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Brand-name semaglutide has more long-term safety data than most weight-loss drugs before it. The SELECT trial (Lincoff et al., NEJM 2023) tested Wegovy in 17,604 adults for more than three years on average, and its main finding was a benefit: 20% fewer major heart events. Past that window, we don’t know. That doesn’t mean “probably fine.” It means no one has measured it, because the trials haven’t run longer.
What 17,604 people over three years showed
SELECT enrolled adults who already had heart disease and didn’t have diabetes, and gave them Wegovy or placebo. It followed them for more than three years on average. That makes it one of the largest long-term safety datasets for semaglutide. On Wegovy, major heart events, meaning heart attack, stroke, or death from heart disease, fell 20% in relative terms compared with placebo (hazard ratio 0.80).
Its size and length are why this trial matters most for safety. Rare harms need lots of people, and slow harms need years. SELECT had both, and its result for Wegovy was protection.
That doesn’t mean it’s easy to take. Nausea, reflux, constipation, and early fullness are common. They follow from slowed gastric emptying (how fast food leaves your stomach). Managing them is its own topic, covered in the GLP-1 side-effects guide.
The boxed warning, in plain words
The brand-name labels for semaglutide and tirzepatide, such as Wegovy’s and Zepbound’s, carry the FDA’s most serious warning, called a boxed warning. It’s worth reading closely. In rodent studies, these drugs caused thyroid C-cell tumors. Whether that applies to humans is unknown. Not “unlikely,” and not “disproven.” Unknown. The warning rests on the rodent finding. The question in people is still open.
Because it can’t be ruled out, one exclusion is absolute. If you or a family member has had medullary thyroid carcinoma (a rare thyroid cancer) or MEN 2 (multiple endocrine neoplasia type 2), you can’t take these drugs at all. Pregnancy is a second hard stop, since GLP-1s are not for use while pregnant.
Pancreatitis calls for caution
The labels flag a history of pancreatitis (an inflamed pancreas) as a reason for care. The concern makes sense, because these drugs act on the pancreas to boost insulin release when blood sugar is high. If you’ve had pancreatitis, say so at intake. It changes the risk, and sometimes the answer.
Tirzepatide has less time on the clock
The evidence for the two drugs is lopsided, and you should know which side yours is on. Brand-name semaglutide (Wegovy) has SELECT. Brand-name tirzepatide’s (Zepbound’s) largest trial, SURMOUNT-1 (NEJM 2022), followed 2,539 adults for 72 weeks. It showed stronger weight loss, but over a much shorter time. No trial as large or as long as SELECT has reported for tirzepatide in people without diabetes. In people with type 2 diabetes and heart disease, SURPASS-CVOT (Nicholls et al., NEJM 2025) found brand-name tirzepatide (Mounjaro) about as good as another GLP-1, dulaglutide (Trulicity), at preventing heart attacks, strokes, and heart-related deaths. That isn’t a mark against it, since it’s a newer drug. But “probably similar” is an assumption, and we’d rather label it as one.
Where the data actually ends
Three things have truly not been measured:
- Anything past SELECT’s follow-up. People on Wegovy in the trial were followed for just over three years on average. Beyond that, there’s no controlled safety data at weight-loss doses. Anyone who claims to be sure past that point, in either direction, is guessing.
- Whether SELECT’s protection applies to everyone. The Wegovy trial enrolled people who already had heart disease. The same benefit in lower-risk people is plausible, but it hasn’t been tested.
- Use over a decade. Stopping usually brings substantial regain. STEP 4 (JAMA 2021) for Wegovy and SURMOUNT-4 (JAMA 2024) for Zepbound both showed this. So many people will take these drugs for ten years or more. Nobody has ten-year data.
Before you start
The screening that matters is short. It covers medullary thyroid carcinoma or MEN 2 in you or your family, past pancreatitis, and pregnancy. Those decide whether a GLP-1 is an option at all. Everything after that is about dose, how fast it goes up, and follow-up. Start with the quiz. A Zappy clinician reviews every case within 24 hours, and that review is built to catch exactly these histories.
