesity is a chronic condition is a question with no scientific answer.

The lean-mass debate

All weight loss takes some lean body mass with it; that is not specific to these medications. The question that has driven a substantial back-and-forth in the medical literature over the last 18 months is whether GLP-1-mediated weight loss takes a higher proportion of lean mass than weight loss from other interventions does.

The honest answer is that the evidence is mixed and the magnitude of any difference is small relative to total weight change. A few imaging substudies have found modestly higher lean-mass loss on GLP-1 treatment than on caloric restriction matched for the same total weight loss; other studies have found no difference. Resistance training during treatment appears to preserve lean mass effectively, though the evidence base for that specific recommendation is still building. Most clinicians are now recommending some structured strength work during the dose-escalation period, which is a reasonable hedge against an evidence base that is not fully settled.

Cost and access

List prices in the United States have settled in around $1,000 to $1,300 per month for cash-paying patients on the obesity-indicated formulations. Commercial-insurance coverage varies widely; many plans cover the drugs for diabetes but explicitly exclude the obesity indications. Medicare does not pay for weight-loss medication in most cases, and Medicaid coverage varies by state.

The supply shortages that drove the rise of compounded versions in 2023–2024 have largely resolved on the manufacturer side. The FDA has been winding down the legal pathway for compounded versions as supply has stabilized, though several state-level enforcement disputes are still in progress as of this writing.

What is still being worked out

Three things, primarily.

The first is whether the cardiovascular benefit demonstrated in patients with existing cardiovascular disease extends to lower-risk populations. The SELECT result is unambiguous in its target population; whether to extrapolate it to a 45-year-old with a BMI of 32 and no cardiovascular disease is an open clinical question. Several trials addressing exactly that question are in progress.

The second is the pediatric question. Adolescent obesity trials of these medications have produced large effect sizes that mirror the adult trials, and FDA has approved Wegovy for use in adolescents as young as 12. The longer-term safety and developmental questions — what these medications do to a body that is still completing puberty — will not have a clean answer for years.

The third is the substitution question. As the drugs become available to more people, what happens to weight-loss surgery rates, to commercial weight-loss programs, to the supplement and “wellness” industry, to disordered-eating treatment? The evidence here is largely sociological, and we will be reporting on it as it develops.

For now, the GLP-1 class represents the largest and most reliable pharmacological effect on body weight that has ever been observed in well-controlled trials. The headlines, for once, are not exaggerating that part. The questions about long-term durability, about cost equity, and about what the drugs displace in the rest of the medical ecosystem are real, and they will determine the actual long-run effect on population health.

Frequently asked questions

Are these medications a permanent fix?

No. The available randomized evidence shows that weight regain is the rule rather than the exception when GLP-1 medications are discontinued, with most patients regaining a substantial fraction of the lost weight within 12 to 18 months of stopping. Whether to interpret this as a problem of the drug or as evidence that obesity is a chronic condition that requires ongoing treatment is a question with no scientific answer; it depends on your prior framework.

How much weight do people typically lose?

The largest randomized trials of semaglutide (the active ingredient in Ozempic and Wegovy) showed an average weight loss of about 15 percent of starting body weight over 68 weeks. The dual-receptor agonists (tirzepatide, the active ingredient in Mounjaro and Zepbound) showed an average weight loss of about 21 percent of starting body weight over 72 weeks. Individual results varied widely; some participants lost more than 25 percent, some lost very little.

What are the most common side effects?

Gastrointestinal symptoms — nausea, vomiting, diarrhea, constipation — are the most common, especially during the dose-escalation phase of treatment. About 40 percent of trial participants reported at least one such side effect. A smaller number — roughly 6 to 8 percent — discontinued the medication during trials due to side effects. The risk of pancreatitis, gallbladder disease, and small-bowel obstruction is elevated but absolute rates remain low.

Do these drugs cause muscle loss?

All weight loss — whether from caloric restriction, exercise, or medication — produces some loss of lean body mass alongside fat mass. Studies of GLP-1 medications suggest the lean-to-fat loss ratio is roughly comparable to caloric restriction without medication, but a few studies have found a higher proportion of lean-mass loss on the medications, especially in older adults. Resistance training during treatment appears to help preserve lean mass, though the evidence base for that recommendation is still building.

What is going on with the cost of these drugs?

List prices in the United States are over $1,000 per month for cash-paying patients. Insurance coverage varies enormously — many commercial plans cover the drugs for diabetes (Ozempic, Mounjaro) but exclude the obesity-indicated versions (Wegovy, Zepbound). Compounded versions, made by compounding pharmacies during recent supply shortages, were cheaper but raised quality and safety questions; the FDA has begun to wind down the legal pathway for compounded versions as supply has improved.

Should someone with metabolic syndrome but not full diabetes be taking these?

That is the question that has driven the largest expansion of prescribing in the last two years, and it does not have a settled answer. The cardiovascular trials have shown clear benefit in people with established cardiovascular disease and obesity. The benefit in lower-risk populations is less clearly established. The clinical question is best addressed with the patient's own physician, with attention to total cardiovascular risk profile rather than to weight alone.

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